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Natural Autoimmunity: Friend or Foe?

Natural Autoimmunity: Friend or Foe?

Rather than signifying an immune system gone haywire, pioneering research reveals that autoantibodies are a biological prerequisite, and that natural autoimmunity is the master orchestrator of physiological homeostasis.

When examining a lab report for autoantibodies, why is there a normal reference range? Classical immunology, adhering to the principle of “Horror autotoxicus,” argues that any level of antibody against self represents loss of self-tolerance and compromised immunoregulatory mechanisms. Although clonal deletion and anergy have previously been conceived as processes by which self-tolerance develops, these concepts fail to explain the prevalence of natural autoimmunity among healthy individuals (1). Novel research is elucidating that autoimmunity is a natural, common phenomenon, and that autoimmune disease occurs as a secondary response to tissue or organ injury.

Revisioning the Role of the Immune System: From Armed Forces to Housekeeper of Homeodynamics

Because immunology was born as an offshoot of applied microbiology, the foundational thinking of the microbiological discipline, which envisions the immune system as engaged in a permanent host struggle against alien invaders, has emerged as a cornerstone of immunology (2). In their seminal paper, Poletaev and colleagues (2012) argue that rather than the stalwart guardian, dispatched to protect the body against microbial breach and trespass of foreign entities, engaged in an ongoing territorial dispute for dominance, the immune system possesses housekeeping functions, maintaining homeodynamics against an onslaught of exogenous and endogenous forces (2). Unlike other messenger-mediated systems such as those orchestrated by neurotransmitters and hormones, the immune system embodies both the far-reaching dispersal and mobility to manage the genetic expression that governs development, growth, and aging of the organism (2). 

Stated otherwise, the war of the immune system against foreign invaders comprises only a small fraction of a “much wider biological predestination of the immune system which is responsible for the control of dynamic self-maintenance, self-reparation, self-construction and self-optimization of an organism” (2, p. 222). This pursuit of physiological homeostasis in which the immune system participates was proposed by Ilya Ilyich Metchnikoff over a century ago, a concept which he infused with Darwinian evolutionary principles, and included as a corollary that the ontogenetic creation of the multi-cellular organism was one of the central purposes of the immune system (2).

Self vs. Non-self Becomes the Stranger-Danger Hypothesis

Echoes of Metchnikoff’s idea of natural autoimmunity and physiological inflammation can be perceived in modern-day work by Matzinger, who put forth the danger hypothesis. For half a century, immunologists had operated on the premise that the immune system functions based on the fundamental differentiation of self from non-self (3). However, this model has been proven to be flawed, as scientists have discovered that the immune system responds in the presence of both stranger and danger. In other words, pathogen-associated molecular patterns (PAMPs), or conserved molecular motifs present in many microorganisms that activate pattern recognition receptors (PRRs) such as transmembrane toll-like receptors (TLRs), would signify the presence of a foe and lead to immune activation (4). PAMPs, which are normally not present in vertebrates, such as bacterial lipopolysaccharide (LPS), double-stranded viral RNA, and peptidoglycan from fungal cell walls, are a red flag to phagocytes and antigen presenting cells (APCs).

Recent research has illuminated that the immune system is more concerned with identifying entities with the potential to do damage, rather than simply discriminating self from non-self. This accounts for such previously mysterious phenomena as the microbiome and microvirome, wherein the body is able to tolerate and oftentimes develop symbiotic relationship with microbial flora. Matzinger’s hypothesis likewise explains how the female body permits the development of a semi-allogenic fetus without rejecting it during pregnancy (2). 

The Immune System as the Conductor of the Physiologic Symphony

These ideas challenge the prevailing notion of autoimmune disease. Rather than harbingers of a defective immune system, autoantibodies may serve as recognizing molecules or immunological mirror images, which act as a mechanism through which the immune system can modulate cell division, differentiation, apoptosis, and other cellular events (2, p. 223). In this way, the principle of immune homunculus manifests, meaning that natural autoimmunity “serves as a mirror in dynamic maintenance of individual self-identity, because it is capable of universal inducible reproduction of complementary molecules,” an effect which Poletaev and colleagues dub the immunological panacea or “Immunacea” (2, p. 223). 

Thus, through autoantibody production, the immune system can replicate or antagonize the physiological function of any biomolecule or bioregulator (2). This notion is reinforced by studies revealing that antibodies resembling pharmaceutical drugs, hormones, locally-acting autacoids, and enzymes have been found in both healthy cohorts and patient populations (2). Autoantibody components, such as the tetra peptide taftsin from immunoglobulin Fc-fragments, exert hormone-like effects that are integral to the neuroendocrine-immune system (5). 

That autoantibodies against nuclear antigens, such as chromatin receptors, can translocate into cell nuclei and alter processes inherent to the central dogma of biology, namely, DNA replication, mRNA transcription, and protein production, “suggests that autoimmunity is one of the mechanisms in the physiological regulation of cellular morphogenesis and function” (5, p. 191). Researchers infer from this data that, “Physiological autoimmunity thus contributes to the bringing-together and co-tuning of genetic information reading” (5, p. 191). Although autoantibodies have been discovered to modify genetic expression and thus down-regulate or stimulate cellular processes, most of the research is still constrained to using antibodies to selectively disable processes or induce cell death (5).

The Role of the Immune Homunculus

The self-organizing immune system detects and engenders biomarkers, such as self-antigens and innate ligands, in order to signify the immunogenic state of body tissues (6). In turn, these biomarkers are translated via immune computation into an immune response (6). As described by Cohen (2007), the immune homunculus, or the hard-wired autoimmune structuring inherent to the immune system, is the representation of the body by the immune system, and the self-reactivities that the homunculus consists of are biomarkers of the immunological health maintenance system which are used to regulate inflammation (6). 

Although conceived of as deleterious within binary medical belief systems, inflammation is intrinsic to such fundamental processes as wound healing, angiogenesis, cellular regeneration, waste disposal, confinement of pathogens or neoplasia, and degradation of aberrant molecules (6). Cohen (2007) articulates the centrality of inflammation to health, arguing that divergent expressions of inflammation “maintain the integrity of the organism in response to its relentless post-developmental decomposition caused by environmental injuries and infections, accumulations of metabolic products, waste, and other intoxications, and the inexorable advance of entropy” (6). 

The Purpose of Natural Autoimmunity

The early twentieth-century work of Ehrlich paved the way for the concept of physiological autoimmunity, because he perceived autoantibodies as circulating, systematic cellular receptors (5). The development of antibody-based auto-antiidiotypes, or anti-signals and anti-receptors, which serve as structural antonyms, is intrinsic to cell regulation, growth, and signaling, and processes whereby “receptors and their ligands may use complementary peptide sequences or their analogs to facilitate binding” (7).

The complementary binding affinities of autoantibodies for autoantigens also crystallizes a structural foundation not only for the “processes of biologically active molecule neutralization or prevention of their interaction with receptors and ligands, but also for stimulation of some cellular and humoral effectors” (5). Autoantibodies can thus replicate the purpose of signaling molecules, as well as act as repressors or derepressors at particular genomic sites in order to facilitate synchronized growth, development, and differentiation of various tissues and organs (5).

Physiological autoantibodies convey information about the body state, both locally and globally, in order to initiate and manage inflammation (6). For instance, a congenital immunological homunculus, consisting of antibodies binding to 300 self-antigens, was recently discovered (8). Tissue-specific antigens, such as thyroglobulin, glutamic acid decarboxylase, and myelin oligodendrocyte glycoprotein, delineate the site where an immune response is required, whereas autoantibodies to stress-associated proteins such as heat shock proteins (HSPs) or immune modulators can indicate the nature and course of the immune intervention (6). Autoantibody-mediated anti-idiotypic mechanisms, translated by autoimmune images of fetal antigens, may also convey information from fetus to mother (5).

Natural autoimmunity may likewise serve to create an immune response against pathogens possessing highly conserved motifs that are cross-reactive with self-antigens, such as bacterial HSPs (1, 9). Paradoxically, “Natural autoantibodies bind to self or self-mimicking epitopes and so prevent the initiation of a damaging autoimmune response” (10, p. 3663). It has likewise been proposed that natural autoantibodies produce regulatory circuits and facilitate creation of a dynamic network via interaction with self-constituents, which effectively prevents pathogenic autoimmunity (11).

Autoantibodies: Nature’s Clean-Up Crew

One important function of natural autoimmunity is disposal of residual metabolic byproducts, defective cells, and catabolic substances (12). Natural autoantibodies can tag cells fated for opsonin-dependent phagocytosis, which attracts macrophages, or ‘big eaters’, to dispose of aberrant cells (5). Via cell surface Fc-receptors, macrophages and other phagocytes recognize soluble and particulate antigen-antibody complexes and remove them via endocytosis (2). This explains the nearly constant serum levels of autoantibodies produced by healthy adults, where rates of waste generation and disposal remain relatively consistent (2).

In addition, antibodies can inhibit or promote the self-dismantling processes that constitute apoptosis, or cell-suicide (13). Furthermore, a natural autoimmune response mediates the programmed death of senescent cells in ontogenesis, during the development of an organism, via autoimmunity targeted to cell surface non tissue-specific glycoprotein band-III AG (14). Metchnikoff even speculated that autoantibodies are responsible for age-related organ atrophy (5).

A surplus in antigenic waste production notifies the body to intensify production of antibodies to withdraw this emission from the body (2). This accounts for the increase in organotropic autoantibody generation that accompanies pathological changes in organs, as virtually all long-latency, chronic illnesses are accompanied in tandem by increased apoptosis in certain cell subsets, leading to substantial release or splash of their antigens (2).

The Downside of Natural Autoimmunity: Autoimmune Disease

Tissue injury, secondary to toxicant exposure, infection, oxidative stress, and other environmental insults incites apoptosis, or programmed cell death, to eliminate defective cells. When excessive discharge of apoptotic debris takes place, normally sequestered auto-antigens are liberated from perishing cells, inciting elevated levels of auto-antibody production targeted to the antigens that are plentiful in apoptotic bodies (2). 

Under normal physiological circumstances, macrophages rapidly withdraw apoptotic garbage and prevent uptake of these self-antigens by antigen-presenting cells (APCs) (2). However, with organ pathology and autoimmune diseases such as systemic lupus erythematosus (SLE), the rate of elimination of apoptotic debris by lymph node macrophages is substantially compromised (15, 16). When APCs pick up the slack, an autoimmune response is invoked. This accounts for the increase in antibodies against chromatin-associated and caryolemma-associated antigens such as cardiolipin, nucleohistones, and double-stranded DNA, which accompanies autoimmune conditions such as scleroderma, rheumatoid arthritis, or SLE (2). In its infinite wisdom, via an adaptive, secondary autoimmune reaction, the body attempts to normalize homeodynamics, augment clearance of waste products, and stimulate repair (2). 

Predictive Autoimmunity: An Opportunity to Intervene 

Thus, an elevation in autoantibodies titers that occurs months or years before symptom manifestation can predict future somatic disease and overt organ insufficiency (17). These predictive autoantibodies serve as biomarkers that confer a certain positive predictive value (PPV), or percentage risk, that a patient will develop a specific autoimmune disease within a particular time period.

For instance, positive anti-thyroid antibodies equate to an odds ratio of 8 for women and 25 for men for development of clinical hypothyroidism (18). In another study, anti thyroid peroxidase (TPO) antibodies predicted postpartum thyroiditis with a 97% sensitivity and 91% specificity (19). Anti-double-stranded DNA antibodies were present in patients with SLE approximately 2.2 years before diagnosis (17). In a cohort of patients with anti-mitochondrial antibodies (AMA), predictive for primary biliary cirrhosis (PBC), 50% developed PBC symptoms within five years and 95% did within twenty years (20). In another example, individuals with two or more type 1 diabetes antibodies, such as islet cell antibodies (ICA), 65-kD glutamic acid decarboxylase (GAD), insulin antibodies, and tyrosine phosphatase-like protein (IA-2), had a 50% risk of developing insulin-dependent diabetes within 10 years (21). Lastly, 90% of children positive for adrenal cortex autoantibodies (AcA) went on to develop overt Addison’s disease within ten years (22). 

The clinical utility of predictive antibody screening lies in the fact that it can be used to identify when an abnormal autoimmune mechanism is at play in a silent or reactive stage, before overt disease is diagnosed, and before more invasive, high-risk pharmaceutical drugs with adverse side effect profiles are suggested. Moreover, predictive autoantibodies are valuable in that they reveal which tissue is targeted by an autoimmune attack such that appropriate, disease-specific measures and tissue-specific support can be utilized.

Importantly, “Progression towards a given autoimmune disease, and its severity, can be predicted from the type of antibody, the antibody level, and the number of positive antibodies” (23, p. 330). Predictive autoantibodies are well-situated within the paradigm of functional medicine, which acknowledges a spectrum of gradations from health to disease, as appearance of predictive autoantibodies precede a black-or-white diagnosis and allow for early detection. Moreover, because functional medicine is prevention-oriented, lifestyle, dietary, botanical, and nutraceutical therapies can be employed to mitigate procession along the autoimmune continuum and halt irreparable tissue damage.

Autoimmunity in Health and Disease

In conclusion, the novel conceptualization of natural autoimmunity, derived from Metchnikoff’s speculations about physiological autoimmunity, acknowledges that self-directed immune responses are prerequisite for normal immunological functioning, cellular regulation, and “synchronization of somatic cell functions and their morphogenesis” (5). Researchers state that the existence of autoantibodies against intact self-antigens, including specific nuclear antigens, is essential for optimal organ functioning under physiological conditions (5).

However, when discerned through an evolutionary lens, it is evident that the immunological homunculus comes at a cost. As stated by Cohen (2007), disease-causing T cell subsets and autoantibodies may materialize from the “pathogenic activation of autoimmune progenitor clones resident within the homunculus set of natural autoreactivities” (6). Some researchers are re-classifying autoimmune disorders, or diseases in which natural autoimmunity becomes deranged, as “autoallergy” (24).

Therefore, the view that circumscribes autoantibodies solely to the realm of autoimmune disease is incomplete. Autoantibodies are proven to activate DNA synthesis, enhance rates of mitosis, and promote cellular proliferation (24). Certain neurotropic autoantibodies, for example, are capable of accelerating recovery and regeneration after ischemic stroke (24). Autoantibodies targeting a high mobility group of non-histone chromatin protein (HMGB-1), a lethal mediator of sepsis and multiple organ failure, have likewise been revealed to decrease risk of mortality in shock-like pathologies (25). Fundamentally, autoimmune mechanisms serve as a homeostasis-promoting means of enhancing clearance of cellular debris and aberrant cells.

In essence, this revolutionary research is confirmatory of functional and naturopathic medical approaches, recognizing that autoimmune disease is an adaptive physiological response to pre-existing pathophysiological processes in targeted organs. Moreover, it recognizes that physiological autoimmunity is a mandatory natural phenomenon and that it governs an array of normal cellular functions. Viewing autoimmune disorders through this groundbreaking lens will enable the development of dietary and lifestyle modifications that can address underlying pathology and arrest the deregulated immune responses that engender autoimmune disease.

References

1. Cohen, I.R., & Young, D.B. (1991). Autoimmunity, microbial immunity and the immunological homunculus. Immunology Today, 12(4), 105-110.

2.  Poletaev, A.B. et al. (2012). Immunophysiology versus immunopathology: Natural autoimmunity in human health and disease. Pathophysiology, 19, 221-231. 

3. Matzinger, P. (2002). The danger model: a renewed sense of self. Science, 296(5566), 301-305.

4. Aderem, A., & Ulevitch, R.J. (2000). Toll-like receptors in the induction of the innate immune response. Nature, 406, 782-787.

5. Sh Zaichik, A., Churilov, L.P., & Utekhin, V.J. (2008). Autoimmune regulation of genetically determined cell functions in health and disease. Pathophysiology, 15(3), 191-207. doi: 10.1016/j.pathophys.2008.07.002.

6. Cohen, I.R. (2007). Biomarkers, self-antigens and the immunological homunculus. Journal of Autoimmunity, 29(4), 246-249.

7. Bost, K.L., & Blalock, J.E. (1989). Complementary peptides as interactive sites for protein binding. Viral Immunology, 2($), 229-238.

8. Merbl, Y. et al. (2007). Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. Journal of Clinical Investigations, 117, 712-718.

9. van Eden, W., van der zee, R., & Prakken, B. (2005). Heat-shock proteins induce T-cell regulation of chronic inflammation. Nature Reviews Immunology, 5, 318-330.

10. Cohen, I.R., & Cooke, A. (1986). Natural autoantibodies might prevent autoimmune disease. Immunology Today, 7(12), 3663-3664.

11. Avrameas, S. (1991). Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton’. Immunology Today, 12(5), 154-159.

12. Grabar, P. (1974). “Self” and “not-self” in immunology. The Lancet, 303(7870), 1320-1322.

13. Roos, A. et al. (2001). Induction of renal cell apoptosis by antibodies and complement. Experimental Nephrology, 9, 65-70.

14. Kay, M.M.B. (1983). Appearance of a terminal differentiation antigen on senescent and damaged cells and its implications for physiologic autoantibodies. Biomembranes, 11, 119-156.

15. Gaipl, U.S. et al. (2006). Clearance of apoptotic cells in human SLE. Current Directions in Autoimmunity, 9, 173-187.

16. Gaipl, U.S. et al. (2007). Clearance deficiency and systemic lupus erythematosus (SLE). Journal of Autoimmunity, 28(2-3), 114-121.

17. Arbuckle, M.R. et al. (2003). Development of autoantibodies before the clinical onset of systemic lupus erythematosus. New England Journal of Medicine, 349, 1526–1533.

18. Vanderpump, M.P.J. et al. (1995) The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickam Survey. Clinical Endocrinology, 43, 55–68.

19. Kita, M., Goulis, D.G., & Avramides, A. (2002). Post-partum thyroiditis in a Mediterranean population: a prospective study of a large cohort of thyroid antibody positive women at the time of delivery. Journal of Endocrinology Investigations, 25, 513–519.

20. Prince, M.I. et al. (2004). Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut, 53, 865–870.

21. Bingley, P.J., Williams, A.J.K., & Gale, E.A.M. (1999). Optimized autoantibody-based risk assessment in family members. Diabetes Care, 22, 1796–1801.

22. Betterle, C. et al. (1997). Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases. Journal of Clinical Endocrinology & Metabolism, 82, 939–942.

23. Bizzaro, N. (2007). The predictive significance of autoantibodies in organ-specific autoimmune diseases. Clinical Reviews in Allergy and Immunology, 34, 326-331. doi:10.1007/s12016-007-8059-5

24. Poletaev, A.B. et al. (2004). Dialectics and implications of natural neurotropic autoantibodies in neurological disease and rehabilitation. Clinical Development and Immunology, 11(2), 141-156.

25. Mantell, L.L., Parrish, W.R., & Ulloa, L. (2006). Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock, 25(1), 4-11.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of GreenMedInfo or its staff.
Sayer Ji
Founder of GreenMedInfo.com

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