PCRL 627: Clinical Microbiology and

Immunology 2016
Lectures 2 & 3: Autoimmunity 1 & 2
Autoimmunity 1: 8/22 10:30am
Autoimmunity 2: 8/22 11:30am

Rebecca Shilling, MD
Div. of Pulm., Dept. of Medicine and Dept. of Micro. and Immuno.
Phone: 312-355-4597
Email: shilling@uic.edu

Reading assignment: Janeways Immunobiology 8th edition

Chapter-15; Pages 611-652
Chapter-16; Pages 669-683

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 Objectives: Autoimmunity 1
Describe how the immune system develops
and is regulated to provide tolerance to self

Describe how tolerance can be broken and

autoimmunity can develop

Recognize systemic and organ specific

autoimmune diseases

Understand mechanisms of autoimmune

disease pathogenesis
2
 Outline for Autoimmunity 1
I. Introductory case
II. Overview
III. Making and Breaking of Tolerance
IV. Systemic vs. Organ specific
V. Disease specific mechanisms I
VI. Questions

3
 Case #1 - RJ
18 month old: presents with sluggishness
and dry skin diagnosed with
hypothyroidism

Family History: older sister autoimmunity

Age 16: Addisons disease, autoantibodies

against adrenal gland

Age 18 autoimmune thrombocytopenic

purpura
4
 APECED (autoimmune polyendocrinopathy
candidiasisectodermal dystrophy)

Genetics: autosomal recessive

Clinical pathologies:
Autoantibodies to endocrine glands, skin and liver
antigens, platelets
Ectodermal abnormalities nails, teeth, skin
Susceptible to candidiasis

Gene: AIRE, transcriptional regulator affects

expression of autoantigens in thymus during
development
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 Autoimmunity Overview

Diverse,
Large Autoimmune
Trigger Repertoire Disease
of T and B
cells
-Genetic or
environmental Protect from Immune response
pathogens without infection

Potential for
autoreactivity

6
 Review 1: Adaptive Immunity can be defined by:

A. T and B lymphocytes
B. Cells that have rearranged their genes for
antigen recognition receptors
C. Specificity and memory
D. Diverse repertoire of cells that can recognize
many pathogens
E. All of the above.

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 Review 1: Adaptive Immunity can be defined by:

A. T and B lymphocytes
B. Cells that have rearranged their antigen
recognition receptors
C. Specificity and memory
D. Diverse repertoire of cells that can recognize
many antigens
E. All of the above.

8
Common autoimmune diseases

9
 Development of self-tolerance

Immune system functions to discriminate

self from nonself
No particular molecular signature
Surrogates:
Timing thymus and bone marrow
Concentration high and constant correlates with
self vs. sudden increase non-self
Innate immunity absence of costimulation
No perfect system
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 Why self-reactivity?

Evolutionary advantage to
diversity of T and B cell repertoire
Autoimmune disease usually late-
onset (so you might not weed it
out via evolution since might
manifest after menopause)
Counterbalance: mechanisms 11
12
 Central deletion is first checkpoint of
self-tolerance
T cells are selected in the thymus
B cells are selected in the bone marrow

When cells encounter self-antigens- clonal

deletion occurs. This is known as negative
selection and is key to central tolerance.

When cells are positively selected it is called

clonal selection and these cells populate the
peripheral lymphoid organs.

13
Autoimmune regulator gene, AIRE, promotes the expression
of some tissue specific antigens in medullary thymic
epithelial cells (mTEC) causing deletion of self reactive T
cells

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After development there are multiple mechanisms to
control self-reactivity

Ignorance-
those self
reactive t
cells never
get to the
target
tissue
Anergy
yknow

Walker and Abbas, Nature Reviews Immunology, 2002 15

T cell-intrinsic mechanisms of peripheral tolerance

Walker and Abbas, 2002 16

Damage to an immunologically privileged site can induce
autoimmune response: sympathetic ophthalmia

If uninjured
eye is really
immune
privileged why
can the T cells
attack?
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 Case #2 I.P.
Full term infant boy presents with eczema
shortly after birth
4 months develops watery diarrhea
biopsy finds plasma cells and T cells in small
bowel
6 months develops type 1 diabetes high
levels of autoantibodies to islet antigens
Family Hx: Brother had died at an early age of
similar disease; healthy sister
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 Immune Dysregulation, Polyendocrinopathy,
Enteropathy X-linked Disease (IPEX) Defective
FOXP3 gene

X
X

IAVIReport, Vol. 11. No. 4, 2007 iavireport.org 20

 Regulatory T cells

CD4+ CD25+ (which receptor for IL-2) T helper cells

Suppress other T cells and maintain tolerance

Affect antigen presenting cells or other lymphocytes

Express Foxp3 transcription factor, controls

differentiation and protein expression

Mechanisms cytokines (IL-10, TGF-), contact-

dependent through receptors, cell killing

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 Alternative regulatory cells
Mucosal immune system/Induced
Th3 IL-4, IL-10, TGF
Tr1 - IL-10, TGF
NK cells
NKT cells
CD8 cytotoxic or cytokine
Regulatory B cells IL-10
Tolerogenic dendritic cells
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 Summary 1: Development of Tolerance

Central tolerance: first checkpoint

Immature lymphocytes strongly reactive eliminated
Thymus deletion; bone marrow editing
AIRE (thymus) (important for normal development)
Generation of T regulatory cells (Foxp3)
Does not eliminate all self reactive lymphocytes
Peripheral tolerance: outside bone marrow/thymus to make sure
you have self tolerance
High concentrations of antigen anergize or delete
Absence of costimulation
Counter-regulatory mechanisms of T regulatory cells and other
suppressor cells

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 Objectives: Autoimmunity 1
Describe how the immune system develops
and is regulated to provide tolerance to self

Describe how tolerance can be broken and

autoimmunity can develop

Recognize systemic and organ specific

autoimmune diseases.

Understand mechanisms of autoimmune

disease pathogenesis
24
Breakdown

Disease

25
Breaking of tolerance: lymphocytes that weakly recognize self
can get activated under certain conditions

1. Costimulation or signal 2 provided - Bystander activation

during infection
2. Change in antigen composition- Damage to host tissue and
release of large amounts of unmethylated DNA looks like
microbial DNA
3. Change in availability of antigen- After myocardial infarction
intracellular Ag released
4. Autoantigen form changes- Antibody and antigen form
complexes after infection or vaccination
5. B cells in germinal centers- Somatic hypermutation leads to
autoreactive B cells

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Self-antigens, such as DNA, also recognized by Toll Like Receptors
can activate autoreactive B cells by providing co-stimulation

Result is anti-DNA antibodies which can be found in lupus

 Objectives: Autoimmunity 1
Describe how the immune system develops
and is regulated to provide tolerance to self

Describe how tolerance can be broken and

autoimmunity can develop

Recognize systemic and organ specific

autoimmune diseases

Understand mechanisms of autoimmune

disease pathogenesis
28
Some common autoimmune diseases classified according to
organ- specific or systemic nature
 Mechanisms of Pathogenesis
Myasthenia Gravis antibodies to acetylcholine receptor
at neuromuscular junction

Type 1 Diabetes multiple mechanisms target pancreatic

beta cells

IBD Crohns and Ulcerative Colitis, T cells recognize

antigens-derived from commensal microbiota
autoantigen?

SLE antibodies against DNA, chromatin, antigens are

ubiquitous, multiple organs can be affected

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Identification of autoAbs that can transfer disease in MG patients
Autoimmunity can be a combination of
altered pathogenicity and regulation

Anderson and Bluestone, Annual Review of Immunology 32

Vol. 23: 447-485 (April 2005)
Some autoimmune diseases that can be transferred across the
placenta by pathogenic IgG autoantibodies
 Transplacental antibody transfer of autoimmune
disease from mother to fetus supports
pathogenicity of autoantibodies in some diseases,
such as Graves disease

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T and B cells are involved in autoimmune diseases
even when one response dominates

35
 Chronic Inflammation
Mechanisms Lead to
Perpetuation of Autoimmune
Disease

36
Inflammation leads to release of autoantigen from
damaged tissues, promote further activation of
autoreactive B cells

37
 Summary II
Discrimination between self and nonself is imperfect;
balance of no autoimmune disease and immune
competence
Inherent are lymphocytes with self-reactivity
Multiple mechanisms to keep self-reactive lymphocytes
in check
Autoimmune disease occurs with activation of previously
quiescent self-reactive lymphocytes
Persistent activation of self-reactive lymphocytes leads
to ongoing inflammation and tissue damage;
mechanisms identical to pathogen-mediated immunity
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 Objectives: Autoimmunity 1
Describe how the immune system develops
and is regulated to provide tolerance to self

Describe how tolerance can be broken and

autoimmunity can develop

Recognize systemic and organ specific

autoimmune diseases

Understand mechanisms of autoimmune

disease pathogenesis
39
 Question #1
All of the following contribute to self-tolerance EXCEPT:
A.Thymus eliminates self-reactive T cells during
development
B.Bone marrow through elimination of autoreactive B
cells
C.T regulatory cells
D.Neutrophils recognize self-reactive T cells and kill them
E.Absence of costimulation when a self-reactive T cell
encounters self antigen
F.Apoptosis of activated T cells as an immune response
wanes
40
 Question #1
All of the following contribute to self-tolerance EXCEPT:
A.Thymus eliminates self-reactive T cells during
development
B.Bone marrow through elimination of autoreactive B
cells
C.T regulatory cells
D.Neutrophils recognize self-reactive T cells and kill them
E.Absence of costimulation when a self-reactive T cell
encounters self antigen
F.Apoptosis of activated T cells as an immune response
wanes
41
 Question #2:
Thymus-derived natural T regulatory cells are
characterized by all of the following EXCEPT:
A.Expression of the transcription factor Foxp3

B.Ability to suppress proliferation of other lymphocytes

via cell-contact dependent mechanisms

C.Suppress proliferation of other lymphocytes through

secretion of cytokines like IL-10, TGF

D.Secretion of inflammatory cytokines

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 Question #2:
Thymus-derived natural T regulatory cells are
characterized by all of the following EXCEPT:
A.Expression of the transcription factor Foxp3

B.Ability to suppress proliferation of other lymphocytes

via cell-contact dependent mechanisms

C.Suppress proliferation of other lymphocytes through

secretion of cytokines like IL-10, TGF

D.Secretion of inflammatory cytokines

43
 Question #3:
Tolerance may be broken and lead to autoimmunity:

A.Lack of sleep

B.Reading Janeway

C.Taking USMLE Step 1

D.Release of large amount of antigens normally

intracellular into the blood activates an immune response
i.e. after myocardial infarction

44
 Question #3:
Tolerance may be broken and lead to autoimmunity:

A.Lack of sleep

B.Reading Janeway

C.Taking USMLE Step 1

D.Release of large amount of antigens normally

intracellular into the blood activates an immune response
i.e. after myocardial infarction

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