A Revolutionary Revisioning: Natural Autoimmunity as the Master Conductor of Homeostasis

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What if everything we thought we knew about autoantibodies, which are pathologically elevated in autoimmune diseases, was wrong? Rather than a biomarker of deranged immunoregulation, novel research is uncovering that antibodies directed against self are an essential physiological phenomena, mandatory for homeodynamics.

How Microbiology Distorted the Foundations of Immunology

Through the lens of applied microbiology, a discipline which informed the inception of immunology, the immune system has been fashioned as the armed forces, vigilant against hostile intrusion. In fact, that the founders of immunology were microbiologists such as Paul Ehrlich and Louis Pasteur enabled the persistence of a framework whereby the immune cells were conceived as sentinels or alerted border guards, on the offensive against microbial invasion. Thus, as articulated by Poletaev and colleagues in their recent review, "'Microbiological' thinking, namely its idea of war against aliens, has persisted in minds for decades due to the fact that generations of immunologists have been educated by microbiologists" (1, p. 221). 

However, when imagined through the foundations of physiology and pathophysiology, a dramatically divergent view of the immune system emerges. In fact, over a century ago, Ilya Ilyich Metchnikoff incorporated Darwinian logic into a theory suggesting that the objective of the immune system is not war against non-self, but rather ""harmonization of self," or even ontogenetic creation of multi-cellular organism" in the face of environmental and internal challenges (1, p. 221). 

Therefore, rather than an instrument of war against foreign entities, the immune system represents the master orchestrator of self-regulatory mechanisms, designed to participate in growth, maintenance, repair, signaling, and optimization of physiology (1, 2).

The Flawed Self vs. Non-Self Model of Immune Function

According to classical immunology, the role of the immune system was to differentiate self from non-self, and to eliminate intruders that fell into the latter category. Clonal deletion and clonal anergy were considered failsafe mechanisms built into the immune system in order to neutralize auto-reactive (self-directed) T cells. 

T lymphocytes (T cells), components of the adaptive, cell-mediated arm of the immune system that appear secondarily on the scene after non-specific innate defenses are deployed, mature in the thymus. They undergo functional inactivation (clonal anergy) or functional elimination (clonal deletion) if they are self-reactive—bearing receptors that recognize components of self (3). Immature thymocytes that efficaciously bind to elements of self called self-ligands are committed to apoptosis, also known as programmed cell death. On the other hand, those that are not self-reactive escape negative selection and become incorporated into the repertoire of mature T cells (4). This theory was previously conceptualized as a safeguard to protect against the development of autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous (SLE).

However, the simplistic self versus non-self model has been proven flawed, as in fact  "Autoreactive repertoires are predominantly selected early in ontogeny," meaning that the survival of self-reactive cell subsets is ensured in normal developmental processes (5, p. 117). In addition, clonal deletion and anergy fail to account for how a pregnant mother can tolerate a semi-allogenic fetus, or how the body cannot only permit the existence of, but develop symbiotic relationships with, the billions of organisms in the microbial communities existing throughout the body.

Commensal flora and physiological pregnancy can be reconciled with newfound research by Matzinger, who proposed in her groundbreaking "danger hypothesis" that the immune system functions to identify and neutralize potentially dangerous threats, rather than indiscriminately targeting non-self entities (6). In other words, signals of stranger and danger in concert are what produce an immune response.

The Immune System: From the Body's Militia to a Reservoir of Regulatory Mechanisms

In tandem with this revised view, researchers are consigning the immune system to the all-important role of supervising the morphogenesis, development, aging, self-harmonization, and self-assessment of the organism, as it is the only system that encompasses the "ontogenetic and event-driven variability" as well as the "mobility and all-embracing dispersal" necessary to coordinate the sequence, timing, and intensity of expression of genetic material (1, p. 222).

Under this model, the maligning of autoantibodies as exclusively agents of autoimmune disease and harbingers of doom no longer holds water. Instead, it paves the way for novel notions such as natural autoimmunity and physiological inflammation, both of which are integral to homeodynamics and health. 

Although vilified in many circles, inflammation is responsible for the essential recruitment of leukocytes and plasma proteins to affected sites, for mobilizing an immune response to infection, for limiting damage by walling off infections, and for repair and resolution of injury (7).

With regard to natural autoantibodies, on the other hand, "It is now well established that autoreactive antibodies and B cells, and auto-reactive T cells, are present in healthy individuals, and in virtually all vertebrate species" as well as in different age groups of healthy individuals, indicating that autoreactivities remain stable with aging (5, p. 117; 8). Both human and mouse models have elucidated that autoantibodies targeted to an array of evolutionary conserved circulating, superficial, and intracellular antigens is a natural phenomenon (9, 10, 11). 

A vast reservoir of self-reactive autoantibodies has been found in the cord blood of newborns, implying, paradoxically, that both the collections of neonatal autoreactive autoantibody-producing B cells and fetal IgM autoantibodies are evolutionary selected for during fetal development (5). In fact, during the first two years of human life, the diversity of autoreactive antibodies and immune cells expands (8).

Natural autoantibodies regulate and modify processing of genetic information in disparate cell sets and oversee ontogeny, or the development of an organism across its lifespan (1). Encoded by unmutated germline genes, natural autoantibodies have been proven to comprise a dynamic network that modulates organismal homeodynamics (12).

That the immune system supervises homeodynamics is a departure from the "classical homeostatic idea that emphasizes the stability of the internal milieu toward perturbation" (13, p. 133). Homeodynamics, in contrast, represents the culmination of all the dynamic and complex behaviors that an organism engages in at bifurcation points to self-organize and restore stability, encompassing all its fluctuating properties such as "bistable switches, thresholds, waves, gradients, mutual entrainment, and periodic as well as chaotic behaviour" (13, p. 133).

Autoantibodies: A Physiological Immunacea

Autoantibodies are critical to regulatory interactions and homeodynamics because regulation revolves around cross-recognition by complementary molecules (1). Stated otherwise, natural autoimmunity is the ultimate regulatory device because autoantibodies can replicate the function of any complementary molecule, which Poletaev and colleagues (2012) call the principle of immune homunculus or Immunculus (1). 

In this way, autoantibodies can reproduce or inhibit the biological function of any bioregulator, including pharmaceuticals and endogenous messenger systems mediated by neurotransmitters, hormones, enzymes, or other signaling molecules, serving as an on-demand means for the transmission of certain signals as well as turning on or off particular biological effects (1). Autoantibodies with these activities have been observed both in patient populations and in healthy individuals (14, 1). 

Not only can a system of natural autoimmunity influence molecular events such as DNA replication and mRNA transcription, but autoantibodies also represent a means by which the immune system can modulate cellular differentiation, proliferation, and death (1). Autoantibodies, therefore, instead of merely constituting harbingers of autoimmune disease, represent an assemblage of immunological images that can signify the collective immunological experience of an individual (1). The potency of this immunological panacea, or Immunacea effect, may explain the efficacy of intravenous immunoglobulin (IVIG) therapy in a host of conditions (5).

Natural Autoimmunity as Nature's Garbage Disposal

One of the instrumental housekeeping functions played by the immune system is clearance of virulent agents, immune complexes, and metabolic debris. For instance, macrophages, phagocytic "big eaters" of the immune system that swallow and dismantle defective or infected cells, express superficial scavenger receptors to recognize modified alien or self proteins, as well as Toll-like receptors to bind to evolutionary conserved microbial moieties (1).

Within this phagocytic enterprise, however, macrophages cannot differentiate normal from misfolded proteins, or aberrant from intact cells (1). As articulated by Poletaev and colleagues (2012), autoantibodies, or opsonins, attach themselves to these garbage products to alert macrophages about their defective state, acting in the same way scent marks do for blind dogs (1).

One of the primary sources of physiological garbage is apoptosis, or cell suicide, an orderly, energy-intensive collapse of the cell accompanied by predictable morphological alterations and engulfment of the lingering cell corpses by phagocytes such as macrophages (15). With any ongoing disease process, the rate of apoptosis accelerates, and generation of trash increases in tandem (1). 

Necrosis, on the other hand, occurs secondary to cellular injury, and proceeds in an uncontrolled fashion, leading to cellular swelling, membrane fracture, recruitment of complement and cell lysis, which spills intracellular components and leads to inflammation. With increases in either apoptosis or necrosis, which are up-regulated during pathological processes, antigenic 'splash' occurs, meaning that cell components normally contained within the cell become visible and accessible to the immune system (1). 

The production of autoantibodies is thus directly proportional to the quantity of complementary antigens. Therefore, under normal physiological conditions, autoantibody levels remain constant and within 'normal range,' as specified on lab reports. However, increased output of cellular 'trash', which accompanies pathophysiological changes in any organ, augments synthesis of autoantibodies as an adaptive mechanism to withdraw this potentially damage-inflicting discharge (1). 

For instance, pre-existing pathology in thyroid tissue leads to excessive release of normally sequestered intracellular antigenic material, such as thyroglobulin (TG) and thyroid peroxidase (TPO) (1). With continued inflammatory processes and death of thyrocytes, TG and TPO continue to be liberated, leading to the escalating levels of autoantibodies directed against these proteins that occurs with Hashimoto's thyroiditis (1). 

Therefore, the increase in autoantibodies that occurs with autoimmune diseases is a compensatory mechanism, attempting to rectify the excessive emission of garbage material that occurs with pre-existing tissue or organ damage. A fundamental implication of this paradigm-shifting concept is that autoimmune disease, rather than solely an immune system gone haywire, is an adaptive, secondary response to pre-existing tissue or organ damage.

Anti-Pathogen, Anti-Inflammatory, and Anti-Cancer Effects of Natural Autoantibodies

Not only do natural autoantibodies clear metabolic waste, catabolic byproducts, senescent erythrocytes, and soluble immune complexes, but they also function in the innate first line of defense against infection by serving as opsonins for pathogens with which they cross react (5; 16). Opsonins coat microorganisms to facilitate their subsequent clearance by white blood cells.

As noted by Lacroix-Desmazes and colleagues (1998), natural autoantibodies even possess anti-inflammatory effects (5). For example, IgG and IgM autoantibodies can prevent the complement cascade that forms a membrane attack complex (17, 18). Complement is a network of proteins whose inappropriate activation mediates cell lysis and tissue damage in diseases such as asthma and SLE (27). Autoantibodies are similarly anti-inflammatory due to their selective ability to induce synthesis of anti-inflammatory cytokines, such as IL-1ra and IL-8, while suppressing production of pro-inflammatory cytokines such as IL-6 (5, 19). 

By binding to cross-reactive microbial epitopes, natural autoantibodies may even prevent the development of autoimmune disease (20). For instance, in the early twentieth century, Besredka found autoantibodies that could disarm the hemolytic effects of anti-erythrocyte autoantibodies (5). Lacroix-Desmazes and colleagues (1998) also catalogue how remission from various autoimmune diseases, including Guillain–Barré syndrome, anti-fibrinogen autoimmune disease, anti-FVIII autoimmune disease, myasthenia gravis, and systemic vasculitis is "associated with the presence in autologous serum of 'protective' anti-idiotypic antibodies that neutralize the activity of pathogenic autoantibodies of the patients" (20). Thus, natural autoantibodies exhibit peripheral control of pathological autoimmunity. 

Lastly, natural autoantibodies may also participate in tumor surveillance and cancer inhibition, by attaching to cell surface antigens on malignant cells in order to modulate growth of neoplasms (21, 22, 23).

Differentiating Natural from Pathological Autoimmunity

Autoantibodies of the pathologic type tend to demonstrate high binding affinity for self antigens and are oligoreactive, whereas most natural autoantibodies are polyreactive, recognizing multiple self and foreign antigens, and exhibit a range of binding affinities (5; 24). Natural autoantibodies, which belong predominately to the IgG class of immunoglobulins, likewise exhibit a high degree of connectivity, or the ability of the variable (V) region of one antibody to interact with the V region of another (24). 

However, natural autoantibodies do target some of the same antigens that pathogenic autoantibodies react with in autoimmune disease, such as thyroglobulin (TG), factor VIII (FVIII), intrinsic factor, and the glomerular basement membrane (5).

Revisioning Autoimmunity: From Pathological to Protective

With publications by Jerne (1974), it became accepted that self-directed autoantibodies are a compulsory normal part of the immune system that can exist without autoimmune disease (25). In fact, the ability of the immune system to discriminate non-self is theorized to have been acquired later in evolutionary history, "due to the redeployment of a system invented for other reasons" (26, p. 396). 

Thus, the original purpose of the immune system was self-monitoring, which is accomplished in part via autoantibody production. Reinforcement for this hypothesis comes from the molecular homology, or structural similarity, in immunoglobulin domains between cell adhesion molecules and antibodies, which supports the notion that natural antibodies evolved as a mechanism by which to survey and recognize self (26).

In their pivotal paper, Poletaev and colleagues (2012) argue that the vast majority of cases of autoimmunity are sanogenic, or beneficial, signifying abnormal stimulation of cell death events in a tissue or organ due to some primary damage (1). According to their research, which is consistent with functional medicine principles, elevation of autoantibody titers is the earliest sign of incipient disease, which may develop in preliminary phases of chronic pathology before any overt symptomatic manifestations or laboratory parameters of disease or organ insufficiency appear (1). Thus, measuring autoantibodies represents a potential population-level screening tool for detecting pre-nosologic changes in organs and tissues that may predict disease (1). 

Poletaev et al. (2012) propose that the nomenclature "autoallergy" is better suited to describing primary autoimmune reactions, which are poorly regulated, misdirected, or not warranted or conditioned by the needs of an organism (1). They make this didactic distinction on the basis that the vast majority of cases of autoantibody production are "autoimmune" in origin, related to natural or physiological autoimmunity, and based on the need to enhance clearance of apoptotic debris (1). Compared to secondary autoimmune reactions, which they observe in 95% of cases, Poletaev and colleagues (2012) clarify that autoallergy occurs in only 5% of cases (1).

This linguistic shift reinforces the notion advanced by holistic and traditional medical systems, that all seemingly pathological changes are governed by the body's innate wisdom and represent attempts to restore homeostasis. Just as a fever or a cough are adaptive mechanisms intended to expel invading pathogens, autoimmunity may be symptomatic of the body's efforts to restore physiological homeodynamics and normalize abnormal rates of apoptosis induced by organ damage. 

Therefore, rather than an immune system gone rogue, autoimmunity is often the body's attempt to rectify imbalances in the rate of clearance of potentially damaging waste products and to correct other deviations in the biochemical milieu. Rather than a proxy for loss of self-tolerance, then, autoantibodies may represent an expression of the body's inherent self-healing capacity—an attempt to restore homeodynamics and heal itself from pre-existing disease.

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