HOLISTIC SCIENCE JOURNAL VOLUME 1 ISSUE 4 Signatures of Health

BIOMARKERS, SELF-ANTIGENS &

THE IMMUNOLOGICAL HOMUNCULUS

Irun R. Cohen

Authors note
[Since 2007 when this article first appeared], we are still working on the development of the normal
autoantibody repertoire and cannot say at this time that we have uncovered a specific signature indicative of
health.

Abstract
The notion of the immunological homunculus arose from the observations [1] that the healthy adaptive
immune system is inclined to respond (T cell reactivity and auto antibodies) to particular sets of body
molecules (self-antigens) and [2] that autoimmune diseases are characterized by sets of autoimmune reactivity
to some of the very same self-antigens recognized by healthy subjects - with an obvious difference in outcome.
I termed this natural autoimmune structuring of the immune system, the immunological homunculus - the
immune system’s representation of the body. What might be the selective advantage of an immune system
expressing patterns of built-in autoimmunity to particular sets of self-molecules? To better characterize the
homunculus, we have used informatic tools to study patterns of antibodies to many hundreds of self-
molecules arrayed on glass slides - an antigen chip of our design. Results using the antigen chip suggest that
the particular self-reactivities comprising the homunculus could serve as a set of biomarkers that help the
immune system initiate and regulate the inflammatory processes that maintain the body.

1. Biomarkers
A biomarker is a substance or measurement that indicates important facts about a living organism, usually a
patient. The Wikipedia defines a biomarker to be “a substance used as an indicator of a biological state ..
More specifically, a ‘biomarker’ indicates a change in expression or state of a protein that correlates with the
risk or progression of a disease, or with the susceptibility of the disease to a given treatment. . . it can be used
… to tailor treatments for the disease in an individual . [and] …may be used as a surrogate for a natural
endpoint.’’ (http://en.wikipedia.org/wiki/Biomarker).

In other words, biomarkers can provide the physician with useful information about:
1. biologic state of an individual;
2. disease risk;
3. disease diagnosis;
4. disease progression;
5. treatments of choice;
6. monitoring responses to treatment; and
7. endpoints for assessing treatment efficacy.

Biomarkers thus allow the physician a preventive or therapeutic jump on the individual’s disease process. How
can a biomarker provide so much information?

Biomarkers serve because they make life simple. Complexity characterizes biology: the healthy state of a cell,
organ, or organism emerges from dazzling amounts of information involving molecules, processes, cells, and
organ systems. Disease too is the outcome of a great complexity of factors; so is risk; so is effective treatment.

www.holisticsciencejournal.co.uk
HOLISTIC SCIENCE JOURNAL VOLUME 1 ISSUE 4 Signatures of Health

Biomarkers replace with a relatively few simple measurements our need to otherwise detect, collect and judge
all the facts of the matter. An effective biomarker, a high concentration of ‘bad’ cholesterol, for example, can
inform us about associated complexities related to genes, heredity, metabolism, diet, blood vessel walls, and
the risks of vascular embolism and occlusion [1]. The biomarker, in short, reflects and summarizes all the agents
and processes that are needed to produce it - however many and complex these agents and processes may be.
A simple biomarker is informative when it faithfully signifies for us the complex factors from which the
biomarker emerges. This reduction of biological complexity to one or a few simple biomarkers makes it
possible to act quickly without having to wait for real-time events to take place; you can, for example,
anticipate, treat and monitor the state of the individual to prevent a future heart attack or stroke. Medical
health-maintenance systems do well to prioritize biomarkers.

2. Immune health maintenance

The immune system in both its innate and adaptive arms can be viewed as a type of biological health-
maintenance system. In this paper we attempt to place in perspective in physiological terms, the immune
system with respect to the self. In physiological terms, we can say that the cells and molecules comprising the
[2,3]
immune system act to manage inflammation . Inflammation is classically defined as the processes activated
by injury that lead to healing [4]. The immune system, by the way it initiates and manages inflammation,
maintains health by healing wounds, containing pathogens, organizing the structure of connective tissue,
growing (angiogenesis) or destroying blood vessels, triggering regeneration of certain organs, activating the
apoptosis of aged, sick or dangerous cells, degrading accumulations of abnormal molecules, disposing of
waste, and performing other vital activities [2]. These varied expressions of inflammation maintain the
integrity of the organism in response to its relentless postdevelopmental decomposition caused by
environmental injuries and infections, accumulations of metabolic products, waste, and other intoxications,
and the inexorable advance of entropy. Well-regulated and timely inflammation maintains health. Hence, to
the extent that the immune system initiates and regulates healthy inflammation, the immune system is a
health-maintenance system. But, like many other well-intentioned agents, inflammation itself can cause harm;
dysregulated or misapplied inflammation produces disease that may require anti-inflammatory therapy [5].
There is considerable discussion on immune regulation in patients with autoimmune disease [6-8]. Let us focus,
for now, on the immune regulation of healthy inflammation.

3. Immune computation for health maintenance

Health maintenance performed by the immune system, like health-maintenance systems devised by humans,
requires that the systems have access to information regarding biologic state (is something wrong?) and
information regarding disease process and choice of therapy - how the problem can best be handled (choice of
inflammatory response type: Th1 or Th2; induce cell growth or apoptosis; and so forth). Moreover, the
inflammatory process has to be adjusted dynamically as healing progresses and terminated when repair is
achieved. It may be said that the healthy immune system functions to translate the dynamic state of the body
into the dynamic state of the immune response (Fig. 1). Elsewhere I have proposed that the translation of body
[9-10]
state into a fitting immune response state can be termed immune computation . Successful immune
computation is a boon; immune miscalculation is a misfortune. How can the immune system manage
inflammation properly given the complexity of the organism?

www.holisticsciencejournal.co.uk
HOLISTIC SCIENCE JOURNAL VOLUME 1 ISSUE 4 Signatures of Health

Fig.1. Immune computation. The immune system in both its innate and adaptive arms is affected by signals that reflect the immunogenic
states of body tissues; these signals are molecular patterns generated by infection, neoplasia, trauma, aging, and so forth. The immune
system transforms these signals into varieties of immune response - immune response states - leading to a variety of inflammatory effects:
[9]
apoptosis, angiogenesis, etc. The transformation of immunogenic tissue states into immune response states constitutes computation .
The immune response feeds back to affect the state of the tissues - usually to induce healing. Note that the immune system itself is
[2]
influenced by feedback from its own reactions; in this way, the immune system is self-organizing .

4. Biomarkers for immune health maintenance

Complexity reduction is key; living systems are just too complex to control without reducing the information to
manageably small pieces [11]. It is impossible to measure every factor relevant to the state of any living
organism; indeed, even a sample of the information, if too large, can be confusing if not paralyzing. The
immune system, like any good physician, has to focus on essentials; to function, the immune system needs to
attend to a relatively few, but informative signals.
The immune system, like health-maintenance systems generally, needs biomarkers. I propose that an
important function of the immunological homunculus is to create and detect biomarkers (Fig. 2).

Fig. 2. Immune biomarkers. The self-antigens and innate ligands that transmit the states of the body to the immune system can be viewed
as biomarkers. These biomarkers are detected by natural autoimmunity - the immunological homunculus – leading to immune response
states that initiate and regulate inflammation. Physiological inflammation maintains the health of the body.

www.holisticsciencejournal.co.uk
HOLISTIC SCIENCE JOURNAL VOLUME 1 ISSUE 4 Signatures of Health

5. Innate-ligand and self-antigen biomarkers

The classical formulation of the clonal selection theory proposed that the healthy immune system must be
blinded to body molecules by the deletion of self-reactive lymphocytes during development [12]. Neo-clonal
selection theories continue to teach that the healthy immune system must not respond to self-molecules, but
[13] [14]
add ignorance and/or active regulation to clonal deletion to annul autoimmunity. To regulate healthy
inflammation, however, the immune system must be sensitive to the state of the body and intimately
responsive to it; autoimmunity, rather than shunned, has to be built into the system; a degree of
autoimmunity must be physiological. Indeed, the immune system appears to scan and respond to body
molecules by way of several sets of receptors. Innate receptors belonging to the Toll-like receptor family
respond to both foreign and self-molecules [15]; innate receptors for cytokines, chemokines and other
molecules allow immune cells to detect and respond to molecules produced by body cells [16]. The classical
clonal selection theory did not view innate receptors as ‘real’ immune receptors; ‘real’ receptors were limited
to adaptive antigen receptors [12]. Now, however, it is clear to immunology that the innate and adaptive classes
of immune receptors are functionally integrated into a single immune system [2,9]. The immune system inspects
the body using both its innate and adaptive receptors. Which body molecules are recognized by adaptive
antigen receptors?

6. Homuncular biomarkers
We recently studied the autoantibodies present at birth in human cord blood - the congenital immunological
[17]
homunculus – using an antigen microarray chip . We surveyed IgG, IgA and IgM antibodies binding to about
300 self-antigens. IgG antibodies are actively transported from the mother to her developing fetus, so the
repertoire of IgG autoantibodies in cord blood represents primarily the homunculus repertoire developed by
the mother. The cord blood IgA and IgM antibodies, which do not cross the placenta, were produced by the
babies in utero. Although the 300 self-molecules spotted on the microarray are likely to be a relatively small
selection of homunculus reactivities, the set of self-antigens bound by the congenital repertoire of homuncular
autoantibodies is informative: The self-molecules included tissue antigens (glutamic acid decarboxylase,
myelin oligodendrocyte glycoprotein, myosin, collagen 1, thyroglobulin), immune modulator molecules
(gelectins, ubiquitin, gelsolin, interleukins), and stress proteins (HSP40, HSP47, HSP60 peptides, HSP70
peptides) [17]. It seems reasonable to suspect that these selfmolecules can provide the immune system with
just the right kinds of biomarker information about body state needed to manage a healthy inflammatory
program (Fig. 2). Tissue-associated antigens can mark the address - the site where immune intervention is
needed; stress-associated molecules can mark the nature of the insult and its progression. Indeed, the immune
system - by anti-ergotypic T cells and antibodies, cytokine networks and immune memory - is able to monitor
[2,9,10,16]
its own state in the course of the immune response .

7. Advantages of the immunological homunculus

Many of the self-antigens implicated in autoimmune diseases are recognized by autoimmune T cells and B cells
present in the healthy immunological homunculus from birth [17]. Thus it is reasonable to conclude that the
structuring of autoimmune reactivity encoded in the homunculus in health probably plays a role in the
pathophysiology of autoimmune disease; disease-causing T cells and autoantibodies could arise from the
pathogenic activation of autoimmune progenitor clones resident within the homunculus set of natural
autoreactivities [2]. Hence, the immunological homunculus, from an evolutionary perspective, is costly to
maintain. The fact that the homunculus exists implies that the occasional cost in disease must be offset by a
general benefit of natural autoimmunity to health. What are the advantages of having natural autoimmunity
built into the immune system?

It has been proposed that natural autoimmunity could help rid the body of troublesome waste molecules and
[18]
cells . Natural autoimmune T cells and B cells and autoantibodies, in addition, could provide an early
immune response to pathogens expressing molecules that are cross-reactive with particular self-antigens [19];
an example is the response to bacterial heat shock proteins and other molecules that are highly conserved
and cross-reactive with self [20]. Natural autoimmunity has also been proposed to prevent pathogenic
autoimmunity by generating regulatory circuits [21,22] or by blocking the access of potentially pathogenic agents
to key self-antigens [23]. Note that these proposed health-promoting attributes of natural autoimmunity are
not mutually exclusive; the immunological homunculus might help maintain health in a variety of ways. Here I
suggest we might add to the list of benefits the idea that the self-antigens recognized by homuncular agents
can also serve as biomarkers that inform the immune system of the state of the body, both locally and globally.

www.holisticsciencejournal.co.uk
HOLISTIC SCIENCE JOURNAL VOLUME 1 ISSUE 4 Signatures of Health

If this is true, then we might be able to gain some insight into states of health and disease by studying an
individual’s patterns of autoimmunity [9]. The immunological homunculus, as a natural biomarker system for
immune health-maintenance, might be enlisted to serve our medical health-maintenance system. It might also
help us choose the correct medication for patients [24]. We just have to listen to what the immunological
[25,26]
homunculus can tell us .

Acknowledgement
I thank artist Elly Rubin (http://www.ellyrubin.com/) for allowing me to insert a photograph of her print into Fig. 2.

(Originally published by Irun Cohen / Journal of Autoimmunity 29 (2007) reproduced with permission of the author)
References
[1] Oh RC, Lanier JB. Management of hypertriglyceridemia. Am Fam Physician 2007;75:1365e71.
[2] Cohen IR. Tending Adam’s garden: evolving the cognitive immune self. London: Academic Press; 2000.
[3] Cohen IR. Discrimination and dialogue in the immune system. Semin Immunol 2000;12:215e9. discussion 257e344.
[4] Ebert R. The inflammatory process. In: Zweifach BW, Grant L, McCluskey RT, editors. General pathology, vol. 1. New York: Academic
Press; 1965.
[5] Fitzgerald MF, Fox JC. Emerging trends in the therapy of COPD: bronchodilators as mono- and combination therapies. Drug Discov
Today 2007;12:472e8.
[6] Abbas A, Lohr J, Knoechel B. Balancing autoaggressive and protective T cell responses. J Autoimmun 2007;28:59e61.
[7] Krebs P, Kurrer MO, Kremer M, De Giuli R, Sonderegger I, Henke A, et al. Molecular mapping of autoimmune B cell responses in
experimental myocarditis. J Autoimmun
2007;28:224e33
[8] Jacobson EM, Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid
autoimmunity: back to the future. J Autoimmun 2007;28:85e98.
[9] Cohen IR. Real and artificial immune systems: computing the state of the body. Nat Rev Immunol 2007;7:569e74.
[10] Cohen IR. Immune system computation and the immunological homunculus. In: Niestrasz O, Whittle J, Harel D, Reggio G, edi tors.
Lectures notes in computer science 4199 MoDELS 2006. Berlin: Springer-Verlag;
2006. p. 499e512.
[11] Cohen IR, Harel D. Explaining a complex living system: dynamics, multi-scaling and emergence. J R Soc Interface 2007;4:175e82.
[12] Burnet M. Auto-immunity and auto-immune disease. Philadelphia: F.A. Davis Company; 1972.
[13] Erlebacher A, Vencato D, Price KA, Zhang D, Glimcher LH. Constraints in antigen presentation severely restrict T cell recognition of the
allogeneic fetus. J Clin Invest 2007;117:1399e411.
[14] Nomura T, Sakaguchi S. Foxp3 and Aire in thymus-generated Treg cells: a link in self-tolerance. Nat Immun 2007;8:333e4.
[15] Mitchell JA, Paul-Clark MJ, Clarke GW, McMaster SK, Cartwright N. Critical role of toll-like receptors and nucleotide oligomerisation
domain in the regulation of health and disease. J Endocrinol 2007;193: 323e30.
[16] Frankenstein Z, Alon U, Cohen IR. The immune-body cytokine networkdefines a social architecture of cell interactions. Biol Direct
2006;1:32.
[17] Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by
antigen microarray informatics. J Clin Invest 2007;117:712e8.
[18] Grabar P. ‘‘Self’’and ‘‘not-self’’ in immunology. Lancet 1974;1:1320e2.
[19] Cohen IR, Young DB. Autoimmunity, microbial immunity and the immunological homunculus. Immunol Today 199 1;12:105e10.
[20] van Eden W, van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 2005;5:
318e30.
[21] Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’. Immunol Today 1991;12:154e9.
[22] Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol 1995;7:812e8.
[23] Cohen IR, Cooke A. Natural autoantibodies might prevent autoimmunedisease. Immunol Today 1986;7:363e4.
[24] Ross CJ, Katzov H, Carleton B, Hayden MR. Pharmacogenomics and its implications for autoimmune disease. J Autoimmun
2007;28:122e8.
[25] Quintana FJ, Hagedorn PH, Elizur G, Merbl Y, Domany E, Cohen IR. Functional immunomics: microarray analysis of IgG autoa ntibody
repertoires predicts the future response of mice to induced diabetes. Proc Natl
Acad Sci U S A 2004;101(Suppl. 2):14615e21.
[26] Quintana FJ, Merbl Y, Sahar E, Domany E, Cohen IR. Antigen-chip technology for accessing global information about the state of the
body. Lupus 2006;15:428e30.

Photo: Dr. Sondra Barrett: A living human white blood cell (neutrophil)
recognizing and going after a cell (red blood cell) from another species
(sheep). An example of immune recognition. www.sondrabarrett.com

Irun Cohen is Professor of Immunology, Emeritus at The Weizmann

Institute of Science, Israel

www.holisticsciencejournal.co.uk