CHAPTER 6: DISEASES OF THE IMMUNE SYSTEM  Capture protein antigens and display peptides for recognition by T

lymphocytes; antigen presenting cells (APCs)

 Endowed with receptors that sense microbes and cell damage 
 Immune system – vital for survival; protects us from infectious pathogens in the
stimulate secretion of cytokines
environment  Involved in initiation of innate immune responses
 Capable of causing tissue injury and disease Natural Killer  Provide early protection against many viruses and intracellular
o E.g., allergies, autoimmunity Cells bacteria
Mast cells  Capable of producing many mediators of inflammation
THE NORMAL IMMUNE SYSTEM  Also epithelial and endothelial cells
Innate  Cells with the appearance of lymphocytes but w/ features more
 Immunity – protection from infectious pathogens lymphoid cells like cells of innate immunity
 Innate immunity – natural or native immunity  Contribute to early defense against microbes
Proteins of  Plasma proteins that are activated by microbes using the
o Refers to the mechanisms that are ready to react to infections even before
complement alternative and lectin pathways in innate immune response
they occur; have evolved to specifically recognize and combat microbes system  In adaptive immunity: activated by antibodies using classical
o First line of defense pathway
o Mediated by cells and molecules that recognize products of microbes and  Mannose-binding lectin and CRP  coat microbes and
dead cells and induce rapid protective host reactions promote phagocytosis
 Adaptive immunity – acquired or specific immunity  Lung surfactant – also a component of innate immunity provide
o Consists if mechanisms that are stimulated by (“adapt to”) microbes protection against inhaled microbes
o Capable of recognizing microbial and nonmicrobial substances
o Develops later after exposure to microbrs and other foreign substances
Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances
o More powerful than innate immunity
o “immune response”
 Cells that participate in innate immunity are capable of recognizing certain
microbial components that are shared among related microbes and are
Innate Immunity
often essential for infectivity (thus cannot be mutated to allow the
microbes to evade the defense mechanism)
 Innate immunity is always present, ready to provide defense against microbes and to
o These microbial structures are called pathogen-associated molecular
eliminate damaged cells
patterns
 Functions in stages:
 Damaged-associated molecular patterns – where leukocytes recognize
o Recognition of microbes and damaged cells
molecules released by injured and necrotic cells
o Activation of various mechanisms
 Pattern recognition receptors – cellular receptors that recognize these molecules
o Elimination of the unwanted substances
 Pattern recognition receptors are located in all the cellular compartments where
Components of Innate Immunity microbes may be present:
o Plasma membrane receptors detect extracellular microbes
 The major components of innate immunity are epithelial barriers that block o Endosomal receptors detect ingested microbes
the entry of microbes, phagocytic cells (mainly neutrophils and o Cytosolic receptors detect microbes in the cytoplasm
macrophages), dendritic cells, natural killer cells, and several plasma
proteins of the complement system Toll-Like Receptors  Best-known of the pattern recognition receptors; Toll was
discovered in Drosophila
 10 TLRs in mammals; present in plasma membrane and
Epithelia of  Provide mechanical barriers to the entry of microbes from the
endosomal vesicles
skin and GIT external environment
 All these receptors signal by a common pathway that
 Also produce antimicrobial molecules such as defensins, and
culminates in the activation of two sets of transcription
lymphocytes located in the epithelial combat microbes at these
factors:
sites
o NF-kB – stimulates the synthesis and secretion of
Monocytes  Phagocytes in blood; rapidly recruited at sites of infection
cytokines and the expression of adhesion
and  Macrophages – matured monocytes in tissues; “professional
molecules
neutrophils phagocytes”; sense and ingest invaders
o Interferon regulatory factors (IRFs) –
o Dominant cells in chronic inflammation
stimulate the production of the antiviral cytokines,
Dendritic cells  Specialized cell population present in epithelia, lymphoid organs, type I interferons
and most tissues

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NOD-Like  NLRs – cytosolic receptors; recognize wide variety of Adaptive Immunity
Receptors and the substances including:
Inflammasome o Products of necrotic cells (uric acid, released ATP)  The adaptive immune system consists of lymphocytes and their products, including
o Ion disturbances (loss of K+) antibodies
o Microbial products
 Two types of adaptive immunity:
 NLRs signal via a cytosolic multiprotein complex called
o Humoral immunity – protects against extracellular microbes and their
inflammasome, w/c activates enzyme (caspase-1) that
cleaves IL-1 to generate active form toxins
 IL-1 – mediator of inflammation that recruits leukocytes and  Mediated by B lymphocytes, antibodies or immunoglobulins (Ig)
induce fever o Cell-mediated or cellular immunity – responsible for defense against
 Gain-of-function mutations of NLRs lead to periodic fever intracellular microbes
syndromes, called autoinflammatory syndromes  Mediated by T lymphocytes
o Respond to treatment w/ IL-1 antagonist
Other Receptors for  C-type lectin receptors (CLRs) – expressed on the
Cells of the Immune System
Microbial Products plasma membrane of macropahges and dendritic cells
o Detect fungal glycans and elicit inflammatory
reactions to fungi  Lymphocytes and other cells involved in immune response constantly circulate
 RIG-like receptors (RLRs) – located on the cytosol of among lymphoid and other tissues via blood and lymphatic circulation
most cell types and detect nucleic acids of viruses that o Promotes immune surveillance
replicate in the cytoplasm  Naive cells – mature lymphocytes that have not encountered the antigen for which
 These receptors stimulate the production of antiviral they are specific
cytokines  Effector cells – differentiated lymphocytes after they are activated by recognition of
 G protein coupled receptors on neutrophils, macrophage
antigens and other signals; functions to eliminate microbes
 recognize short bacterial peptides containing N-
formylmethionyl residues  Memory cells – live in a state of heightened awareness; able to react rapidly and
o GPCR enables neutrophils to detect bacterial strongly combat the microbe in case it returns
proteins and stimulate chemotactic response
 Mannose receptors – recognize microbial sugars and Lymphocyte Diversity
induce phagocytosis  Lymphocytes specific for a large number of antigen exist before exposure to
antigen, and when an antigen enters, it selectively activates the antigen-
specific cells  “clonal selection”
Reactions of Innate Immunity o Lymphocytes express receptors for antigens and mature to competent cells
before exposure to antigen
 Innate immune system provides host defense by two main reactions o Clone – lymphocytes of the same specificity ; all members of a clone have
identical antigen receptors
 Antigen receptor diversity is generated by somatic recombination of the genes that
Inflammation  Cytokines and products of complement activation are
encode the receptor proteins
produced during innate immune reactions and trigger the
o All cells of the body contain antigen receptor genes in the germline
vascular and cellular components of inflammation
(inherited) configuration  consist of spatially separated segments that
 Recruited leukocytes destroy microbes and ingest and
cannot be expressed as proteins
eliminate damaged cells
o During lymphocyte maturation (thymus and MB), gene segments
Antiviral defense  Type I interferons produced in response to viruses act on cells recombine, transcribed and translated into functional antigen receptors
and activate enzymes that degrade viral nucleic acids and  Enzyme in developing lymphocytes that mediates recombination of these gene
inhibit viral replication  inducing antiviral state segments is the product of RAG-1 and RAG-2
Others  Innate immunity provides the danger signals that stimulate o Inherited defects of RAG proteins  failure to generate mature lymphocytes
more powerful adaptive immune response  Germline antigen receptor genes are present in all cells in the body, but only T and B
cells contain recombined antigen receptor genes  TCR in T cells; Ig in B cells
 TCR or Ig genes  marker of T or B lineage cells
 Innate immunity does not have memory of fine antigen specificity  Analysis of antigen receptor gene rearrangements is a valuable assay for detecting
o Uses about 100 different receptors to recognize 1,000 molecular patterns tumors derived from lymphocytes
 Adaptive immunity uses two types of receptors (antibodies and T cell receptors) to
recognize millions of antigens

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T Lymphocytes B Lymphocytes
 Have three major populations:  B lymphocytes are the only cells in the body capable of producing antibody
1. Helper T lymphocytes (HTL) – stimulate B lymphocyte to make molecules, the mediators of humoral immunity
antibodies and activate other leukocytes to destroy microbes  B lymphocytes develop from bone marrow
2. Cytotoxic T lymphocytes (CTL) – kill infected cells o Mature B cells – 10-20% of the circulating peripheral lymphocyte
3. Regulatory T lymphocytes (RTL) – limit immune responses and prevent o Also present in peripheral lymphoid tissues such as lymph nodes, spleen,
reaction against self antigens and MALT
 T lymphocytes develop in the thymus  B cells recognize antigen via the B-cell antigen receptor complex
 Mature T cells are found in the blood (60-70% of lymphocytes) and in T cell zones of  Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of
peripheral lymphoid organs all mature, naive B cells, are the antigen-binding component of the B-cell receptor
 T cell recognize an antigen by antigen-specific TCR complex
o TCR consist of a disulfide-linked heterodimer made up of α & β o After stimulation by Ag and other signals, B cells develop into plasma cells
polypeptide chain, each have a variable (antigen-binding) region and (factories for antibodies)
constant region  Plasmablasts – antibody-secreting cells detected in human peripheral blood
 The αβ TCR recognizes peptide antigens that are presented by MHC molecules on  B-antigen receptor complex also contains a heterodimer of two invariant proteins
the surfaces of APC called Igα and Igβ (essential for signal transduction)
 MHC restriction – limiting the specificity of T cells for peptides displayed by cell o Igα (CD&(a)
surface MHC molecules; ensures that T cells see only cell associated antigens o Igβ (CD79Bb)
 Each TCR is noncovalently linked to six polypeptide chains, w/c form the CD3  B cell also express type 2 complement receptor (CR2, or CD21)  recognizes
complex and the ζ chain dimer complement products generated during innate immune responses to microbes
o CD3 and ζ proteins are invariant or identical in all T cells  CD40 – receives signals from helper T cells
o Involve in transduction signals  CR2 – also used by the EBV as a receptor to enter and infect B cells
o Form TCR complex (TCR, CD3 and ζ protein)
 Small population of mature T cells express TCR composed of γ and δ polypeptide
chains
 γδ TCR – recognizes peptides, lipids, and small molecules, w/o a requirement for Dendritic Cells
display by MHC proteins  Dendritic cells – aka interdigitating dendritic cells; the most important APC
o γδ T cells – aggregate at epithelial surfaces (skin and mucosa of GIT and for initiating T-cell responses against protein antigens
urogenital tracts); these cells are sentinels that protect against microbes o Have numerous fine cytoplasmic processes that resembles dendrites
that try to enter the epithelia o Langerhans cells – immature dendritic cells w/in epidermis
 Another small subset of T cells expresses markers that are also found on NK cells   Features of dendritic cells as APC:
called NK-T cells o (1) Located under the epithelia (common site of entry), and interstitial of all
o NK-T cells – express a very limited diversity of TCRs; recognize tissues (where Ag are produced)
glycolipids displayed by MHC like molecule CD1 o (2) Express many receptors for capturing and responding to microbes,
 T cell express several other proteins that assist the TCR complex in functional including TLRs and lectins
responses: CD4, CD8, CD28 o (3) They are recruited to the T-cell zones of lymphoid organs where they
o CD4 and CD8 – expressed on subsets of αβ T cells;
function as APC
 Serve as coreceptors in T-cell activation; recognize part of the
same ligand o (4) They express high levels of MHC and other molecules needed for
 CD4+ - 60% of mature T cells presenting Ag to and activating T cells
 CD8+ - 30%  Follicular dendritic cells– second type of cell w/ dendritic morphology; present in
 CD4+ T cells – function as cytokine-secreting helper cells that assist macrophages the germinal centers of lymphoid follicles in spleen and lymph nodes
and B cells to combat infections o Bear Fc receptors for IgG and receptors for C3b
o Recognize and respond to antigen displayed only by class II MHC o Can trap antigen bound to antibodies or complement proteins
 CD8+ T cells – functions as cytotoxic (killer) T lymphocytes (CTLs) to destroy host o Play a rle in humoral immune responses by presenting antigens to B cells
cells harbouring microbes and selecting the B cells that have the highest affinity for the antigen, thus
o Recognize cell-bound antigens only in association with class I MHC improving the quality of the antibody produced
molecule
 CD4 or CD8 coreceptors initiates signals needed for activation of T cells
 Integrins – adhesion molecules that promote the attachment of T-cells to APCs
 T cells have to recognize antigen-MHC complexes and signals provided by APC 
CD28

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Macrophages Tissue of the Immune System
 Part of the mononuclear phagocyte system
 Important functions in the induction and effector phases of adaptive immune  Consist of:
response: o Generative (primary or central) lymphoid organs – T and B
lymphocytes mature and become competent to respond to antigens
 Macrophages that have phagocytosed microbes and protein Ags process the Ags and
o Peripheral (secondary) lymphoid organs – adaptive immune responses
present peptide fragments to T cells. Thus, macrophage function as APC in T-cell
activation to microbes are initiated
 Macrophages are key effector cells in certain forms of cell-mediated immunity, the
reaction that serves to eliminate intracellular microbes. In this response, T cells Generative Lymphoid Organs
activate macrophages and enhance their ability to kill ingested microbes  Thymus – where T cells develop
 Macrophages participate in the effector phase of humoral immunity. They  Bone marrow – the site of productionof all blood cells and where B lymphocytes
phagocytose, and destroy microbes that are opsonized mature

Natural Killer Cells Peripheral Lymphoid Organs

 The function of NK cells is to destroy irreversibly stressed and abnormal  Organize to concentrate antigens, APC, and lymphocytes in a way that
cells, such as virus-infected cells and tumor cells optimizes interactions among this cells and the development of adaptive immune
 5-10% of peripheral blood lymphocytes response
 They do not express TCRs or Ig o Lymph nodes
 Larger than lymphocytes and contain abundant azurophilic granules o Spleen
 Have the ability to kill virus-infected cells and tumor cells w/o prior exposure to or o Mucosal and Cutaneous lymphoid tissues
activation by these microbes or tumors
o Early line of defense against viral infections and tumors Lymph nodes  Nodular aggregates of lymphoid tissues located along
 CD16 and CD56 – commonly used to identify NK cells lymphatic channels
 CD16 – is an Fc receptor for IgG; confers on NK cells the ability to lyse IgG-coated  Dendritic cells pick up and transport transport antigens of
target cells  called antibody-dependent cell-mediated toxicity (ADCC) microbes from epithelia via lymphatic vessels to lymph nodes
 The functional activity of NK cells is regulated by a balance between signals from  Antigens of microbes that enter through the epithelia or
activating and inhibitory receptors colonize tissues become concentrated in draining lymph nodes
 NKG2D family – activating receptor; recognize surface molecules induced by various Spleen  Abdominal organ; functions like lymph nodes
kinds of stress (e.g., infection, DNA damage)  Blood entering the spleen flows through a network of sinusoids
 NK cell inhibitory receptors recognize self class I MHC molecules (in healthy cells)  Blood-borne Ags are trapped by dendritic cells and
o Prevent NK cells from killing normal cells macrophages in the spleen
 Infection or neoplasm  enhance expression of activating receptors and reduces Cutaneous  Located under the epithelia of skin and GIT and respiratory
expression of class I MHC molecules  balance is tilted toward activation and infected and mucosal tract, respectively
or tumor cell is killed lymphoid  Respond to Ags that enter through branches in the epithelium
 NK cells also secrete cytokines: systems  Pharymgeal tonsils and Peyer’s patches – anatomically defined
o IFN-y – activates macrophages to destroy ingested microbes; thus NK cells mucosal lymphoid tissues
provide early defense against intracellular microbial infections  More than half the body’s lymphocytes are in the mucosal
 NK cells activity is regulated by many cytokines: tissues, mostly are memory cells
o IL-2 & IL-5 – stimulate proliferation if NK cells
o IL-12 - activates killing and secretion of IFN-y  Within peripheral lymphoid organs, T an B lymphocytes are segregated into
regions
 Follicles – located around the periphery or cortex or each lymph node; where B cells
Innate Lymphoid Cells (ILC) are concentrated
 Lack TCRs but produce cytokines similar to T cells o Contain follicular dendritic cells – involved in the activation of B cells
 NK cells – first defined ILC  Germinal centers – central region contained in a follicle if the B cells have recently
 Other ILC produce: IFN-y, IL-5, IL-17, IL-22 responded to an antigen
 Functions:  Paracortex – adjacent to the follicles; where T cells are concentrated
o Early defense against infections o Contains dendritic cells that present antigens to T lymphocytes
o Recognition and elimination of stressed cells (“stress surveillance”)  Periarteriolar lymphoid sheaths (PALS) – located in spleen surrounding small
o Shaping the later adaptive immune response, by providing cytokines that arterioles; where T lymphocytes are located
influence the differentiation of T cells o Follicles – where B cell resides

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Lymphocyte Circulation Class II MHC  Encoded in a region called HLA-D  has three subregions:
 Lymphocytes constantly recirculate between tissues and home to particular sites; molecules HLA-DP, HLA-DQ, HLA-DR
o Naive lymphocytes traverse the peripheral lymphoid organs where  Heterodimer w/ noncovalently associated α and β chain, both
immune responses are initiated are polymorphic
o Effector lymphocytes migrate to sites of infection and inflammation o Extracellular portions of α & β chains both have two
 Plasma cells remain in lymphoid organs and the bone marrow domain: α1, α2, β1, β2
o Do not need to migrate to sites of infection because they secrete antibodies  Crystal structure have peptide binding clefts facing outward
that are carried to distant tisues o Cleft is formed by interaction of α1 and β1 domains
 portion that most class II differs
 Polymorphism is asso.w/ differential binding of antigenic
Major Histocompatibility Complex (MHC) Molecules: The Peptide Display System of peptides
 Class II MHC molecules present antigens that are internalized
Adaptive Immunity
into vesicles, and are typically derived from extracellular
microbes and soluble proteins
 The function of MHC molecules is to display peptide fragments of protein o Internalized proteins are digested in endosomes or
antigens for recognition by antigen-specific T cells lysosomes
o Fundamental to the recognition of antigens by T cells o Peptides then asso.w/ class II heterodimers in the
o Linked to autoimmune diseases vesicles  the stable peptide-MHC complexes are
 Human leukocyte antigens – MHC in human; small segment of chromosome 6 transported to the cell surface
o Highly polymorphic o Class II β2 domain has a binding site for CD4
 recognize by CD4+ (fxnx as helper cells)
o Formidable barrier in organ transplant
 CD4+ T cells  class II MHC-restricted
 MHC has two major products:  Class II MHC molecules are mainly expressed on cells
o Class I MHC molecules that present ingested Ags and respond to T-cell help
o Class II MHC molecules (macrophages, B lymphocytes, dendritic cells)
MHC locus  Contains genes that encode some complement components
Class I MHC  Expressed on all nucleated cells and platelets and the cytokine TNF and lymphotoxin
molecules  Heterodimers w/ polymorphic α, or heavy, chain (44kD) linked
noncovalently to a smaller (12kD) nonpolymorphic protein
called B2-microglobulin  HLA haplotype – combination of HLA alleles in each individual
 α chains are encoded by three genes: HLA-A, HLA-B, HLA- o 1 set of HLA from each parent
C  lie close to one another in the MHC locus  No two individuals (other than identical twins) are likely to express the same MHC
 Extracellular region of α chain is divided into three domain:
molecules
α1, α2, α3
o α1 & α2 domains – form a cleft or groove, where  MHC molecules play several key roles in regulating T cell-mediated immune
peptides bind responses:
 Class I MHC molecules display peptides that are derived from o (1) an individual mounts an immune response against a protein Ag only if
proteins, such as viral and tumor Ags, that are located in the he or she inherits the genes for those MHC molecules that can bind peptides
cytoplasm and usually produced in the cell derived from Ag and present it to T cells
o Class-I associated peptides are recognized by
o (2) by segregating cytoplasmic and internalized antigens, MHC molecules
CD8+ T lymphocytes
 Cytplasmic proteins are degraded in proteasomes  ensure that the correct immune response is mounted against different
peptides are transported in ER and bind to class I molecules microbes – CTL-mediated killing cells harbouring microbes, and helper T
o Peptide-loaded MHC associate w/ B2- cell-mediated antibody and macrophage activation to combat extracellular
microglobulin  form a stable trimer  microbes
transported to cell surface  A number of autoimmune and other diseases are associated with the inheritance of
o α3 domain has a binding site for CD8+  particular HLA alleles
recognized by CD8+ (CTLs)
o TCR recognize MHC-peptide complex and CD8
molecule (coreceptor) binds to class I heavy chain
 CD8+ T cells  class I MHC-restricted
o Eliminate virus  all nucleated cells express class I
HLA that can be surveyed by CD8+

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Cytokines: Messenger Molecules of the Immune System Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of
Intracellular Microbes
 Many cellular interactions and functions of leukocytes are mediated by secreted  Naive T lymphocytes are activated by Ag and costimualtors in peripheral lymphoid
proteins called cytokines organs and proliferate and differentiate into effector cells that migrate to site of
 Interleukins – molecularly defined cytokines; mediate communications between antigens
 Secretion of IL-2 – earliest responses of CD4+ cells and expression of high-affinity
meukocytes
receptors for IL-2
 Majority of cytokines act on the cells that produce them (autocrine reactions) or on  IL-2 – growth factor that acts on these T lymphocytes and stimulates their
neighboring cells (paracrine) and rarely at a distance (endocrine) proliferation, leading to increase in number of antigen-specific lymphocytes
 Cytokines contribute to different types of immune responses.  Functions of helper T cells are mediated by the combined actions of CD40L and
 In innate immune response, cytokines are produced rapidly after encounter w/ cytokines
microbes and other stimuli o When CD4+ helper T cells recognize antigens displayed by macrophage or B
cells, the T cells express CD40L w/c engages CD40 on macrophages or B
o Function to induce inflammation and inhibit virus replication
cells and activates these cells
o TNF, IL-1, IL-12, type I IFNs, IFN-y, chemokines  major source:  Some of the activated CD4+ cells differentiate into effector cells that secrete different
macrophages, dendritic cells, NK cells; also epithelial cells sets of cytokines and perform different functions
 In adaptive immune responses, cytokines are produced mainly by CD4+ T  IFN-y – potent macrophage activator secreted by TH1
lymphocytes o Combination of CD40- and IFN-y mediated activation results in “classical
o Functions to promote lymphocyte proliferation and differentiation and macrophage activation “  lead to destruction of ingested microbes
activate effector cells  IL-2, IL-4, IL-5, IL-17, IFN-y  TH2 produces:
o IL-4 – stimulates B cells to differentiate into Ig-E secreting plasma cells
o Some cytokines limit and terminate immune responses TGF-b, IL-10
o IL-5 – activates eosinophils
 Some cytokines stimulate hematopoiesis  colony-stimulating factors  Eosinophils and mast cells bind to IgE-coated microbes (helminthic parasites) and
o Stimulate formation of blood cell colonies from BM eliminate
o Increase leukocyte numbers during immune and inflammatory responses  TH2 also induce “alternative pathway” of macrophage activation  asso.w/
o Produced by: marrow stromal cells, T lymphocytes, macrophages tissue repair and fibrosis
o E.g., CSFs such as GM-CSF, IL-7  TH17 cells – releases IL-17 w/c recruit neutrophils and monocytes and destroy
extracellular bacteria and fungi, also involved in inflammatory diseases
 Activated CD8+ T lymphocytes differentiate into CTLs  kills microbes in cytoplasm
Overview of Lymphocyte Activation and Immune Responses
o CTLs eliminate the reservoirs of infection
 Steps in developing an adaptive immune response:
1. Antigen recognition
Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular
2. Activation of specific lymphocytes to proliferate and differentiate into effector and Microbes
memory cells  Upon activation, B lymphocytes proliferate and then differentiate into
3. Elimination of the antigen plasma cells that secrete different classes of antibodies with distinct
4. Decline of the response (memory cells being the long-lived survivors) functions
 Antibody responses to most protein antigens require T cell help  T-dependent
Display and Recognition of Antigens o In these responses, B cells ingest Ags into vesicles and degrade them, and
 Microbes and their protein antigens are captured by dendritic cells display peptides bound to class II MHC for recognition by helper T cells
o They carry their antigenic cargo to draining lymph nodes  Ag are o Helper T cells are activated, express CD40L and secrete cytokines 
processed and displayed w/ MHC molecules on the cell surface  antigens stimulate B cells
are recognized by T cells  Many polysaccharide and lipid antigens cannot be recognized by T cells but have
 B lymphocytes use their Ag receptors (membrane-bound antibody molecules) to multiple antigenic determinants (epitopes) that are able to engage many antigen
recognize Ags of many different chemical types (e.g., protein, polysaccharides, lipids) receptor molecules on each B cell and initiate the process of B-cell activation  T-
 Adjuvants – microbial mimics; given w/ the antigen and stimulate innate immune independent
response (e.g., immunizations)  Polysaccharides and lipids stimulate secretion mainly of IgM antibody
o Activates APCs to express molecules called costimulators and to secrete  Protein antigens (thru CD40L- and cytokine mediated helper T cell actions) induce
cytokines that stimulate the proliferation and differentiation of T cells production of antibodies IgG, IgA, IgE
o Principal costimulators for T cells are the B7 proteins (CD80 and CD86)  Isotype switching – induced by cytokines IFN-y and IL-4
 expressed on APCs and recognize by CD28 receptor on naive T cells  Helper T cells also stimulate production of antibodies w/ high affinities for the Ag
 Signal 1 (antigens) and costimulatory molecules produced during innate immune o Called affinity maturation  improves quality of humoral response
responses to signal 2 (microbes) function cooperatively to activate antigen-specific  Isotype switching and affinity maturation occur mainly in germinal centers
lymphocytes  Follicular helper T cells (TFH) – helper T cells that stimulate these processes in B
lymphocytes migrate to and reside in the germinal centers

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  IgG  opsonises microbes and target them for phagocytosis (neutrophils and  CD4+ helper T cells help B cells to make antibodies, activate macrophages to destroy
macrophages  has receptors for Fc tails of IgG) ingested microbes, stimulate recruitment of WBC, and regulate all immune responses
o Crosses the placenta; protects newborn until immune system matures to protein antigens. The function of CD4+ T cells are mediated by secreted proteins
o Half-life: 3 weeks (plasma cells have months or years in BM) called cytokines. CD8+ cytotoxic T lymphocytes kill cells that express antigens in the
 IgG and IgM  activate classical pathway cytoplasm that are seen as foreign and can also produce cytokines
 IgA  secreted from mucosal epithelia and neutralizes microbes in the lumens of  Antibodies secreted by plasma cells neutralize microbes and block their infectivity, and
respiratory and GIT promote phagocytosis and destruction of pathogens. Antibodies also confer passive
 IgE and eosinophils  kills parasites thru granules immunity to neonates
o TH2 cytokines stimulate production of IgE and activate eosinophils

HYPERSENSITIVITY: IMMUNOLOGICALLY MEDIATED TISSUE INJURY

Decline of Immune Responses and Immunologic Memory
 Majority of effector lymphocytes die by apoptosis after elimination of microbes   Hypersensitivity – injurious immune reactions; basis of the pathology asso.w/
returns the immune system to its resting state immunologic diseases
 Initial activation of lymphocytes also generates memory cells  survive for years o Individuals who have been previously exposed to an antigen manifest
after the infection
detectable reactions to that antigen  sensitized
 Memory cells expanded pool of antigen-specific lymphocytes; respond faster and
more effectively when reexposed to antigen than do naive cells (important in o Excessive or harmful reaction to antigen
vaccination  Hypersensitivity reactions can be elicited by exogenous environmental antigens
(microbial and nonmicrobial) or endogenous self antigens
o Allergy – most common reaction to environmental antigens
KEY CONCEPTS: The Normal Immune Response: Cells, Tissues, Receptors, Mediators, o Autoimmune diseases – immune responses against self or autologous
and Overview antigens
 The innate immune system uses several families of receptors, notably the Toll-like  Hypersensitivity usually results from an imbalance between the effector mechanisms
receptors, to recognize molecules present in various types of microbes and produced of immune responses and the control mechanisms that serve to normally limit such
by damaged cells
responses
 Lymphocytes are the mediators of adaptive immunity and the only cells that produce
specific and diverse receptors for antigens  The development of hypersensitivity diseases (both allergic and autoimmune) is often
 T lymphocytes express antigen receptors called TCR that recognize peptide fragments asso.w/ the inheritance of particular susceptibility genes
of protein antigens that are displayed by MHC molecules on the surface of APCs  The mechanisms of tissue injury in hypersensitivity reaction are the same as the
 B lymphocytes express membrane-bound antibodies that recognize wide variety of effector mechanisms of defense against infectious pathogens
antigens. B cells are activated to become plasma cells, w/ secrete antibodies
 Natural killer cells kill cells that are infected by microbes, or are stressed and damaged Classification of Hypersentivity Diseases
beyond repair. NK cells express inhibitory receptors that recognize MHC molecules
that are normally expressed on healthy cells, and are thus prevented from killing
 Classified based on the immunologic mechanism that mediates the diseases
normal cells
 Antigen presenting cells (APCs) capture microbes and other antigens, transport them
to lymphoid organs, and display them for recognition by lymphocytes. The most 1. Type I hypersensitivity (immediate hypersensitivity)
efficient APCs are dendritic cells (live in epithelial and most tissues) o Injury is caused by TH2 cells, IgE, mast cells and other leukocytes
 The cells of the immune system are organized in tissues, some of w/c are the sites of 2. Type II hypersensitivity (antibody-mediated disorders)
production of mature lymphocytes (generative lymphoid organs: thymus and BM) and o Secreted IgG and IgM antibodies injure cells by promoting their
others are the sites of immune responses (peripheral lymphoid organs: lymph nodes, phagocytosis or lysis and injure tissues by inducing inflammation
spleen, mucosal lymphoid tissues)
3. Type III hypersensitivity (immune-complex mediated disorders)
 The early reaction to microbes is mediated by innate immunity. Includes epithelial
barriers, phagocytes, NK cells, plasma proteins of the complement system. Reaction of o IgG and IgM antibodies bind antigens usually in the circulation, and the Ag-
innate immunity is often manifested as inflammation. Does not have fine antigen Ab complexes deposit in tissues and induce inflammation
specificity or memory 4. Type IV hypersensitivity (cell-mediated immune disorders)
 Defense reactions of adaptive immunity develop slowly, but are more potent and o Sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of
specialized the tissue injury
 Microbes and other foreign antigens are captured by dendritic cells and transported to o TH2 cells induce lesions that are part of type I reaction (nor part of type IV)
lymph nodes, where antigens are recognized by naive lymphocytes. Lymphocytes are
activated to proliferate and differentiate into effector and memory cells
 Cell-mediated immunity is the reaction of T lymphocytes, designed to combat cell-
associated microbes. Humoral immunity is mediated by antibodies and is effective
against extracellular microbes (in circulation and mucosal lumens)

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TYPE MECHANISM HISTOPATHOLOGIC PROTOTYPICAL  Most immediate hypersensitivity disorders are caused by excessive TH2 responses
LESION DISORDERS and these cells play a central role by stimulating IgE production and promote
Type I Prdxn of IgE  release of Vascular dilation, Anaphylaxis; inflammation.
(immediate) vasoactive amines and other edema, smooth muscle allergies; bronchial
mediators from mast cells; contraction, mucus asthma (atopic Activation of TH2 cells and Production of IgE Antibody
later recruitment of production, tissue injury, forms)
inflammatory cells inflammation
 First step in generation of TH2 cells is the presentation of the Ag to naive CD4+
helper T cells by dendritic cells
Type II Prdxn of IgG, IgM  binds to Phagocytosis and lysis Autoimmune o In response to Ag, and also IL-4 produced at local site, T cells differentiate
(antibody- Ag on target cell or tissue  of cells; inflammation; haemolytic anemia; into TH2 cells
medaited) phagocytosis or lysis of functional derangements Goodpasture o New TH2 cells produce cytokines upon encounter w/ antigen  IL-4, IL-5,
target cell by activated w/o cell injury syndrome
IL-13
complement or Fc receptors;
recruitment of WBC  IL-4 – acts on B cells to stimulate class switching to IgE and
Type III Deposition of Ag-Ab complex Inflammation, SLE, some forms of promotes the development of additional TH2 cells
(immune-  complement activation  necrotizing vasculatits glomerulonephritis;  IL-5 – involved in the development and activation of eosinophils
complex recruitment of WBC by (fibrinoid necrosis) serum sicknesss; (important effector of Type I hypersensitivity)
mediated) complement products and Fc Arthus reaction  IL-13 – enhances IgE production and acts on epithelial cells to
receptors  release of stimulate mucus secretion
enzymes and other toxic
 TH2 cells also produce chemokines to attract more TH2 cells
molecules
Type IV Activated T lymphocytes  Perivascular cellular Contact dermatitis;
(cell- infiltrates; edema; multiple sclerosis; Sensitization and Activation of Mast Cells
(1) release of cytokines,
mediated) inflammation and granuloma formation, type 1 DM,
macrophage activation; (2) cell destruction tuberculosis  Mast cells – BM-derived cells; widely distributed in the tissues
T-cell mediated cytotoxicity o Abundant near blood vessels and nerves and in subepithelial tissues
o Have cytoplasmic membrane-bound granules that contain active mediators
 Granules also contain acidic proteoglycans that bind basic dyes
Immediate (Type I) Hypersensitivity (toluidine blue)
o Basophils – circulating counterpart
 Immediate or type I hypersensitivity  rapid immunologic reaction occurring in  Mast cells (and basophils) are activated by the cross-linking of high-affinity IgE Fc
a previously sensitized individual that is triggered by the binding of an antigen to IgE receptors
on the surface of mast cells o Can also be triggered by C5a and C3a (anaphylatoxins)  act by
o Often called allergy binding to receptors on mast cell membrane
 Allergen – antigen that caused the allergy  Other mast cell secretagogues: chemokines (IL-8), drugs (codeine, morphine,
 May occur as systemic or local reaction adenosine, melittin in venom), and physical stimuli (heat, cold, sunlight)
o Systemic reaction – most often follows injection of an Ag (e.g., bee sting)  Basophils – similar w/ mast cells in terms of IgE Fc receptors and granules
or ingestion (e.g., peanut allergens) o Differes in location; basophils are present in citculating blood
o Sometimes, w/in minutes the patient goes into a stae of shock  fatal  FcεRI – high-affinity receptors found on mast cells and basophils; specific for the Fc
o Local reaction – diverse and may vary; localized cutaneous rash or blisters portion of IgE
(skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis,  IgE coated mast cells are said to be sensitized, because they are sensitive to
conjunctivitis), hay fever, bronchial asthma, allergic gastroenteritis (food subsequent encounter w/ specific Ag
allergy)  When a mast cell, armed w/ IgE antibodies, is exposed to the same Ag, the cell is
 Local type I hypersensitivity reactions have two phases: activated, leading eventually to the release of an arsenal of powerful mediators
1) Immediate reaction – cxd by vasodilation, vascular leakage, smooth responsible for immediate hypersensitivity reactions
muscle spasm or glandular secretions; evident w/in minutes after exposure  In the first step of mast cell activation, Ag binds to IgE antibodies. Multivalent Ags
to allergen; subside in a few hours bind and cross-link adjacent IgE antibodies. Receptors (FcεRI) are brought together
2) Late-phase reaction – sets in 2-24 hrs later w/o additional exposure to and activate signal transduction pathway. Signal leads to production of mediators
Ag and may last for several days; cxd by infiltration of tissues w/ responsible for symptoms of immediate hypersensitivity
eosinophils, neutrophils, basophils, monocytes, CD4+ cells, and tissue
destruction (mucosal epithelial cell damage

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Mediators of Immediate Hypersensitivity  These mediators are responsible for the manifestations of immediate hypersensitivity
reactions
 Mast cell activation leads to degranulation, w/ the discharge of preformed o E.g., histamine and leukotrienes – released rapidly, responsible for intense
(primary) mediators stored in granules, and de novo synthesis and release of immediate reactions cxd by: edema, mucus secretion smooth muscle spasm
secondary mediators, including lipid products and cytokines
Late Phase Reaction
Preformed  Contained w/in mast cell granules; first to be released
Mediators  Divided in three categories  In the late-phase reaction, leukocytes are recruited that amplify and sustain
Vasoactive  Histamine – most important mast-cell the inflammatory response w/o additional exposure to the triggering
amines derived amine; causes: antigen
o Intense smooth muscle contraction
 Eosinophils – abundant WBC in this reaction
o Increased vascular permeability
o Increased mucus secretion by o Recruited by eotaxin
nasal, bronchial, and gastric  IL-5 – produced by TH2 cells; most potent eosinophil-activating cytokine
glands  Upon activation eosinophils liberate proteolytic enzymes and two unique proteins:
Enzymes  Contained in the granule matrix o Major basic protein (MBP)
 Include neutral proteases (chymase, o Eosinophils cationic protein (ECP)
tryptase) and acid hydrolase  Late phase reaction is a major cause of symptoms in some type 1
 Cause tissue damage and lead to generation
hypersensitivity disorders (e.g., allergic asthma)
of kinins and activated components of
complement (C3a)  Treatment: steroids
Proteoglycans  Heparin – anticoagulant
 Chondroitin sulfate Development of Allergies
 Serve to package and store the amines in
the granules  Susceptibility to immediate hypersensitivity reactions is genetically determined
 Atopy – increased propensity to develop immediate hypersensitivity reactions
Lipid  Major lipid mediators are arachidonic acid-derived products o Atopic individuals have higher serum IgE levels and more IL-4-producing
Mediators  Reactions in mast cell membranes  activates PLA2  converts TH2 cells
membrane phospholipids to arachidonic acid
 Studies in px w/ asthma reveal linkage to polymorphisms in genes
 Arachidonic acid – parent compound of:
o 5q31 region
o Leukotrienes (5-lipoxygenase pathway)
o Prostaglandins (cyclooxygenase pathway) o Encodes IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF
Leukotrines  Leukotrines C4 and D4  most potent  Environmental factors are also important in the development of allergic reactions
vasoactive and spasmogenic agents; more o Predisposing factor for allergy  exposure to pollutants
active than histamine  Nonatopic allergy – immediate hypersensitivity reactions triggered by non-antigenic
 Leukotriene B4  highly chemotactic for stimuli (e.g., temperature extremes, exercise) and do not involve TH2 cells or IgE
neutrophils
 The incidence of many allergic diseases is increasing in developed countries
Prostaglandin  Most abundant mediator by COX pathway
o Hygiene hypothesis – early childhood exposure to microbial antigens
D2  Cause intense bronchospasm and increased
mucus secretion educates immune system in such a way that pathologic responses against
PAF  Platelet-activating factor allergens are prevented
 Lipid mediator produced by mast cells, not
derived from arachidonic acid Systemic Anaphylaxis
 Causes platelet aggregation, release of
histamine, bronchospasm, increased vascular  Systemic anaphylaxis is characterized by:
permeability, vasodilation o Vascular shock
o Widespread edema
Cytokines  TNF, IL-1, chemokines
o Difficulty in breathing
 Chemokines – promote WBC recruitment; typical of late-phase
reaction  It may occur in sensitized individuals,
 IL-4 – amplifies TH2 response o In hospital setting (after administration of foreign proteins (entisera),
 Cause further mast cell degranulation hormones, enzymes, polysaccharides, drugs (antibiotic penicillin)
o Community setting (exposure to food allergen or insect toxin)

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  Within minutes after exposure, itching, hives, and skin erythema appear o Complement system generates C3b and C4b  deposited on the surfaces of
o Followed by contraction of respiratory bronchioles and distress the cells and recognize by phagocytes  phagocytosis and opsonization
o Laryngeal edema  hoarsness  compromise breathing o Complement activation also leads to formation of membrane attack complex
o Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow  “drill holes”  osmotic lysis of cells (e.g., Neisseria bacteria)
o Patient may go into shock and die w/in an hour  Antibody-dependent cellular cytotoxicity (ADCC)  antibody-mediated
destruction of cells
Local Immediate Hypersensitivity Reactions o Cells coated w/ IgG are killed by different effector cells: NK cells,
macrophages, etc.
 E.g., pollen, animal dander, house dust, foods
 ADCC and phagocytosis occur in following situations:
 Urticaria, allergic rhinitis (hay fever), bronchial asthma, food ellergies
1) Transfusion reactions
2) Haemolytic disease of the newborn (erythroblastosis fetalis)
Examples of Disorders Caused by Immediate Hypersensitivity
3) Autoimmune haemolytic anemia, agranulocytosis, thrombocytopenia
Clinical Syndrome Clinical and Pathologic Manifestations
Anaphylaxis (drugs, Fall in BP (shock) caused by vascular dilation; airway obstruction due 4) Certain drug reactions (drugs acts as a”hapten”)
bee sting, food) to laryngeal edema
Bronchial asthma Airway obstruction caused by bronchial smooth muscle hyperactivity; Inflammation
inflammation and tissue injury caused by late-phase reaction
Allergic rhinitis, Increased mucus secretion; inflammation of upper airways, sinuses  When antibodies deposit in fixed tissues (e.g., basement membrane, ECM) 
sinusitis (hay fever) resultant injury is due to inflammation
Food allergies Increased peristalsis due to contraction of intestinal muscles  Deposited antibodies activate complement (chemotactic agent C5a, anaphylatoxins
C5a and C3a), increase vascular permeability
 Leukocytes are activated  results in production of substances that damage tissues
KEY CONCEPTS: Immediate (Type 1) Hypersensitivity such as lysosomal enzymes, protease (digest basement membrane, collagen, elastin,
 Also called allergic reactions, or allergies
cartilage, ROS)
 Induced by environmental antigens (allergens) that stimulate strong TH2 responses
and IgE production in genetically susceptible individuals  Antibody-mediated inflammation  glomerulonephritis, vascular rejection
 IgE coats mast cells by binding to Fcε receptors; reexposure to the allergen leads to
cross linking of the IgE and FcεR, activation of mast cells, and release of mediators Cellular Dysfunction
 The principal mediators are histamine, proteases, and other granule contents,
prostaglandins, and leukotrienes, and cytokines  In some cases, antibodies directed against cell surface receptors impair or dysregulate
 The mediators are responsible for the immediate vascular and smooth muscle function without causing cell injury or inflammation
reactions and the late-phase reaction (inflammation)  Myasthenia gravis – antibodies reactive w/ acetylcholine receptors in the motor end
 The clinical manifestations may be local or systemic, and range from mildly annoying
plates of skeletal muscles block neuromuscular transmission and cause muscle
rhinitis to fatal anaphylaxis
weakness
 Graves disease – antibody-mediated stimulation of cell function; antibodies against
Antibody-Mediated (Type II) Hypersensitivity the thyroid stimulating hormone receptor on thyroid epithelial cells stimulate the cells,
resulting in hyperthyroidism
 Antibodies that react w/ antigens present on cell surfaces or in the extracellular matrix
cause disease by destroying these cells, triggering inflammation, or interfering w/ Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Disease Target Antigen Mechanism of Clinicopathologic
normal functions
Disease Manifestation
 Antibodies may be specific for normal cell or tissue antigens (autoantibodies) or for
Autoimmune RBC membrane proteins Opsonisation and Hemolysis, anemia
exogenous antigens, such as chemical or microbial proteins, that bind to a cell surface Hemolytic Anemia (Rh blood group Ags, I phagocytosis of RBC
or tissue matrix Ag)
Autoimmune Platelet membrane Opsonisation and Bleeding
Opsonization and Phagocytosis thrombocytopenic proteins (GpIIb-IIIa phagocytosis of
purpura integrin) platelets
 Phagocytosis – largely responsible for depletion of cells coated with antibodies Pemphigus Proteins in intercellular Ab-mediated Skin vesicles (bullae)
 Deposition of IgG or IgM antibodies on surfaces of cells  activate complement vulgaris junctions of epidermal activation of
system by classical pathway cells (epidermal proteases, disruption
cadherin) of intracellular
adhesions

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Vasculitis caused Neutrophil granule Neutrophil Vasculitis 2) Deposition of immune complexes
by ANCA proteins (released from degranulation and  Circulating Ag-Ab complex is deposited in tissues
activated neutrophils) inflammation  Often affects glomeruli and joints
Goodpasture Noncollagenous protein Complement- and Nephritis, lung 3) Inflammation and tissue injury
syndrome in basement Fc- receptor hemorrhage
 Deposition initiates acute inflammation
membranes of mediated
glomeruli and alveoli inflammation  During this phase (10 days after Ag administration), clinical
Acute rheumatic Streptococcal cell wall Inflammation, Myocarditis, arthritis features such as fever, urticaria, joint pains (arthralgias), lymph
fever Ag; Ab cross-reacts w/ macrophage node enlargement, and proteinuria appear
myocardial Ag activation  Resultant inflammatory lesion: vasculitis, glomerulonephritis,
Myasthenia Acetylcholine receptor Ab inhibits Ach Muscle weakness, arthritis
Gravis binding, down- paralysis  Complement-fixing Abs (IgG, IgM) and Abs that bind to leukocyte Fc receptor (IgG)
modulates receptors
induce pathologic lesions of immune complex disorders
Graves Disease TSH receptor Ab-mediated Hyperthyroidism
o Consumption of complement leads to a decreased on C3 levels
stimulation of TSH
receptors o C3 levels can be used to monitor disease activity
Insulin-resistant Insulin Receptor Ab inhibits binding Hyperglycemia,  Principal morphologic manifestation of immune complex injury  vasculitis asso.w/
diabetes of insulin ketoacidosis necrosis or the vessel wall and intense neutrophilic infiltration
Pernicious Intrinsic factor of Neutralization of IF, Abnormal o Fibrinoid necrosis – smudgy eosinophilic area compose of necrotic tissue
anemia gastric parietal cells decreased erythropoiesis, and deposits of immune complexes, complement and plasma protein
absorption of B12 anemia o Kidney (IF microscopy)  appears granular lumpy deposits of
immunoglobulin and complement
o EM  electron-dense deposits along the glomerular basement membrane
Immune Complex-Mediated (Type III) Hypersensitivity
Local Immune Complex Disease (Arthus Reaction)
 Antigen-antibody complexes produce tissue damage mainly by eliciting
inflammation at the sites of deposition
 Arthus reaction – localized area of tissue necrosis resulting from acute immune
 Pathologic reaction is initiated when antigen complexes w/ antibody in the circulation
complex vasculitis, usually elicited in the skin
 created immune complexes that deposits in vessel walls
o Cause by intracutaneous injection of Ag in a previously immunized animal
 Antigens that form immune complexes may be:
that contains circulating Abs against Ag
o Exogenous – foreign protein that is injected or produced by an infectious
o As Ag diffuses to vascular wall, it binds the preformed Ab, and large
microbe
immune complexes are formed locally
o Endogenous – if individual produces antibody against self antigens
o Precipitate in vessel walls and cause fibrinoid necrosis, and superimposed
(autoimmunity)
thrombosis worsens the ischemic injury
 Immune complexes-mediated diseases tend to be systemic, but often preferentially
involve the kidney (glomerulonephritis), joint (arthritis), and small blood vessels KEY CONCEPTS: Pathogenesis of Diseases Caused by Antibodies and Immune
(vasculitis) Complexes
 Antibodies can coat (opsonised) cells, with or without complement proteins, and
Systemic Immune Complex Disease target these cells for phagocytosis vy phagocytes (macrophages), w/c expresses
receptors for the Fc tails of IgG and for complement proteins. The result is depletion
 Acute serum sickness – prototype of a systemic immune complex disease of the opsonised cells
o Frequent sequela to administration of large amount of proteins  Antibodies and immune complexes may deposit in tissues or blood vessels, and elicit
o Seen in px who receive antibodies from other individuals or species an acute inflammatory reaction by activating complement, w/ release of breakdown
products, or by engaging Fc receptors of leukocytes. The inflammatory reaction
 Pathogenesis of systemic immune complex disease can be divided in three phases:
causes tissue injury
1) Formation of immune complexes  Antibodies can bind to cell surface receptors or other essential molecules and cause
 Protein Ag triggers Ab formation (a week after) and Abs are functional derangements (inhibition or unregulated activation) without cell injury
secreted into blood where it reacts w/ the Ag still present in the
circulation  forms Ag-Ab complexes

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 Examples of Immune Complex-Mediated Diseases microorganisms is markedly augmented, express more class II
Disease Antigen Involved Clinicopathologic MHC, facilitate further Ag presentation; secrete TNF, IL-1,
Manifestations chemokines (promote inflammation); produce more IL-12 
SLE Nuclear Ags (circulating or Nephritis, skin lesions, arthritis, etc amplify TH1 response
“planted” in kidney)  Activated TH17 cells secrete IL-17, IL-22, chemokines,
Poststreptococcal Streptococcal cell wall Ag; may Nephritis and cytokines  recruit neutrophils and monocytes 
glomerulonephritis be “planted” in GBM prmote inflammation
Polyarteritis Hepatitis B virus Ag in some Systemic vasculitis  TH17 also produce IL-21  amplifies TH17 response
nodosa cases Clinical  Tuberculin reaction – caused by intracutaneous injection of
Reactive arthritis Bacterial Ag (e.g., Yersinia) Acute arthritis examples of PPD (contain tubercle bacillus Ag)
Serum sickness Various proteins (e.g., foreign Arthritis, vasculitis, nephritis CD4+ T cell- o Appears 8-12 hrs (peaks 24-72 hrs)
serum protein (horse Mediated  DTH – cxd by accumulation of mononuclear cells, mainly CD4+
antithymocyte globulin) Inflammatory T cells and macrophages around venules, producing perivascular
Arthus reaction Various foreign proteins Cutaneous vasculitis Reactions “cuffing”  marked endothelial hypertrophy
(experimental)  Macrophage transform into epitheloid cells with sustained
activation  granuloma (microscopic aggregation of epitheloid
cells, surrounded by a collar of lymphocytes) 
granulomatous inflammation
T Cell-Mediated (Type IV) Hypersensitivity
 Granulomatous inflammation – asso.w/ strong TH1-cell
activation and high-level production of cytokines (IFN-y)
 The cell-mediated type of hypersensitivity is caused by inflammation resulting from o Can also be caused by indigestible foreign bodies, w/c
cytokines produced by CD4+ T cells and cell killing by CD8+ cells activate macrophages w/o eliciting an adaptive
 CD4+ T-cell mediated hypersensitivity – induced by environmental and self-Ags immune response
is the cause of many chronic inflammatory diseases, including autoimmune diseases  Contact dermatitis – tissue injury resulting from DTH rxns;
 CD8+ cells may also be involved in some autoimmune diseases and may be evoked by contact w/ urushiol (from poison ivy or poison oak)
 Rheumatoid arthritis, multiple sclerosis, inflammatory
dominant effector cells in some reactions (esp those that follow viral infections)
bowel disease
CD4+ T Cell-Mediated Inflammation
CD8+ T Cell-Mediated Cytotoxicity
 Delayed-type hypersensitivity (DTH) – prototype of T cell-mediated
 CD8+ CTLs kill antigen-expressing target cells
inflammation;
o E.g., Type 1 DM
o A tissue reaction to Ags given to immune individuals
 CTLs directed against cell surface histocompatibility antigens  graft rejection
o Administered Ag results in a detectable cutaneous reaction w/in 24-48 hrs
 Viral peptides are displayed by MHC I and complex is recognized by TCR of CD8_ cells
o Both TH1 and TH17 contribute to inflammation
 Tumor-associated Ags are also presented on the cell surface, and CTLs are involved in
 TH1 cells – dominated by active macrophages
the host response to transformed cells
 TH17 cells – greater neutrophil component
 The principal mechanism of T cell-mediated killing of targets involves perforins and
 Inflammatory reactions stimulated by CD4+ T cells can be divided into stages:
granzymes (preformed mediators w/in lysosome-like granules of CTLs)
a. Activation of CD4+ T cells
o Perforins facilitates the release of granzymes from the complex
b. Responses of Differentiated Effector T cells
o Granzymes – proteases that cleave and activate caspases  induce
apoptosis of the target cells
Activation of  CD4+ T cells recognize peptides displayed by dendritic cells and
CD4+ T cells secrete IL-2, w/c functions as an autocrine growth factor to  CD8+ express Fas ligand  trigger apoptosis
stimulate proliferation of Ag responsive T cells  CD8+ T cells produce IFN-y
 APCs also produce IL-2  induces differentiation of CD4+ T
cells to the TH1 subset KEY CONCEPTS: Mechanisms of T Cell-Mediated Hypersensitivity Reactions
 IFN-y  produced by effector cells; promotes further TH1  Cytokine-mediated inflammation: CD4+ T cells are activated by exposure to a protein
development, amplifying the reaction Ag and differentiate to TH1 and TH17 effector cells. Subsequent exposure to the Ag
 If APCs produce IL-1, IL-6, IL-23  stimulate results in the secretion of cytokines, IFN-y activates macrophages to produce
differentiation of T cells to the TH17 subsets substances that cause tissue damage and promote fibrosis; IL-17 recruit leukocytes
Responses of  TH1 cells secrete IFN-y upon repeated exposure to Ag  and promote inflammation
Differentiated responsible for many manifestations of delayed-type  Classical T cell-mediated inflammatory reaction is DTH
Effector T cells hypersensitivity  T cell mediated cytotoxicity: CTLs recognize cells expressing the target Ag and kill
 IFN-y-activated macrophages  ability to kill these cells. CD8+ also secrete IFN-y

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 T Cell-Mediated Diseases
Disease Specificity of Principal Mechanism Clinicopathologic Autoimmune Diseases
Pathogenic T Cells of Tissue Injury Manifestations ORGAN-SPECIFIC SYSTEMIC
Rheumatoid Collagen; Citrullinated Inflammation mediated Chronic arthritis w/ Diseases Mediated by Antibodies
arthritis self proteins by TH17 cytokines; role inflammation, Autoimmune haemolytic anemia Systemic lupus erythematosus
of Abs and immune destruction of Autoimmune thrombocytopenia
complexes articular cartilage Autoimmune atrophic gastritis of pernicious
Multiple Protein Ags in myelin Inflammation mediated Demyelination in CNS anemia
sclerosis (e.g., MBP) by TH1 and TH17 w/ perivascular Myasthenia gravis
cytokines, myelin inflammation; Graves disease
destruction by activated paralysis Goodpasture syndrome
macrophages Diseases Mediated by T cells
Type 1 DM Ag of pancreatic islet B T cell-medaited Insulitis (chronic Type 1 diabetes mellitus Rheumatoid arthritis
cells inflammation, destruction inflammation in Multiple sclerosis Systemic sclerosis (scleroderma)
of islet cells by CTLs islets), destruction of Sjogren syndrome
B cells; diabetes Diseases Postulated to be Autoimmune
Inflammatory Enteric bacteria, self Inflammation mediated Chronic Intestinal Inflammatory bowel diseases (Crohn disease, Polyarteritis nodosa
bowel disease Ag by TH1 and TH17 inflammation, ulcerative colitis) Inflammatory myopathies
cytokines obstruction Primary biliary cirrhosis
Psoriasis Unknown Inflammation mediated Destructive plaques Autoimmune (chronic active) hepatitis
mainly by TH17 cytokines in the skin
Contact Various environmental Inflammation mediated Epidermal necrosis, Immunologic Tolerance
sensitivity chemicals (e.g., by TH1 cytokines dermal inflammation,
urushiol) causing skin rash and  Immunologic tolerance is the phenomenon of unresponsiveness to an
blisters
antigen induced by exposure of lymphocytes to that antigen
 Self-tolerance – refers to lack of responsiveness to a individual’s own antigens
 Mechanism of self-tolerance is classified into two groups:
AUTOIMMUNE DISEASES
o Central tolerance
 Autoimmunity – immune reactions against self antigens o Peripheral tolerance
 Mere presence of autoantibodies does not indicate an autoimmune disease exist
o Autoantibodies are normally found in older individuals Central Tolerance
 Immature self-reactive T and B lymphocyte clones that recognize self
 Three requirements of a pathologic autoimmunity:
antigens during their maturation in the central lymphoid organs are killed
1) The presence of an immune reaction specific for some self antigen or self or rendered harmless
tissue  Mechanisms of central tolerance in T and B cells show similarities and differences:
2) Evidence that such a reaction is not secondary to tissue damage but is of
primary pathogenic significance  In developing T cells, TCRs are generated. Antigen-independent TCR
3) The absence of another well-defined cause of the disease generation produces lymphocytes that high-affinity receptors for self-
 Immune-mediated inflammatory disease – disorders in w/ chronic inflammation antigens.
o When immature lymphocytes encounter the antigens in thymus, many cells
is a prominent component; may be autoimmune, or the immune response may be
die by apoptosis. This process, negative selection or deletion, is
directed against normally harmless microbes responsible for eliminating self-reactive lymphocytes from T-cell pool.
 Clinical manifestations of autoimmune disorders are extremely varied: o A protein called AIRE (autoimmune regulator) stimulates expression of
o Organ-specific – directed against a single organ or tissue “peripheral tissue-restricted” self antigens in thymus  critical for deletion
 E.g., DM 1, Multiple sclerosis of immature T cells specific for these antigens
o Systemic or generalized disease – autoimmune reactions are against o Mutation in AIRE gene causes autoimmune polyendocrinopathy
o In CD4+ T-cell lineage, cells that see self Ag in thymus develop into
widespread antigens
regulatory T cells
 E.g., SLE
 When developing B cells recognize self antigens in bone marrow, they
 Goodpasture syndrome – falls in the middle of the spectrum reactivate the machinery of antigen receptor gene rearrangement and
begin to express new antigen receptors, not specific for self antigens
o The process is called receptor editing
o If receptor editing does not occur, the self-reactive cells undergo apoptosis
 purging potentially dangerous lymphocytes from mature pool

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Peripheral Tolerance o Lymphocytes express death receptor Fas (CD59), member of TNF family
 Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues: o FasL (Fas ligand), homologous to cytokine TNF, is expressed mainly on
activated T lymphocytes
 Anergy. Lymphocytes that recognize self-antigens may be rendered o Engagement of Fas by FasL induces apoptocis of activated T cells
functionally unresponsive, a phenomenon called anergy. o Mutations in Fas gene – autoimmune lymphoproliferative
o Activation of antigen-specific T cells require two signals: syndrome (ALPS)
 Recognition of peptide Ag in asso.w/ self MHC on APC o Immune privileged sites  testis, eye, brain; hidden from immune
 Second signals or costimulatory signals from APCs (from CD28) system because tissues do not communicate w/ blood and lymph
o If antigen is presented to T cells w/o adequate levels of costimulators 
cells become anergic
o T cells recognize self antigens receive inhibitory signal from receptors Mechanism of Autoimmunity: General Principles
homologous to CD28 but serve opposite functions:
 CTLA-4 – binds to B7 molecules; have higher affinity to B7 than  Autoimmunity arises from a combination of the inheritance of susceptibility
CD28; preferentially engaged when B7 levels are low
genes, w/c may contribute to the breakdown of self-tolerance, and
 PD-1 – binds to two ligands that expressed on some cells
o Microbial products elicit innate immune reactions during high levels of B7 environmental triggers, such as infections and tissue damage, w/c promote
and low-affinity receptor CD28 is engaged more the activation of self-reactive lymphocytes
 Thus, affinity of the activating an inhibitory receptors and  Susceptibility genes and environmental triggers induce a number of changes that
the level of B7 may determine the outcome of T cell contribute to the development of autoimmunity:
antigen recognition o Defective tolerance or regulation
o Polymorphisms in CTLA4 genes are asso.w/ some autoimmune
o Abnormal display of self antigens
endocrine diseases in humans
o Anergy also affects mature B cells in peripheral tissues
o Inflammation or an initial innate immune response
 If B cells encounter self antigen in peripheral tissues in the
absence of specific helper T cells  B cells become unable to Role of Susceptibility Genes
respond to antigenic stimulation and may be excluded from
lymphoid follicles and result to their death  Most autoimmune diseases are complex multigenic disorders
 Suppression by regulatory T cells. A population of T cells called regulatory T
cells functions to prevent immune reactions against self antigens Association with HLA Alleles with Disease
o Regulatory T cells – CD4+ cells that express high levels of CD25, the α
chain of the IL-2 receptor, and a transcription factor of the forkhead family,  Among the genes known to be asso.w/ autoimmunity, the greatest
called FOXP3
contribution is that of HLA genes
o IL-2 and FOXP3  both required for development and maintenance of
functional CD4+ regulatory T cells  Most striking associations is between ankylosing spondylitis and HLA-B27
o Mutation in FOXP3 – lead to severe autoimmunity; cause of systemic o Individuals who inherit class I HLA allele have 100-200 fold greater chance
autoimmune disease called IPEX (immune dysregulation, of developing the disease compared to those who do not carry HLA-B27
polyendocrinpathy, enteropathy, X-linked)  Table 6-7
o Mutation in IL-2 – severe multi-organ autoimmunity (IL-2 is essential for  21-hydroxylase deficiency – asso.w/ HLA-BW47
maintenance of regulatory T cells)  Hereditary hemochromatosis – asso.w/ HLA-A
o Polymorphisms in the CD25 gene – asso.w/ multiple sclerosis and
autoimmune diseases
Association of Non-MHC Genes w/ Autoimmune Diseases
o Regulatory T cells suppress immune responses and have inhibitory activity
through secretion of immunosppressive sytokines such as IL-10 and TGF-b
 inhibit lymphocyte activation and effector functions  Some genes are disease specific and seen in multiple disorders
o Regulatory T cells also express CTLA-4  Three genetic associations:
o Regulatory T cells may play a role in the acceptance of the fetus  Table 6-8
 Developing fetus express paternal antigens
 Regulatory T cells prevent immune reactions against fetal  Polymorphisms in a gene PTPN22
antigens inherited from the father
o PTPN22 – encodes tyrosine phosphatase; most frequently implicated in
 Deletion by apoptosis. T cells that recognize self antigens may receive
signals that promote their death by apoptosis autoimmunity
o Two mechanisms of deletion of mature T cells have been postulated: o Defective phosphatase  unable to fully control activity of tyrosine
o (1) If T cells recognize self antigens, they express a pro-apoptotic member kinase  excessive lymphocyte activation
of Bcl family called Bim triggers apoptosis by the mitochondrial pathway o Asso.w/ RA, DM 1, ets
o (2) Another mechanism Fas-Fas ligand system.  Polymorphisms in gene for NOD2

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 o Asso.w/ Crohn disease  inflammatory bowel disease General Features of Autoimmune Diseases
o NOD2 – cytoplasmic sensor of microbes expressed in intestinal epithelial
and other cells 1) Autoimmune diseases tend to be chronic, sometimes with releases and
o Disease-associated variant is ineffective at sensing microbes, including remissions, and the damage is often progressive
commensal bacteria, resulting in entry and chronic responses against these o Immune system contains intrinsic amplification loops that allow small
normally well-tolerated organisms numbers of antigen-specific lymphocytes to accomplish their tasks of
 Polymorphisms in genes encoding the IL-2 receptor (CD25) and IL-7 eradicating infections
receptor α o When response is inappropriately directed against self tissues  exacerbate
o Asso.w/ multiple sclerosis and prolong the injury
o Cytokines may control the maintenance of regulatory T cells o Epitope spreading  immune response against one self antigen causes
tissue damage  release other antigens  activate lymphocytes
2) The clinical and pathologic manifestations of an autoimmune disease are
Role of Infections determined by the nature of the underlying immune response
o Some are caused by autoantibodies whose formation may be associated w/
 Autoimmune reaction may be triggered by infections dysregulated germinal center reactions
 Two mechanisms explain the link between infections and autoimmunity: o Most inflammatory diseases are caused by abnormal and excessive TH1
1) Infections may upregulate the expression of costimulators on and TH17 responses (e.g., psoriasis, MS, IBD)
APCs. If these cells are presenting self antigens, the result may be a  Systemic diseases tend to involve blood vessels and connective tissues  collagen
breakdown of anergy and activation of T cells specific for the self antigens vascular diseases or connective tissue diseases
2) Some microbes may express antigens that have the same amino
acid sequences as self antigens and may activate self-reactive lymphocytes Systemic Lupus Erythematosus (SLE)
 molecular mimicry (e.g., RHD)
 Microbes may induce other abnormalities that promote autoimmune reactions:  SLE is an autoimmune disease involving multiple organs, characterized by a
o E.g., EBV and HIV  cause polyclonal B-cell activation  production of vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in
autoantibodies w/c injury is caused mainly by deposition of immune complexes and
 Infections may protect against some autoimmune diseases binding of autoantibodies to various cells and tissues
o Infections promote low-level IL-2 production (essential for maintaining  Onset may be acute or insidious; chronic; remitting and relapsing; febrile illness
regulatory T cells)  Injury to skin, joints, kidney and serosal membranes is prominent
 Table 6-9
KEY CONCEPTS: Immunologic Tolerance and Autoimmunity
 Tolerance (unresponsiveness) to self antigens is a fundamental property of the Spectrum of Autoantibodies in SLE
immune system, and breakdown of tolerance is the basis of autoimmune diseases
 Central tolerance: immature lymphocytes that recognize self antigens in the central  The hallmark of SLE is the production of autoantibodies
lymphoid organs are killed by apoptosis in the B-cell lineage, some of the self-reactive o Major pathogenic significance
lymphocytes switch to new antigen receptors that are not self-reactive
o Recognize diverse nuclear and cytoplasmic components of cells
 Peripheral tolerance: mature lymphocytes that recognize self antigens in peripheral
o Table 6-10
tissues become functionally inactive (anergic), or are suppressed by regulatory T
lymphocytes, or die by apoptosis.  Antinuclear antibodies (ANAs) – directed against nuclear antigens; 4 categories
 The factors that lead to a failure of self-tolerance and the development of 1. Antibodies to DNA
autoimmunity include 2. Antibodies to histones
o (1) inheritance of susceptibility genes that may disrupt different tolerance 3. Antibodies to nonhistone proteins bound to RNA
pathways, and 4. Antibodies to nucleolar antigens
o (2) infections and tissue injury that may expose self antigens and activate
 Indirect immunofluorescence – most widely used method for detecting ANAs
APCs and lymphocytes
 Autoimmune diseases are usually chronic and progressive, and the type of tissue o Identify antibodies bound to nuclear antigens including DNA, RNA, and
injury is determined by the nature of the dominant immune response proteins (called generic ANAs)
o Pattern of nuclear fluorescence determine type of Ab present; 4 basic
patterns
o Figure 6-24

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Homogeneous or  Reflects antibodies to chromatin, histones, and coccasionally Immunologic Factors
diffuse nuclear double-stranded DNA  Several immunologic aberrations that collectively may result in the persistence and
staining controlled activation of self-reactive lymphocytes
Rim or peripheral  Indicative of antibodies to double-stranded DNA and
staining sometimes to nuclear envelope proteins  Failure of self-tolerance in B cells
Speckled pattern  Presence of uniform of variable-sized speckles o Results from defective elimination of self-reactive B cells in the bone
 Most commonly observed pattern and the least specific marrow or defects in peripheral tolerance mechanisms
 Reflects presence of antibodies to non-DNA nuclear  CD4+ helper T cells specific for nucleosomal antigens escape tolerance and
constituents such as Sm antigen, ribonuclepprotein, SS-A contribute to production of autoantibodies
and SS-B reactive antigens  TLR engagement by nuclear DNA and RNA contained in immune complexes may
Nucleolar pattern  Presence of a few discrete spots of fluorescence w/in the activate B lymphocytes.
nucleus; represents antibodies to RNA  Type 1 interferfons play a role in lymphocyte activation in SLE. High IFN 1 levels
 Reported most often in patients w/ systemic sclerosis is reported in px.
Centromeric  Patients w/ systemic sclerosis contain antibodies specific for  Other cytokines that may play a role in unregulated B-cell activation include the TNF
pattern centromeres family member BAFF, w/c promoted survival of B cells

 Patterns are not absolutely specific; combinations are frequent Environmental Factors
 Exposure to UV light exacerbates the disease
 Antibodies to double-stranded DNA and the so-called Smith (Sm) antigen
o UV radiation may induce apoptosis in cells and may alter the DNA making it
are virtually diagnostic of SLE immunogenic
o UV light modulate immune response (stimulate keratinocytes to produce IL-
Other Antibodies 1 to promote inflammation)
 The gender bias of SLE
 Antiphospholipid antibodies – directed against epitopes of plasma proteins that o Related to hormones and genes on X chromosomes
are revealed when proteins are in complex w/ phospholipids  Drugs such as hydralazine, procainamide, and D-penicillamine can induce an SLE-like
o Proteins include prothrombin, annexin V, B2-glycoprotein I, protein S, response
protein C
 Antibodies against phospholipid-B2-glycoprotein complex also bind to
Mechanism of Tissue Injury
cardiolipin antigen  used in syphilis serology  SLE px have false positive test
 Different autoantibodies are the cause of most of the lesions of SLE
for syphilis
 Also called lupus anticoagulant  these antibodies interfere w/ clotting tests (PTT)  Most of the systemic lesions are caused by immune complexes (type III
 However px w/ antiphospholipid antibodies have hypercoagulable state hypersensitivity)
o DNA-anti-DNA complexes can be detected in the glomeruli and small blood
Etiology and Pathogenesis of SLE vessels
o T cell infiltrates are also seen in kidneys
 Fundamental defect in SLE is a failure of the mechanisms that maintain  Autoantibodies specific for red cells, white cells, and platelets opsonise
self-tolerance these cells and promote their phagocytosis and lysis
o Nuclei of damaged cells react w/ ANAs, lose their chromatin pattern, and
become homogenous, to produce so-called LE bodies or hematoxylin
Genetic Factors bodies
 SLE is a genetically complex disease w/ contributions from MHC and o LE cell – any phagocytic leukocyte that has engulfed the denatured nucleus
multiple non-MHC genes of an injured cells (sometimes found in pericardial or pleural effusions in
px)
 Family members of px have increased risk of SLE.  Antiphospholipid antibody syndrome
 Higher rate in monozygotic twins compared to dizygotic twins o Px w/ antiphospholipid antibodies may develop venous and arterial
 MHC genes regulate production of autoantibodes. Alleles of HLA-DQ locus is linked thromboses (may be asso.w/ recurrent spontaneous miscarriages and focal
to the production of anti-double-stranded DNA, anti-Sm, and anti phospholipid cerebral or ocular ischemia)  secondary antiphospholipid antibody
antibodies syndrome
 Some SLE px have inherited deficiencies of complement components (C2, C 4, C1q). o Some px develop these autoantibodies and the clinical syndrome without
May impair removal of circulating immune complexes and favour tissue deposition. associated SLE  primary antiphospholipid antibody syndrome
Deficiency of C1q results in defective phagocyte clearance of apoptotic cells  Neuropsychiatric manifestations is attributed to antibodies that react w/
 Genome-wide association studies have identified several genetic loci asso.w/ the neurons or receptors for neurotransmitters and cross the blood brain
disease. barrier

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  READ MORPHOLOGY Drug-Induced Lupus Erythematosus
 May develop in px receiving: hydralazine, procainamide, isoniazid, D-
 Table 6-11
penicillamine
 Anti-TNF can also cause the disease
Clinical Features  Arthralgias, fever, serositis
 SLE is a multisystem  Multiple organs are affected (renal and CNS involvement is uncommon)
 Typically the patient is a young women w/ some features:  Antibodies specific for ds-DNA are rare, but there is extremely high frequency of
o Butterfly rash over the face antibodies specific for histones
o Fever  Persons w/ the HLA-DR4 allele are at a greater risk of developing lupus
o Pain but no deformity in joints erythematosus-like syndrome after administration of hydralazine
o Pleuritic chest pain  Those w/ HLA-DR6 are at high risk with procainamide
o Photosensitivity  The disease remits after withdrawal of offending drug
 “Generic” ANAs are found on 100% of patients (but not specific for SLE)
 Other clinical findings:
o Renal involvement (hematuria, red cell casts, proteinuria, classic
KEY CONCEPTS: Systemic Lupus Erythematosus
nephrotic syndrome)
 SLE is a systemic autoimmune disease caused by autoantibodies produced against
o Hematologic derangement (anemia, thrombocytopenia)
numerous self antigens and the formation of immune complexes
o Mental aberrations (psychosis, convulsions)
 The major autoantibodies, and the ones responsible for the formation of circulating
o Coronary artery disease
immune complexes, are directed against nuclear antigens. Other autoantibodies react
 Patients are prone to infection  because of the underlying immune dysfunction and
with erythrocytes, platelets, and various complexes of phospholipids
treatment w/ immunosuppressive drugs
 Disease manifestations include nephritis, skin lesions, and arthritis, (caused by
 During acute flare-ups, increased formation of immune complexes results in
deposition of immune complexes), and hematologic and neurologic abnormalities
complement activation  lead to hypocomplementemia
 The underlying cause of the breakdowns in self-tolerance in SLE is unknowns; it may
o Usually treated w/ steroids or other immunosuppressive drugs
include excess or persistence of nuclear antigens, multiple inherited susceptibility
 Most common causes of death are renal failure and intercurrent infections
genes, and environmental triggers (e.g., UV irradiation  results in cellular apoptosis
 Involvement of skin along w/ multisystem disease is common:
and release of nuclear proteins)
o Chronic discoid lupus erythematosus
o Sub acute cutaneous lupus erythematosus

Chronic Discoid  Disease in w/c the skin manifestation may mimic SLE, Rheumatoid Arthritis
Lupus but systemic manifestations are rare
Erythematosus  Cxd by presence of skin plaques showing varying  Chronic inflammatory disease; affects primarily the joints but may involve
degrees of edema, erythema, scaliness, follicular extraarticular tissues (skin, blood vessels, lungs, heart)
plugging, and skin atrophy surrounded by an  Autoimmune disease
elevated erythematous border
 Face and scalp are usually affected; disseminated lesions
Sjogren Syndrome
occasionally occur
 35% of px show positive test for generic ANAs but
antibodies to double-stranded DNA are rarely present  Sjogren syndrome us a chronic disease cxd by dry eyes (keratoconjunctivitis
 IF studies of skin biopsy show deposition of Ig sicca) and dry mouth (xerostomia) resulting from immunologically mediated
and C3 at the dermoepidermal junction similar to destruction of the lacrimal and salivary glands
SLE  Primary form  isolated disorder, aka sicca syndrome
Subacute  Skin rash tends to be widespread, superficial, and  Secondary form  often asso.w/ another autoimmune disease (e.g., RA, SLE,
Cutaneous Lupus nonscarring polymyositis, scleroderma, vasculitis, mixed CT disease, thyroiditis)
Erythematosus  Most patients have mild systemic symptoms consistent
with SLE
Etiology and Pathogenesis
 There is a strong association with antibodies to the SS-A
antigen and with the HLA-DR3 genotype
 Intermediate between SLE and lupus  Sicca syndrome – decrease in tears and saliva; result of lymphocytic infiltration and
erythematosus localized to skin (hence, the fibrosis of the lacrimal and salivary glands
name)  Infiltrate contain predominantly activated CD4+ helper T cells and some B cells and
plasma cells
 75% of patients have rheumatoid factor (Ab reactive with self IgG) whether or not
coexisting RA is present
o 50-80% of px have ANAs

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  Antibodies directed against two ribonucleoprotein antigens: SS-A (Ro) and SS-B Systemic Sclerosis (Scleroderma)
(La) (Table 6-10)
o Considered as serologic markers of the disease  Systemic sclerosis is characterized by:
 High titers of antibodies to SS-A  early disease onset, longer disease duration, 1. Chronic inflammation thought t be the result of autoimmunity
and extraglandular manifestations (cutaneous vasculitis, nephritis) 2. Widespread damage to small blood vessels
 Px w/ anti SS-A or anti-SS-B antibodies, specific alleles of HLA-DQA1 and HLA- 3. Progressive interstitial and perivascular fibrosis in the skin and multiple
DQB1 are frequent organs
 α-fodrin  candidate autoantigen for the disease  Classified into two major categories:
 READ MORPHOLOGY o Diffuse scleroderma – cxd by widespread skin involvement at onset, with
rapid progression and early visceral involvement
Clinical Features o Limited scleroderma – skin involvement is often confined to fingers,
forearms, and face;
 Occur mostly in women ages 50-60  Some also develop a combination of calcinosis, Raynaud
 Symptoms result from inflammatory destruction of the exocrine glands phenomenon, esophageal dysmotility, sclerodactylyl, and
 Keratoconjunctivitis produces blurring of vision, burning, and itching and thick telangiectasia  CREST syndrome
secretions accumulate in the conjunctival sac
 Xerostomia results in difficulty in swallowing solid foods, a decrease in the ability to Etiology and Pathogenesis
taste, cracks and fissures in the mouth, and dryness of the buccal mucosa
 Parotid gland enlargement, dryness of nasal mucosa, epistaxis, recurrent bronchitis,  The cause is unknown; but likely results from three interrelated processes:
pneumonitis o Autoimmune responses
 Extraglandular disease – seen in 1/3 of px; include synovitis, diffuse pulmonary o Vascular damage
fibrosis, peripheral neuropathy o Collagen deposition
o Common in px w/ antibodies for SS-A
 Mikulicz disease – combination of lacrimal and salivary gland inflammation  Autoimmunity
 Mikulicz syndrome – includes lacrimal and salivary gland enlargement from any o CD4+ T cells respond to unidentified Ag accumulate in the skin and release
cause, including sarcoidosis, lymphoma, and other tumors cytokines that activate inflammatory cells and fibroblasts
 Biopsy of the lip (to examine minor salivary glands) is essential for the o TH2 cells have been isolated from the sin of px
diagnosis of the Sjogren syndrome o TGF-B and IL-13 (produced by T cells)  stimulate genes that encode
 Lymph nodes are hyperplastic collagen and ECM proteins (e.g., fibronectin) in fibroblasts
o Salivary and lacrimal glands have intense lymphocytic response o There is also inappropriate activation of humoral immunity and presence of
 5% of cases develop to marginal zone lymphoma autoantibodies ANAs  provide diagnostic and prognostic information
 Vascular damage
KEY CONCEPTS: Sjogren Syndrome o Microvascular disease is consistently present in the course of systemic
 Inflammatory disease that affects primarily the salivary and lacrimal glands, causing sclerosis and may be the initial lesion  leads to ischemic injury and
dryness of the mouth and eyes scarring
 The disease is believed to be caused by an autoimmune T-cell reaction against an o Intimal proliferation in arteries is evident, capillary dilation w/ leaking and
unknown antigen expressed in these glands, or immune reactions against the antigens
destruction is also common; nailfold capillary loops are distorted and
of a virus that affects the tissues
disappear
o Telltale signs of endothelial activation and injury (increased levels of von
Willebrand factor) and increased platelet activation (increased percentage of
circulating platelet aggregates)
 Fibrosis
o Culmination of multiple abnormalities (e.g., accumulation of alternatively
activated macrophages, actions of fibrogenetic cytokines produced by
infiltrating WBCs, hyperresponsiveness of fibroblasts to cytokines, and
scarring)
 READ MORPHOLOGY

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Clinical Features Mixed Connective Tissue Disease

 3:1 (female to male ratio); more severe in black women  Mixed connective tissue disease – used to describe a disease with clinical features
 Distinctive features  cutaneous changes, skin thickening that are a mixture of the features of SLE, systemic sclerosis, and polymyositis
 Raynaud phenomenon – manifested as episodic vasoconstriction of the arteries and  Characterized serologically by high titers of antibodies to ribonuceoprotein
arterioles of the extremities particle-containing U1 ribonucleoprotein
 Dysphagia – attributable to esophageal fibrosis and its resultant hypomotility  The disease presents w/ synovitis of the fingers, Raynaud phenomenon and mild
o Destruction of esophageal wall leads to atony and dilation at lower end sinusitis, and renal involvement is modest; there is good response to corticosteroids
 Abdominal pain, intestinal obstruction, or malabsorption syndrome w/ weight loss and  Has been suggested that MCTD is not a distinct entitiy but that different px represent
anemia reflect involvement of small intestine subsets of SLE, systemic sclerosis, and polymyositis
 Respiratory difficulties caused by pulmonary fibrosis may result in right-sided cardiac  Serious complications include:
dysfunction, and myocardial fibrosis may cause arrhythmias or cardiac failure o Pulmonary hypertension, interstitial lung disease, renal disease
 Most ominous manifestation is malignant hypertension, w/ subsequent development
of fatal renal failure Polyarteritis Nodosa and Other Vasculitides
 All px have ANAs that react w/ nuclear antigens
o Two ANAs strongly associate w/ systemic sclerosis  Polyarteritis nodosa – cxd by necrotizing inflammation of the walls of blood vessels
o DNA topoisomerase I (anti-Scl 70)  highly specific; present in 10- and showing strong evidence of an immunologic pathogenic mechanisms
20% of px w/ diffuse systemic sclerosis (px are more likely to have  Non-infectious vasculitis – term differentiates the condition from those due to
pulmonary fibrosis and peripheral vascular disease) direct infection of vessel wall
 Anticentromere antibody - found in 20-30% pf px who have CREST syndrome; px
have limited involvement of skin (fingers, forearms, face, and calcification of IgG4-Related Disease
subcutaneous tissue)
 IgG4-related disease (IgG4-RD) – cxd by tissue infiltrates dominated by IgG4
antibody-producing plasma cells and lymphocytes (T cells), storiform fibrosis,
KEY CONCEPTS: Systemic Sclerosis
 Systemic sclerosis or scleroderma is cxd by progressive fibrosis involving the skin, obliterative phlebitis, and increased serum IgG4
gastrointestinal tract, and other tissues  Extra-pancreatic manifestations were identified; also described in every organ system:
 Fibrosis may be the result of activation of fibroblasts by cytokines produced by T cells, the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes,
but what triggers T-cell responses is unknown meninges, aorta, breasts, prostate, thyroid, pericarcium, and skin
 Endothelial injury and microvascular disease are commonly present in the lesions of  Medical conditions part of the IgG4-RD spectrum
systemic sclerosis, perhaps causing chronic ischemia, but the pathogenesis of vascular
o Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal
injury is not known
glands)
o Riedel thyroiditis
Inflammatory Myopathies o Idiopathic retroperitoneal fibrosis
o Autoimmune pancreatitis
 Inflammatory myopathies comprise an uncommon, heterogenous group of o Inflammatory pseudotumors of the orbit, lungs and kidneys
disorders cxd by injury and inflammation of mainly the skeletal muscles  Hallmark of disease  IgG4 production in lesions
(immunologically mediated)
 Three distinct disorders are included:
o Dermatomyositis
o Polymyositis
o Inclusion-body myositis

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REJECTION OF TISSUE TRANSPLANTS mechanism of cellular rejection may be T-cell cytokine production
and inflammation
 Rejection – process that serves as a major barrier to transplantation; the recipient’s  Frequency of T cells that can recognize the foreign antigens in a graft is much higher
immune system recognizes the graft as being foreign and attacks it than the frequency of T cells specific for microbes
o Immune responses to allografts are stronger than responses to pathogens
Mechanism of Recognition and Rejection of Allografts  B lymphocytes also recognize antigens in the graft
o Activation of these B cells typically requires T cell help
 Rejection is a process in which T lymphocytes and antibodies produced against graft
antigens react against and destroy tissue grafts T Cell-Mediated Reactions

Recognition of Graft Alloantigens by T and B Lymphocytes  T cells contribute to both acute and chronic rejection

 The major antigenic differences between a donor and recipient that result in rejection Acute  Aka acute T cell-mediated rejection
of transplants are differences in HLA alleles cellular  Commonly seen w/in the initial months after trhansplantation and is
 Allografts – grafts exchange between individuals of the same species rejection heralded by signs of organ failure
 Xenografts – grafts from one species to another  Direct killing of graft cells by CD8+ CTLs is a major component of
the reaction
 Following transplantation, the recipient’s T cells recognize donor antigens from the
 Inflammatory reaction in the graft triggered by cytokines secreted by
graft by two pathways: activated CD4+ T cells
o Direct pathway of allorecognition  Inflammation leads to increased vascular permeavility and local
o Indirect pathway of allorecognition accumulation of mononuclear cells (lymphocytes and macrophages),
and graft injury is caused by the activated macrophages
Direct  T cells of the recipient recognize allogenic (donor) MHC molecules Chronic  Lymphocytes reacting against alloantigens in the vessel wall secrete
Pathway of on the surface of APCs in the graft rejection cytokines that induce local inflammation and may stimulate the
Allorecognition  Dendritic cells carried in the donor organs are the most important proliferation of vascular endothelial and smooth muscle cells
APCs for initiating the antigraft response
o Express high levess of class I and II MHC molecules
and endowed w/ costimulatory molecules (B7-1 and B7- Antibody-Mediated Reactions
2)
 T cells of host encounter the donor dendrite cells either w/in the  Antibody-mediated reaction can take three forms:
grafted organ or after the dendritic cells migrate to the draining o Hyperacute rejection
lymph nodes
o Acute antibody-mediated rejection
 CD8+ T cells recognize class I MHC molecules and differentiate
into active CTLs o Chronic antibody-mediated rejection
 CD4 T cells recognize allogenic class II molecules and proliferate
and differentiate into TH1 effector cells (also TH17 cells) Hyperacute  Occurs when preformed antidonor antibodies are present in the
 Allogenic MHC molecules (w/ their bound peptide) resemble or rejection circulation of the recipient
mimic self MHC-foreign peptide complexes that are recognized by  Such antibodies may be present in a recipient who has previously
self MHC-restricted T cells rejected a transplant
o Cross reaction of T cells selected to recognize MHC plus  E.g., multiparous women who developed antibodies against paternal
foreign peptides HLA antigens; prior blood transfusions
Indirect  Recipients T lymphocytes recognize MHC antigens of the graft Acute  Caused by antidonor antibodies produced after transplantation
Pathway of donor after they are presented by the recipient’s own APCs antibody-  In recipients not previously sensitized to transplantation antigens,
Allorecognition  Involves uptake and processing of MHC molecules from the mediated exposure to class I and II HLA antigens of the donor graft may
grafted organ by host APCs  similar to the physiologic rejection evoke antibodies
processing and presentation of foreign antigens  These antibodies formed by the recipient may cause injury by
 This pathway generates CD4+ T cells that enter the graft and several mechanisms, including complement-dependent cytotoxicity,
recognize graft antigens being displayed by host APCs inflammation, and antibody dependent cell-mediated cytotoxicity
o Results is a delayed hypersensitivity type of  Initial target of these antibodies in rejection is the graft vasculature
inflammation Chronic  Usually develops insidiously, w/o preceding acute rejection, and
 CD8+ CTLs that may be generated by this pathway cannot kill antibody- primarily affects vascular components
graft cells because these CTLs recognize graft antigens presented mediated  Antibodies are detected in the circulation but are not readily
by hsts APCs and cannot recognize the graft cells directly rejection identified w/in the graft
 When T cells react to a graft by indirect pathway, the principal

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  READ MORPHOLOGY nurture HSCs, thus allowing the transplanted HSCs to engraft two problems that are
unique to HSC transplantation:
Rejection of Kidney Grafts o Graft-versus-host disease (GVHD)
o Immunodeficiency
Methods of Increasing Graft Survival  GVHD occurs when immunologically competent cells or their precursors are
transplanted into immunologically crippled recipients, and the transferred
 In kidney transplants, there is substantial benefit if all the polymorphic HLA alleles are cells recognize alloantigens in the host and attack host tissues
matched (HLA-A, -B & DR) o May occur following transplantation of solid organs rich in lymphoid cells
 However, H:A matching is usually not done for transplants of liver, heart, and lungs (liver) or transfusion of unirradiated blood
because of other considerations (anatomic compatibility, underlying illness,, need to o When immune-compromised recipients receive HSC preperations from
minimize the time of organ storage) allogenic donors, the immunocompetent T cells present in the donor
 Immunosuppressive therapy – practical necessity in all other donor-recipient inoculums recognize the recipient’s HLA antigens as foreign and react
combinations against them
 Immunosuppressive drugs in current use includes: o To minimize GVHD, HSC transplants are done between donor and recipient
o Steroids – reduce inflammation that are HLA-matched using precise DNA sequencing-based methods for
o Mycophenolate – inhibits lymphocyte proliferation molecular typing of HLA alleles.
o Tacrolimus (FK506) – inhibitor of the phosphate calcineurin, w/c is
rewuired for activation of NFAT. NFAT stimulates transcription of cytokine Acute GVHD  Occurs within days to weeks after allogenic bone marrow
genes (IL-2); Tacrolimus inhibits T cell function transplantation
o T cell- & B cell-depleting antibodies; pooled intravenous IgG –  Any organ may be affected; major clinical manifestations result
suppress inflammation from involvement of the immune system and epithelia of
 Plasmapheresis – used in cases of severe antibody-mediated rejection the skin, liver, and intestines
o Skin  generalized rash; may lead to desquamation in
 Another way for reducing antigraft immune responses is to prevent host cells from
severe cases
receiving costimulatory signals from dendritic cells during the initial phase of o Destruction of small bile ducts  jaundice
sensitization o Mucosal ulceration of gut  blood diarrhea
o Accomplished by interrupting the interaction between B7 molecules on Chronic GVHD  May follow the acute syndrome or may occur insidiously
dendritic cells of graft donor w/ CD28 receptors on host T cells (e.g.,  Patients have extensive cutaneous injury w/ destruction of
administration of proteins that bind to B7 costimulators skin appendages and fibrosis of the dermis (changes may
 Polyoma virus – reactivated upon immunosuppression; may infect renal tubules and resemble systemic sclerosis)
 Frequent chronic liver disease manifested by cholestatic
even cause graft failure
jaundice
 Mixed chimerism – recipient lives w/ the injected donor cells  Damage to GIT may cause esophageal strictures
 Immune system is devastated w/ involution of thymus and
Transplantation of Other Solid Organs depletion of lymphocytes in the lymph nodes
 Px experience recurrent and life-theatening infections
 Liver, heart, lungs and pancreas are also transplanted o Others develop autoimmunity
 Rejection reaction against liver transplants is not as vigorous as might be expected
from the degree of HLA disparity
 Because GVHD is mediated by T cells contained in transplanted donor cells, depletion
of donor T cells before transfusion eliminated the disease
Transplantation of Hematopoietic Stem Cells o GVHD is ameliorated, but the recurrence of tumor in leukemic px and
incidence of graft failures and EBV-related B-cell lymphoma increase
 HSCs can be obtained from:  Immunodeficiency is a frequent complication of HSC transplantation
o Bone marrow o May be a result of prior treatment, myeloablative preparation for the graft,
o Peripheral blood after administration of hematopoietic growth a delay in repopulation of the recipient’s immune system, and attack on the
factos host’s immune cells by grafted lymphocytes
o Umbilical cord of newborn infants (rich source) o Cytomegalovirus-induced pneumonitis – fatal complication
 Recipient is irradiated or treated w/ high disease of chemotherapy to destroy the
immune system and to “open up” niches in the microenvirontment of the marrow to

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KEY CONCEPTS: Recognition and Rejection of Transplants (Allografts) Defects in Leukocyte Function
 The rejection response against solid organ transplants is initiated maily by hosts T Inherited defects in  Leukocyte adhesion deficiency type 1 – defect
cells that recognize the foreign HLA antigens of the grafts, either directly (on APCs in leukocyte adhesion in the biosynthesis of the B2 chain shared by the
the graft) or indirectly (after uptake and presentation by host APCs) LFA-1 and Mac-1 integrins
 Types and mechanisms of rejection of solid organ grafts:  Leukocyte adhesion deficiency type 2 – caused
o Hyperacute rejection. Preformed antidonor antibodies bund to graft by the absence of sialyl-Lewis X, the fucose
endothelium immediately after transplantation, leading to thrombosis, containing ligand for E- and P-selectins, as a result
ischemic damage, and rapid graft failure of a defect in fucosyl transferase, the enzyme
o Acute celllar rejection, T cells destroy graft parenchyma (and vessels) by that attaches fucose moieties to protein backbones
cytotoxity and inflammatory reactions  Major clinical problem in both conditions 
o Acute humoral rejection. Antibodies damage graft vasculature recurrent bacterial infections due to
o Chronic rejection – dominated by arteriosclerosis, this type is caused by T- inadequate granulocyte function
cell activation and antibodies. The T-cells may secrete cytokines that induce Inherited defects in  Chediak-Higashi syndrome – autosomal
proliferation of vascular smooth muscles, and the antibodies cause phagolysosome function recessive condition
endothelial injury. The vascular lesions and T-cell reactions cause o Defective fusion of phagosomes and
parenchymal fibrosis lysosomes  result in defective
 Treatment of graft rejection relies on immunosuppressive drugs, w/c inhibit immune phagocytes function and susceptibility to
responses against the graft infections
 Transplantation of HSCs requires careful matching of donor and recipient and is iften  Main leukocytes abnormalities:
complicated by GVHD and immunodeficiency. o Neutropenia
o Defective degranulation
o Delayed microbial killing
 Leukocytes contain giant granules  readily seen
PBS  result from aberrant phagolysosome fusion
IMMUNODEFICIENCY SYNDROMES  Abnormalities in
o Melanocytes  lead to albinism
o Nervous system  nerve defects
 Immunodeficiencies can be divided into:
o Platelets  cause bleeding disorders
o Primary (or congenital) immunodeficiency disorders  genetically  Gene asso.w/ this disorder encodes a large cytosolic
determined protein called LYST  regulate lysosomal trafficking
o Secondary (or acquired) immunodeficiencies  may arise as Inherited defects in  Chronic granulomatous disease – cxd by defects
complications of cancers, infections, malnutrition, or side effects of microbial activity in bacterial killing and render patients susceptible to
immunosuppression, irradiation, or chemotherapy for cancers and other recurrent bacterial infection
diseases  Results from inherited defect in genes encoding
phagocyte oxidase  phagolysosomal enzyme
 Immunodeficiencies are manifested clinically by increased infections, which may be
that generates superoxide
newly acquired or reactivation of latent infections  X-linked defect
o Membrane bound component 
Primary Immunodeficiencies gp91phox)
 Autosomal recessive
 Genetically determined and affect the defense mechanisms of the innate immunity o Cytoplasmic components  p47phox and
(phagocytes, NK cells, or complement) or the humoral and/or cellular arms of p67phox
adaptive immunity (mediated by B and T lymphocytes, respectively)  Controls infection when initial neutrophil defense is
inadequate  granulomas
 Detected between 6 months to 2 years of life
Defects in TLR signaling  Defects in TLR3 (receptor for viral RNA) 
o Telltale signs: susceptibility to recurrent infections recurrent herpes simplex encephalitis
 MyD88 (adaptor protein)  destructive bacterial
Defects in Innate Immunity pneumonias

 Affect leukocyte functions or the complement system  lead to increased vulnerability

to infections

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 Defects Affecting the Complement System Pseudomonas, CMV, varicella
Deficiency of C2  Most common complement protein deficiency  Without HSC death occurs w/in first year of life
 Deficiency of C2 or C4 (early components of classical  Often, SCID defect resides in the T-cell compartment, with a secondary impairment of
pathway)  increased bacterial or viral infections humoral immunity
 Alternative complement pathway is adequate for the  X-linked SCID
control of most infections o Most common form (50%-60%); more common in boys
 C1q deficiency  SLE-like autoimmune disease o Mutation in the common γ-chain (yc) subunit of cytokine receptors
Deficiency of properdin  Alternative pathway; rare o Signal-transducing component of the receptors for: IL2, 4, 7, 9, 11, 15,
and factor D  Recurrent pyogenic infections and 21
Deficiency of C3  Required for both classical and alternative pathway o IL-7  required for the survival and proliferation of lymphoid progenitors
 Results in susceptibility to serious and recurrent (T cell precursors)
pyogenic infections o Defective IL-7 receptor signalling  profound defect in the earliest
 Increased incidence of immune-complex stages of lymphocyte development (T-cell development)
mediated inflammation  caused by Fc receptor- o T-cell are greatly reduced
dependent leukocyte activation o B cells are normal (antibody synthesis is impaired because of lack of T
Deficiency of C5, 6, 7,  Terminal components cell help)
8, 9  Required for the assembly of MAC (membrane attack o IL-15  important for the maturation and proliferation of NK cells 
complex) reduced NK cells
 Increased susceptibility to recurrent neisserial  Autosomal recessive SCID
(gonococcal and meningococcal) infections o Deficiency of the enzyme adenosine deaminase (ADA)  leads to
 Neisseria have thin cell walls  susceptible to lytic accumulation of deoxyadenosine and its derivatives (deoxy-ATP), which
actions of complement are toxic to rapidly dividing immature lymphocytes (T-cell lineage)
 Increased susceptibility to infections o Greater reduction in the number of T cells than B cells
Deficiency of C1  Lead to hereditary angioedema  Other causes of autosomal recessive SCID:
inhibitor  Autosomal dominant disorder o Mutations in recombinase-activating genes (RAG)  prevent somatic
 C1 inhibitor’s targets are proteases (C1r, C1s), factor XII gene rearrangement (essential for assembly of T cell receptor and Ig genes)
(coagulation pathway and kallikrein system)  blocks development of B and T cells
 Unregulated activation of kallikrein  increased o Mutation of Jak3  essential for signal transduction through the common
production of vasoactive bradykinin cytokine receptor y-chain
 Px have episodes of edema affecting skin and mucosal  Thymus is small and devoid of lymphoid cells; lymphoid tissues are hypoplastic
surface such as the larynx and GIT  life-threatening  Marked depletion of T-cell
asphyxia or nausea, vomiting and diarrhea  X-linked  thymus contains lobules of undifferentiated epithelial cells resembling
 Treatment: C1 inhibitor concentrates from plasma fetal thymus
 Autosomal recessive  presence of remnants of Hassall’s corpuscles
 Treatment: HSC transplantation (some may develop T-cell lymphoblastic leukemia)
Defects in Adaptive Immunity

 Often subclassified on the basis of the primary component involved (B cells, T cells, or X-Linked Agammaglobulinemia (Bruton Agammaglobulinemia)
 X-linked agammaglobulinemia is cxd by the failure of B-cell precursors (pro-B
both)
cells and pre-B cells) to develop into mature B cells
 T cells defects almost always lead to impaired antibody synthesis  Caused by mutations in a cytoplasmic tyrosine kinase called Bruton tyrosine
kinase (Btk)  gene that encode it is located on the long arm of the X chromosome
Defects in Lymphocyte Maturation at Xq21.22
 Mutation of Btk  pre-B cell receptor cannot deliver signals and maturation stops
 Genetic deficiencies affecting the maturation of T or B lymphocytes present with  light chains are not produced  complete antigen receptor molecule cannot be
abnormalities in cell-mediated or humoral immunity assembled and transported to the cell membrane
 The disease usually does not become apparent until about 6 months of age, as
Severe Combined Immunodeficiency (SCID) maternal Ig are depleted
 Recurrent bacterial infections of respiratory tract: acute and chronic pharyngitis,
 SCID represents a constellation of genetically distinct syndromes, all having in
sinusitis, otitis media, bronchitis and pneumonia
common defects in both humoral and cell-mediated immune responses
o H.influenzae, S.pneumoniae, S.aureus
 Affected infants present with: prominent thrush (oral candidiasis), extensive
 Susceptibility to certain viral infections: enteroviruses, echovirus, poliovirus,
diaper rash, and failure to thrive
coxsackievirus  infect GIT
 Some px develop morbilliform rash shortly after birth  maternal T cells attack the
o Poliovirus  paralytic poliomyelitis
fetus  cause GVHD
o Echovirus  fatal encephalitis
 Px are extremely susceptible to: Candida albicans, Pneumocystis jiroveci,

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  Susceptibility to Giardia lamblia o This interaction triggers Ig class switching and affinity maturation in B cells,
 Most intracellular viral, fungal and protozoal infections are handled well by the intact T and stimulates the microbicidal functions of macrophages
cell-mediated immunity  X-linked form of the disease (70%)
 The classic form of dx has ff cxc: o Caused by mutations in the gene encoding for CD40L located on Xq26
o B cells are absent or markedly decresed; all classes of  Autosomal recessive pattern
immunoglobulins are depressed. Pre-B cells, which express the B-lineage o Loss-of-function mutations involving either CD40 or the enzyme called
marker CD19 but not membrane Ig, are found in normal numbers in BM activation-induced cytidine deaminase (AID),a DNA-editing enzyme
o Germinal centers of lymph nodes, Peyer’s patches, the appendix, and that is required for Ig class switching and affinity maturation
tonsils are underdeveloped  IgM is normal or elevated
o Plasma cells are absent throughout the body  NO IgA or IgE; extremely low levels of IgG
o T-cell mediated reactions are normal  Number of B and T cell is normal
 Treatment: replacement therapy with immunoglobulins  Patient present with recurrent pyogenic infections because the level of opsonising IgG
antibodies is low
 CD40L mutations  susceptible to pneumonia by intracellular P.jiroveci
DiGeorge Syndrome (Thymic Hypoplasia) o CD40L-mediated macrophage activation, a key reaction of cell-mediated
 DiGeorge syndrome is a T-cell deficiency that results from failure of development of immunity, is also defective
the third and fourth pharyngeal pouches  IgM antibodies may also react with RBC  autoimmune haemolytic anemia,
 The latter give rise to thymus, the parathyroids, some of the C cells of the thyroid and thrombocytopenia, neutropenia
the ultimobrachial body  In older patients, there may be a proliferation of IgM-producing plasma cells that
 Px have: infiltrates the mucosa of the GIT
o Variable loss of T cell-mediated immunity – resulting from hypoplasia
or lack of thymus
o Tetany – resulting from lack of parathyroids Common Variable Immunodeficiency
o Congenital defects of heart and great vessels  This relatively frequent but poorly defined entity encompasses a heterogeneous group
o Appearance of mouth, ears and facies may be abnormal of disorders in which the common feature is hypogammaglobulinemia, generally
 Absence of cell mediated immunity is caused by low numbers of T lymphocytes in the affecting all the antibody classes but sometimes only IgG
blood and lymphoid tissues and poor defense in certain fungal and viral infections  Diagnosis is based on exclusion of other well-defined causes of decreased antibody
 T cell zones of lymphoid organs (paracortical areas of lymph node and PALS in spleen) production
are depleted  Selective IgA deficiency may occur
 Ig levels may be normal or reduced  B cells are not able to differentiate into plasma cells
 Not familial disorder  Both intrinsic B-cell defects and abnormalities in helper T cell-mediated activation of B
 Results from deletion that maps to chromosome 22q11  22p11 deletion syndrome cells may account for the antibody deficiency in this disease
 TBX1  deleted gene  required for the development of the brachial arch and the  Abnormality is in a receptor for cytokine called BAFF that promotes survival and
great vessels differentiation of B cells, or in a molecule called ICOS (inducible costimualtor) that is
homologous to CD28 and is involved in T-cell activation and in interactions between T
and B cells
Other Defects In Lymphocyte Maturation  Clinical manifestations are caused by antibody deficiency and resembles X-linked
 Bare lymphocyte syndrome – caused by mutations in transcription factors that are agammaglobulinemia
required for class II MHC gene expressions o Recurrent sinopulmonary pyogenic infections
 Lack of expression of class II MHC molecules prevents the development of CD4 T cells o 20% gave recurrent herpesvirus infections
 CD4 T cells are involved in cellular immunity and provide help to B cells o Enterovirus infection  meningoencephalitis
 Class II MHC deficiency results in combined immunodeficiency o Gardia lamblia  persistent diarrhea
 Histologically, B-cell areas of the lymphoid tissues (lymphoid follicles of
nodes, spleen and gut) are hyperplastic
 Enlargement of B areas may reflect incomplete activation  B cell proliferate in
Defects in Lymphocyte Activation response to antigen but do not produce antibodies

Hyper-IgM Syndrome
 Affected patients make IgM antibodies but are deficient in their ability to
Isolated IgA Deficiency
produce IgG, IgA, and IgG antibodies
 Isolated IgA deficiency is a common immunodeficiency
 Defect in this disease affects the ability of helper T cells to deliver activating signals to
 Affected individuals have extremely low levels of both serum and secretory IgA
B cells macrophages
o May be familial or acquired (toxoplasmosis or measles)
 *many of the functions of CD4+ helper T cells require the engagement of CD40 on B
 Most individuals are asymptomatic
cells, macrophages and dendritic cells by CD40L (aka CD154) expressed on
o Mucosal defences are weakened, and infections occur in the respiratory,
antigen-activated T cells
gastrointestinal and urogenital tracts

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  Symptomatic patients present with recurrent sinopulmonary infections and Ataxia Telangiectasia
diarrhea  Autosomal recessive disorder characterized by:
 Some individuals may also be deficient in the IgG2 and IgG4 o Abnormal gait (ataxia)
 Transfusion with blood containing normal IgA  px develop severe, even fatal, o Vascular malformations (telangiectases)
anaphylactic reactions, because IgA behaves like foreign antigen o Neurologic deficits
 Defect in IgA deficiency is impaired differentiation of naive B lymphocytes to Ig-A o Increased incidence of tumors
producing plasma cells o Immunodeficiency
 Most prominent humoral immune abnormalities are defective production of isotype
switched antibodies, mainly IgA and IgG2
X-Linked Lymphoproliferative Disease  T cell defects, which are usually pronounced, are associated with thymic hypoplasia
 X-linked proliferative disease is characterized by an inability to eliminate Epstein-  Patients experience upper and lower respiratory tract bacterial infections, multiple
Barr virus (EBV), eventually leading to fulminant infectious mononucleosis and the autoimmune phenomena and increasingly frequent cancers
development of B-cell tumors  Caused by disorder of gene located in chromosome 11 and encodes a protein called
 Disease is due to mutations in the gene encoding an adaptor moelucle called SLAM- ATM (ataxia telangiectasia mutated)  a protein kinase
associated protein (SAP) that binds to a family of cell surface molecules involved in  ATM protein – sensor of DNA damage (double strand breaks) and it activates p53 by
the activation of NK cells and T and B lymphocytes, including signalling lymphocyte phosphorylation which activate cell cycle checkpoints and apoptosis in cells w/
activation molecule (SLAM) damaged DNA
 Defects in SAP lead to attenuated NK and T cell activation  result in increased o Also contribute to the stability of DNA double-strand break complexes
susceptibility to viral infections during V(D)J recombination
 SAP is also required for the development of follicular helper T cells  px are unable  Because of the abnormalities of DNA repair, generation of antigen receptors may
to form germinal centers or produce high affinity antibodies be abnormal
 Commonly manifested by severe EBV infections  infectious mononucleosis  Defective DNA repair may lead to abnormalities in the DNA recombination events that
are involved in antibody isotype switching

Other Defects in Lymphocyte Activation

 Defects in TH1 responses  asso.w/ atypical mycobacterial infections Secondary Immunodeficiencies
 Defective TH17 response  cause of chronic mucocutaneous candidiasis and
bacterial infections of the skin  Job syndrome  Secondary (acquired) immune deficiencies may be encountered in individuals
with cancer, diabetes, and other metabolic diseases, malnutrition, chronic infection,
and in persons receiving chemotherapy or radiation therapy for cancer, or
Immunodeficiencies Associated with Systemic Disease immunosuppressive drugs to prevent graft rejection or to treat autoimmune diseases
 More common than the disorders
Wiskott-Aldrich Syndrome  May be caused by:
 X-linked disease characterized by: o Defective lymphocyte maturation – when the bone marrow is damaged
o Thrombocytopenia by radiation or chemotherapy or involved by tumors, such as leukemias and
o Eczema
metastatic cancers
o Recurrent infection (result to early death)
 Thymus is morphologically normal (early disease), but there is progressice loss of T- o Inadequate IgG synthesis – as in malnutrition
cell zones (paracortical areas) of the lymph nodes (with variable defects in cellular o Lymphocyte depletion – from drugs or severe infections
immunity)  AIDS – most common
 Px do not make antibodies to polysaccharide antigens; response to protein
antigen is poor
 IgM levels in serum are low; levels of IgG are usually normal
 Levels of IgA and IgE are often elevated
 Px are prone to developing B-cell lymphomas
 Caused by the mutations in the gene encoding Wiskott-Aldrich syndrome protein
(WASP), which is located at Xp11.23
 Treatment: HSC transplantation

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Acquired Immunodeficiency Syndrome (AIDS Etiology: The Properties of HIV

 AIDS is caused by the retrovirus HIV and cxd by profound immunosuppression  HIV virus is nontransforming human retrovirus belonging to the lentivirus family
that leads to opportunistic infections, secondary neoplasms and neurologic  Included in this group are feline immunodeficiency virus, simian immunodeficiency
manifestations virus, visna virus of sheep, bovine immunodeficiency virus, and the equine infectious
anemia virus
Epidemiology  Two genetically different by related forms of HIV:
o HIV-1  common in US, Europe, Central Africa
 Five groups of adults at high risk for developing AIDS o HIV-2  West Africa, India
Homosexual or o Constitute the largest group
Bisexual men o >50% of the cases Structures of HIV
Intravenous drug o No previous history of homosexuality
abusers o 20% of cases  HIV virion is spherical and contains electron-densed, cone-shaped core surrounded by
Hemophiliacs o Those who receive large amounts of factor
a lipid envelope derived from the host cell membrane
VIII or factor IX concentrates
o 0.5% of cases  Virus contains:
Recipients of blood o Received transfusions of HIV-infected whole o P24 – major capsid protein
and blood components blood or components (e.g., platelets, plasma) o P7/p9 – nucleocapsid protein
o 1% of patients o Two copies of viral genomic RNA
o Organs from HIV patients can also transmit o Three viral enzymes (protease, reverse transcriptase, integrase)
the virus  P24  most abundant viral antigen; detected by ELISA
Heterosexual contacts o Chiefly intravenous drug abusers  Viral core is surrounded bu a matrix protein called p17 (lies under the virion envelope
o Dominant mode of transmission in Asia and
 Gp120 and gp41  critical for HIV infection of cells
Africa
HIV infection of the o Acquired the transmission of the virus from  HIV-1 RNA genome contains the gag, pol, and env genes, which are typical of
newborn mother to child retroviruses
5% of cases o Risk factors cannot be determined
Pathogenesis of HIV Infection and AIDS
 Three major routes of transmission are sexual contact, parenteral inoculation, and
passage of the virus from infected mothers to their newborns  Two major target of HIV infection are the immune system and the central
Sexual transmission o Dominant mode of infection worldwide nervous system
o 75% of all cases  Profound immune deficiency, primarily affecting cell-mediated immunity, is the
o Viral transmission occurs in two ways: hallmark of AIDS
 Direct inoculation into the blood o Results in subsequent loss of CD4+ T cells
vessels breached by trauma
 Infection of dendritic cells or CD4+ Life Cycle of HIV
cells within the mucosa
o Sexual transmission of HIV is enhanced by
 Consist of infection of cells, integration of the provirus into the host cell genome,
existing sexually transmitted disease
Parenteral o Occurred in three groups of individuals: activation of viral replication, and production and release of infectious virus
transmission  Intravenous drug abusers (largest
group) Infection of Cells by HIV
 Hemophiliacs
 Recipients of blood transfusion  HIV infect cells by using the CD4 molecule as receptor and various chemokine
Mother-to-infant o Major cause of pediatric AIDS receptors as coreceptors
transfusion o Infected mothers can transmit the infection to  HIV gp120 must also bind to other cell surface molecules (coreceptors) for entry into
their offspring by three routes: the cell
 In utero by trasnplacental spread
o CCR5 and CXCR4 serve this role
 During delivery through an infected
birth canal o R5 strains use CCR5  preferentially infects monocyte and macrophage
 After birth by ingestion of breast (M tropic)
milk o X4 strains use CXCR4  infect T cells (T tropic)
o R5X4 – dual tropic

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  The HIV envelope contains two glycoproteins, surface gp120 noncovalently HIV Infection of Non-T cells
attached to a transmembrane protein, gp41
 The initial step in infection is the binding of the gp120 envelope  Infection of macrophages and dendritic cells is also important in the pathogenesis of
glycoprotein to CD4 molecules, which leads to a conformational change that HIV infection
results in the formation of a new recognition site in gp120 for the receptors CCR5 or  Lungs and brain  10% to 50% of macrophages are infected
CXCR4  Several aspects of HIV infection of macrophages should be emphasized:
o Binding of coreceptors induces conformational changes in gp41 that result o HIV can infect nondividing macrophages  through viral vpr gene 
in the exposure of a hydrophobic region called the fusion peptide at the tip allows nuclear targeting of the HIV preintegration complex through the
of gp41 nuclear pore
o This peptide inserts into the cell membrane of the target cells, leading to o Macrophage allow viral replication and are resistant to the cytopahtic
fusion of the virus with the host cell effects of HIV; thus macrophage serve as reservoir of infection
o Macrophages act as portals of infection
Viral Replication o Even uninfected monocytes are reported to have functional defects
 Mucosal dendritic cells are infected by the virus and may transport it to the regional
 Once internalized, the RNA genome of the virus undergoes reverse transcription, lymph nodes, where the virus is transmitted to CD4+ T cells
leading to the synthesis of double-stranded complementary DNA (cDNA; proviral  Follicular dendtritic cells in the germinal centers of lymph nodes are potentially
DNA) reservoirs of HIV
 In quiescent T cells, HIV cDNA is in a linear episomal form
 In dividing T cells, cDNA circularizes, enters the nucleus, and is then integrated B Cell Function in the HIV Infection
into the host genome
 After integration, provirus may be silent for months or years  latent infection  Polyclonal activation of B cells  lead to germinal center B-cell hyperplasia, bone
 HIV infects memory and activated T cell but is inefficient at productively infecting marrow plasmacytosis, hypergammaglobulinemia, and formation of circulating
naive (unactivated) T cells immune complexes
o APOBEC3G  cytidine deaminase; inhibit further DNA replication by  May result from:
mechanisms that are not fully defined o Reactivation or reinfection from CMV and EBV (polyclonal activators)
 Completion of the viral life cycle in latently infected cells occurs only after cell o Gp41 can promote B-cell growth and differentiation
activation, and in the case of most CD4+ T cells virus activation results in cell lysis o HIV-infected macrophages produce increase amounts of IL-6  stimulates
proliferation of B cells
Mechanisms of T-Cell Depletion in HIV Infection
Pathogenesis of CNS Involvement
 Loss of CD4+ T cells is mainly because of infection of the cells and the direct
cytopathic effects of the replicating virus  Macrophage and microglia  predominant cell types in CNS that are infected with
 100 billion new viral particles are produced every day, and 1-2 billion CD4+ T cells die HIV
each day  HIV is carried into the brain by infected monocytes
o As the disease progresses, renewal of CD4+ T cells cannot keep up with o HIV isolated from the brain are M-tropic
their loss
 In addition to direct killing of cells by the virus, other mechanisms may contribute to Natural History of HIV Infection
the loss of T cells. These include:
o Activation-induced cell death  Virus enters through the mucosal epithelia
o Pyroptosis  Sequential pathologic and clinical manifestations can be divided into several phases:
o Destruction of lymphoid tissues 1. Acute retroviral syndrome
o Loss of immature precursors of CD4+ T cells 2. Middle, chronic phase (asymptomatic)
o Fusion of infected and uninfected cells with formation of syncytia 3. Clinical AIDS
(giant cells)
o CD4+ T cells reduction (hallmark of AIDS)  destruction and
qualitative defects
 CD4+ T cells  “master regulator”

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Primary Infection, Virus Dissemination, and the Acute Retroviral Syndrome Clinical Features of AIDS
 Acute (early) infection is cxd by infection of memory CD4+ T cells (w/c
express CCR5) in mucosal lymphoid tissues, and death of many cells  In the US, the typical adult patient with AIDS presents with fever, weight loss,
 Mucosal infection is followed by dissemination of the virus and the development of diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic
host immune responses disease, and in many cases, secondary neoplasms
 Dendritic cells capture the virus and present it to T cells in lymphoid tissue  within
days, viral replication is detected  replication leads to viremia (high # of HIV
Opportunistic Infections
particles in blood)
 Virus disseminates throughout the body and infects helper T cells, macrophages and
dendritic cells in peripheral lymphoid tissue  Account for the majority of deaths in untreated px with AIDS
 3-7 weeks  resposes are evidenced by seroconversion and by development of  Most are reactivation of latent infections
CD8+ cytotoxic T cells  Summary of selected opportunistic infections:
 12 weeks  drop of viremia to low but detectable level o Pneumonia by Pneumocystis jiroveci (15-30%)
 Acute retroviral syndrome  clinical presentation of the initial spread of the o Candida, CMV, atypical and typical mycobacteria, Cryptococcus
n=virus and the host reponse
neoformans, Toxoplasma gondii, Cryptosporidium, HSV, Histoplasma
o Self-limited acute illness with non specific symptoms, ncluding sore throat,
myalgias, fever, weight loss, and fatigue, resembling flu-like syndrome capsulatum
o Others: rash, cervical adenopathy, diarrhea, vomiting o Cadidiasis (most common fungal infection) – sign of immunologic
 The extent of viremia, measured as HIV-1 RNA levels, in the blood is a useful decompensation; transition to AIDS
surrogate marker of HIV disease progression and is of clinical value in the o Cytomegalovirus – may cause disseminated dx; 25% of px; cytomegalo
management of people with HIV infection retinitis
 Viral set point – steady state viremia; predictor of the rate of decline of CD4+ T o Atypical mycobacterium (Mycobacterium avium-intracellulare)
cells or progression of HIV disease
o Cryptococcosis (10%) – meningitis
o Toxoplasma gondii – encephalitis and responsible for 50% of all mass lesion
in the CNS
Chronic Infection: Phase of Clinical Latency
 In this phase of the disease, lymph nodes and the spleen are sites of o JC virus – also cause CNS infection; human papovavirus; progressice
continuous HIV replication and cell destruction multifocal leukoencephalopathy
 Few or no clinical manifestation  clinical latency period o HSV infection – mucocutaneous ulcerations
 The number of circulating CD4+ cells steadily declines o Cryptosporidium, Isospora belli, microspodia – persistent diarrhea
o Virus destroys 1 x 109 – 2 x 10 9 CD4+ T cells everyday o Salmonella, shigella and M.avium may also cause diarrhea
o HIV RNA levels increase
o Coreceptor switching (CCR5 to CXCR4 or both)  asso.w/ more rapid Tumors
decline in CD4+ T cells
 Px are either asymptomatic or develop minor opportunistic infections (oral candidiasis
or thrush, vaginal candidiasis, herpes zoster, MTB)  Kaposi Sarcoma (KS), B cell lymphoma, cervical cancer in womena and anal cancer in
 Autoimmune thrombocytopenia may also be noted men
 Cause by oncogenic DNA viruses
o Kaposi sarcoma herpes virus – KS
AIDS o EBV – B-cell lymphoma
 The final phase is progression to AIDS, cxd by a breakdown of host defense, o HPV – cervical and anal carcinoma
a dramatic increase in plasma virus, and severe, life threatening clinical
disease Kaposi Sarcoma
 Typically px present with long lasting fever (>1 month, fatigue, weight loss, and
diarrhea  Rare vascular tumor in US; most common neoplasm in ox with AIDS
 Px then develop with serious opportunistic infections, secondary neoplasms, or clinical
 Lesions of KS are cxd by the proliferation of spindle-shaped cells that express markers
neurologic disease (AIDS indicator disease)  px is said to have developed AIDS
 Rapid progressors – the middle chronic phase is telescoped to 2-3 years after of both endothelial cells (vascular or lymphatic) and smooth muscle cells
primary infection o Profusion of slit-like vascular spaces
 Long-term non progressors – untreated HIV-1 individuals who remain o Not a malignant tumor
asymptomatic for 10 years or more, with stable CD4+ T cell count and low levels of o Spindle cells in KS are polyclonal or oligoclonal
plasma viremia (<500 viral RNA)  Caused by KSHV or human herpes virus 8 (HHV8)
 Elite controllers – 1%; have undetectable plasma virus (<50-74 RNA copies/mL)

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  KSHV infection is also linked to rare B-cell lymphomas in AIDS patients called primary Properties of Amyloid Proteins
effusion lymphoma and multicentric Castleman disease, a B cell lymphoproliferative
disorder  EM: amyloids consist of continuous, nonbranching fibrils with a diameter of approx
7.5-10nm
Lymphomas  X ray crystallography and infrared spectroscopy: cross beta pleated sheet
conformation
 Two mechanisms underlie the increased risk of B-cell tumors in HIV infected
individuals Chemical Nature of Amyloid
o Unchecked proliferation of B cells infected with oncogenic herpesviruses in
the setting of profound T cell depletion (AIDS)  95% fibril proteins; 5% P component and glycoproteins
o Germinal center B-cell hyperplasia in the setting of early HIV infection  Three most common forms of amyloids:

Central Nervous System Disease AL (amyloid light o Made up of complete immunoglobulin light chains, the amino
chain) protein terminal fragments of light chains, or both
 Self-limited meningoencephalitis o Composed of kappa light chains
 Aseptic meningitis o Deposition is asso.w/ certain forms of plasma cell tumors
AA (amyloid o Type of mayloid fibril protein is derived from a unique non-
 Vacuolar myelopathy
associated) protein Ig protein made by the liver
 Peripheral neuropathies o Fibrils are derived by proteolysis from a larger precursor in
 Progressive encephalopathy designated clinically as HIV-associated the serum called SAA from liver bound to HDL
neurocognitive disorder (most common) o Secondary amyloidosis  associated with chronic
inflammation
Effects of Antiretroviral Therapy on the Clinical Course of HIV Infection Β-amyloid protein o Constitutes the core of cerebral plaques found in the
(Aβ) Alzheimer disease as well as the amyloid deposited in walls
 Highly active antiretroviral therapy (HAART) or combination therapy of cerebral blood vessels in px
 When a combination of at least three effective drugs is used in a motivated, compliant o Derived by proteolysis from a larger transmembrane
glycoprotein, called amyloid precursor protein (APP)
patient, HIV replication is reduced to below the level of detection (<50 copies RNA
/mL) and remains there indefinitely (as long as the patient adheres to therapy)
 Immune reconstitution inflammatory syndrome – paradoxical clinical  Among these rarer cause of amyloidosis, the proteins most often involved are the ff:
deterioration during the period of recovery of the immune system
o Occurs despite increasing CD4+ T cell counts and decreasing viral load Transthyretin o Normal serum protein that binds and transports thyroxine
 Read morphology in book (TTR) and retinol
o Familial amyloid neuropathies  mutant TTR
AMYLOIDOSIS o Senile systemic amyloidosis  normal TTR
β2-microglobulin o Component of MHC class I molecules and a normal serum
 Amyloidosis is a condition asso.w/ a number of inherited and inflammatory disorders protein
in which extracellular deposits of fibrillar proteins are responsible for tissue damage o In px in long term dialysis
Prion proteins o Prion disease in CNS
and functional compromise
o Aggregate in the extracellular space and acquire structural
 Abnormal fibrils are produced by the aggregation of misfolded proteins (soluble in
and staining cxc of amyloid protein
their normal folded configuration) Others o Serum amyloid P component  contribute to amyloid
o Proteoglycans and glycosaminoglycans deposition by stabilizing the fibrils and decreasing their
o Heparan and dermatan sulfate clearance
o Plasma proteins o Proteoglycans
o Serum amyloid P component (SAP)s o Highly sulphated glycosaminoglycans
 Light microscope; H&E stain  amyloid appears as an amorphous, eosinophilic,
hyaline, extracellular substance
 With progressive accumulation, it encroaches on and produces pressure atrophy of
adjacent cells
 Congo red stain  pink or red color to tissue deposits
 Polarizing microscopy  green birefringence

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Pathogenesis and Calcification of Amyloidosis
Hemodialysis-Associated Amyloidosis
 Amyloidosis results from abnormal folding of proteins, which become insoluble,  Px in long-term dialysis
 Deposition of β2 microglobulin
aggregate, and deposits as fibrils in extracellular tissues
 Patients sometimes presented with carpal tunnel syndrome
 Normally, misfolded proteins are degraded intracellularly in proteasomes or
extracellularly by macrophages
 The proteins that form amyloid fall into two general categories: Localized Amyloidosis
o Normal proteins that have an inherent tendency to fold improperly,  Limited to single organ or tissue without involvement of any other site in the body
associate and form fibrils when they are produced in increased amounts  Deposits may produce nodular masses or evident only on microscopic exam
o Mutant proteins that are prone to misfolding and subsequent aggregation  Nodular deposits most often encountered in: lung, larynx, skin, urinary bladder,
 Systemic (generalized) – involving several organ systems tongue and region about the eye
o Primary amyloidosis – associated with plasma cell disorder  There are infiltrates of lymphocytes and plasma cells in the periphery of masses
 Consist of AL protein  plasma cell derived amyloid
o Secondary amyloidosis – occurs as a complication of an underlying
chronic inflammatory or tissue-destructive process
 Localized – when deposits are limited to a single organ, such as the heart
Endocrine Amyloid
 Found in some endocrine tumors: medullary carcinoma of the thyroid gland, islet
Primary Amyloidosis: Plasma Cell Disroders Associated with Amyloidosis tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the
 Systemic in distribution; AL type stomach, and in the islet of langerhans in individuals with type 2 DM
 Most common form in US  In medullary carcinomas of the thyroid, the presence of amyloid is an essential
 Caused by a clonal proliferation of plasma cells that synthesize an Ig that is prone to diagnostic feature
form amyloid due to its intrinsic physiochemical properties
 5-15% occurs in px with multiple myeloma  plasma cell tumor; cxd by multiple
osteolytic lesions throughout the skeletal system
Amyloid of Aging
o Monoclonal gammopathy (single Ig)  produce M (myeloma) protein spike
 Senile systemic amyloidosis – systemic deposition of amyloid in elderly ppx (70s-
o serum electrophoresis
80s)
o Bence-Jones protein  unpaired kappa or lambda light chains; excreted
o Previously called senile cardiac amyloidosis
and concentrated in urine
o Px present with a restrictive cardiomyopathy and arrhythmias
o Monoclonal gammopathy  monoclonal proliferation of plasma cells;
o Amyloid is derived from normal TTR
production of abnormal protein

 READ MORPHOLOGY in book

Reactive Systemic Amyloidosis
 Composed AA protein ; Previously referred to as secondary amyloidosis 
Clinical Features
secondary to an associated inflammatory condition
 Some underlying conditions: tuberculosis, bronchiectasis, chronic osteomyelitis
 Clinical manifestations at first are often entirely nonspecific: weakness, weightloss,
 Complicates rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease
(Crohn disease and ulcerative colitis) light headedness or syncope
 Heroin who inject drug subcutaneously also have high occurrence rate of generalized  Renal involvement – gives rise to proteinuria and cause nephrotic syndrome
AA amyloidosis  “skin popping” o Progressive obliteration of glomeruli  renal failure and uremia
 May also occur in association with solid tumors, the most common being renal cell o Renal failure is common cause of death
carcinoma and Hodgkin lymphoma  Cardiac amyloidosis – may present as insidious CHF
 IL-1, IL-6  increases synthesis of SAA by liver cells
o Conduction disturbances and arrhythmias
o Produce restrictive pattern of cardiomyopathy and masquerades as chronic
constrictive pericarditis
Heredofamilial Amyloidosis
 Gastrointestinal amyloidosis – may be entirely asymptomatic
 Familial Mediterranean fever  autosomal recessive; autoinflammatory syndrome
asso.w/ excessive production of the cytokine IL-1 o Amyloidosis of the tongue – enlargement and inelasticity to hamper speech
o Cxd clinically by attacks of fever accompanied by inflammation of serosal and swallowing
surface (peritoneum, pleura, synovial membrane) o Deposition in stomach and intestine – malabsorption, diarrhea, and
o Pyrin – gene encoded disturbances in digestion
o Armenian, Sephardic Jewish, Arabic origins  Vascular amyloidosis – causes vascular fragility that may lead to bleeding,
o Asso.w/ widespread amyloidosis; made up of AA proteins
sometimes massive

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 AL amyloid binds and inactivates factor X  bleeding disorder
 The diagnosis of amyloidosis depends on the histologic demonstration of amyloid
deposits in tissues
o Kidney – most common sites biopsied
o Rectal or gingival tissues – if px is suspected with systemic amyloidosis
o Congo red – specific but low sensitivity
o In AL amyloidosis – serum and urine protein electrophoresis and
immunoelectrophoresis should be performed
o Scintigraphy w/ radiolabeled seum amyloid P  specific and rapid test;
measure of the extent of amyloidosis and can be used to follow patients
undergoing treatment

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