List and briefly describe various hypothesis to explain why autoimmune phenomenon occur in human body
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hypotheses mechanisms autoimmune disease human body immunology
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Hypotheses to Explain Why Autoimmune Phenomena Occur
Autoimmunity represents a failure of the immune system to distinguish "self" from "non-self." Normally, both central tolerance (thymic deletion of autoreactive T cells and clonal deletion of B cells) and peripheral tolerance (T-reg cells, anergy, apoptosis) prevent self-attack. When these mechanisms break down, autoimmune disease results. Multiple overlapping hypotheses exist to explain why this happens.
1. Molecular Mimicry
A pathogen-derived antigen shares structural or sequence similarity with a host self-antigen. Antibodies and T cells raised against the pathogen inadvertently cross-react with host tissues - autoimmunity arises as "collateral damage."
Classic example: In rheumatic fever, antibodies against the M-protein of Group A Streptococcus cross-react with cardiac myosin, laminin, and valvular proteins, causing carditis, and with neuronal antigens, causing Sydenham's chorea.
Other viruses implicated through molecular mimicry include Epstein-Barr virus (linked to SLE, MS, RA, Sjögren syndrome), Coxsackievirus (myocarditis, Hashimoto's thyroiditis, T1DM), and influenza A. - Harrison's Principles of Internal Medicine 22E, p.2867
2. Bystander Activation
An infection triggers strong innate immune activation (cytokine storm, danger signals, TLR stimulation) in the vicinity of self-tissues. This "danger milieu" provides the co-stimulatory signals needed to activate previously anergic autoreactive lymphocytes, even without molecular mimicry. The autoreactive cells are activated non-specifically by the inflammatory environment rather than by a specific shared epitope.
Example: Coxsackievirus B3-induced autoimmune myocarditis partly operates through bystander activation of cardiac-antigen-specific T cells. - Harrison's, p.2868
3. Epitope Spreading
An immune response begins against one epitope (often a microbial antigen). As tissue damage releases intracellular self-antigens, the immune response broadens to attack additional self-epitopes - both on the same molecule (intramolecular spread) and on entirely different proteins (intermolecular spread). This perpetuates and amplifies the autoimmune attack.
Mechanism: Activated autoreactive B cells capture the autoantigen, process it, and present new cryptic epitopes to T-helper cells, which sustain and expand the response. - Roitt's Essential Immunology, p.531
4. Sequestered / Hidden Antigen Release (Immunologically Privileged Sites)
Certain self-antigens are normally sequestered behind tissue barriers (brain behind the blood-brain barrier, eye, testis, thyroid follicular antigens). These antigens never contact the immune system during development, so central tolerance is not established. If injury, infection, or inflammation breaches these barriers and releases these antigens into circulation, autoreactive lymphocytes - which were never deleted because they never "saw" the antigen - can mount an attack.
Examples: Myelin basic protein in multiple sclerosis, lens antigens in sympathetic ophthalmia following eye trauma, thyroid antigens in Hashimoto's thyroiditis. - Janeway's Immunobiology 10e, p.15-3; Robbins & Cotran Pathologic Basis of Disease
5. HLA / Genetic Susceptibility
Specific HLA (human leukocyte antigen) alleles are strongly associated with particular autoimmune diseases. Certain HLA molecules present self-peptides particularly efficiently to T cells, or exhibit poor negative selection of autoreactive thymocytes. Non-MHC genes such as PTPN22 (affects TCR signaling thresholds), CTLA-4, and FOXP3 also modify autoimmune risk.
Examples:
- HLA-B27: ankylosing spondylitis
- HLA-DR3/DR4: type 1 diabetes, SLE
- FOXP3 mutations: IPEX syndrome (severe multi-organ autoimmunity in children)
This is not one single mechanism but explains who is predisposed to autoimmunity. - Goodman & Gilman's Pharmacological Basis of Therapeutics, p.782
6. Altered / Defective Thymic Selection (Altered Thymic Function)
The thymus normally deletes autoreactive T cells through negative selection. Type I interferons (massively induced during infections) regulate several steps of thymic T-cell selection. Disturbances in thymic function - whether from infection, inflammation, or genetic defects - impair deletion of self-reactive T cells, allowing them to escape into the periphery where they can attack self-tissues. - Goodman & Gilman's, p.782
7. Failure of Peripheral Tolerance / Regulatory T-Cell (Treg) Defects
Even autoreactive T cells that escape the thymus are normally kept in check by:
- Treg cells (CD4+CD25+FoxP3+): suppress autoreactive lymphocytes
- Anergy: T cells exposed to self-antigen without co-stimulation become unresponsive
- Apoptosis: Fas/FasL-mediated deletion of self-reactive clones
When these peripheral checkpoints fail, autoimmunity results. In patients with relapsing-remitting multiple sclerosis, Treg cell responsiveness to myelin basic protein declines in parallel with clinical disease. Fas gene mutations (as in MRL/lpr lupus mice) prevent apoptotic deletion of self-reactive clones, leading to lymphoproliferation and lupus-like disease. - Roitt's Essential Immunology
8. Polyclonal Lymphocyte Activation (Superantigen Hypothesis)
Microbial superantigens (e.g., staphylococcal enterotoxins, staphylococcal protein A) bypass normal antigen-specific activation and stimulate large populations of T and B cells non-specifically by binding outside the normal antigen-binding groove. If autoreactive lymphocytes happen to express the targeted receptor, they are activated en masse regardless of antigen specificity - potentially triggering autoimmunity. - Harrison's, p.2868
9. The Hygiene Hypothesis (Microbial Exposure Hypothesis)
Exposure to diverse microorganisms (parasites, bacteria, commensal gut flora) during childhood promotes immune regulatory pathways (Treg induction, IL-10 production, anti-inflammatory Th2/Th3 responses). In populations with reduced microbial exposure (developed countries with modern sanitation), this regulatory "education" is lacking. The result is a default toward pro-inflammatory Th1/Th17 responses that favor autoimmunity and allergy. This explains the geographic and temporal rise in autoimmune diseases in industrialized societies. - Harrison's, p.2868
10. Aberrant Cell Death and Defective Debris Clearance
When cells die (especially by NETosis, pyroptosis, or secondary necrosis after delayed apoptosis clearance), intracellular contents including nuclear DNA, RNA, and modified proteins are released into the extracellular space. Certain Toll-like receptors (TLR7, TLR9) and cytosolic DNA sensors can mistake self-nucleic acids for pathogen-associated signals, triggering type I interferon production and innate immune activation.
Defects in complement (especially C1q, C2, C4) impair clearance of apoptotic debris, leading to accumulation of nuclear antigens and immune complex formation - a major mechanism in SLE. Oxidized DNA during NETosis resists enzymatic degradation and acts as a prolonged self-antigen. - Harrison's, p.2867
11. Immune Aging (Inflammaging)
With aging, accumulation of senescent immune cells with pro-inflammatory properties (termed "inflammaging"), genomic instability, mitochondrial dysfunction, and impaired clearance of intracellular debris promote aberrant T-cell and myeloid cell dysfunction. In genetically predisposed individuals, this age-related immune dysregulation can tip the balance toward autoimmunity - a proposed mechanism for RA and giant cell arteritis. - Harrison's, p.2867
12. Sex Hormones
Autoimmune diseases are significantly more common in women (9:1 female:male ratio for some conditions like SLE). Estrogen enhances B-cell survival and antibody responses while potentially impairing Treg function. Testosterone tends to be immunosuppressive. This explains higher female susceptibility and the observation that autoimmunity can flare during pregnancy or postpartum. - Rheumatology 2-Volume Set (Elsevier)
Summary Table
| Hypothesis | Core Mechanism | Key Example |
|---|---|---|
| Molecular mimicry | Pathogen-self antigen cross-reactivity | Rheumatic fever / Streptococcus |
| Bystander activation | Non-specific co-stimulation by infection | Coxsackievirus myocarditis |
| Epitope spreading | Progressive broadening of self-attack | SLE, RA |
| Sequestered antigen | Release of immunologically naive self-antigens | MS, sympathetic ophthalmia |
| HLA/genetic susceptibility | Efficient autoreactive T cell activation | T1DM (DR3/DR4), AS (B27) |
| Altered thymic function | Escape of autoreactive T cells to periphery | Infection-altered thymopoiesis |
| Treg / peripheral tolerance defects | Loss of suppressive control | IPEX syndrome, SLE (Fas mutation) |
| Superantigen polyclonal activation | Mass non-specific lymphocyte stimulation | Staphylococcal toxins |
| Hygiene hypothesis | Loss of microbial immune regulation | Rising autoimmunity in developed nations |
| Defective cell death clearance | Self-nucleic acid sensing by TLRs/innate system | SLE, complement deficiencies |
| Inflammaging | Senescent pro-inflammatory immune cells | RA, giant cell arteritis |
| Sex hormones | Estrogen-driven immune hyperreactivity | SLE female predominance |
In most real-world autoimmune diseases, several of these mechanisms operate simultaneously. A genetically susceptible individual, exposed to an environmental trigger, with defective immune regulation, represents the intersection where clinical autoimmunity emerges.
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