Autoimmunity

Definition

Body’s own cells/antibodies attack self-antigens → structural/functional damage. Paul Ehrlich — “horror autotoxicus.” Normal state = tolerance.

Immunological Tolerance

Central Tolerance

Deletion of self-reactive T/B cells during maturation. Thymus (T cells): self-antigen recognized by developing T cell → negative selection → apoptosis. Bone marrow (B cells): self-antigen recognized → Receptor editing (light chain gene re-rearrangement, new specificity) → if still self-reactive → Negative selection (apoptosis).

Imperfect — many self-reactive cells escape → need peripheral tolerance.

Peripheral Tolerance

• Ignorance — self-antigen never encountered
• Anergy — no costimulation (B7-CTLA4 instead of B7-CD28) → negative signal, unresponsive
• Phenotypic skewing — activated but secretes nonpathogenic cytokines, no autoimmune effect
• Apoptosis by AICD — activation → ↑FasL → binds Fas → apoptosis
• Treg cells — suppress via IL-10, TGF-β, or direct contact
• Dendritic cells (immature/tolerogenic) — capture self-Ag → ↓costimulatory molecules (CD40, B7) or induce Treg
• Sequestration — privileged sites (cornea, testis, brain) never encountered by immune system

B cells: 10% escapees further culled in spleen (↓BAFF).

Mechanisms of Autoimmunity (breakdown of tolerance)

1. Breakdown of T cell anergy — necrosis/inflammation induces B7 on normal cells. Postulated: MS, RA, psoriasis.
2. Failure of AICD — Fas-FasL apoptosis fails. Seen in SLE.
3. Loss of Treg cells — removes suppression.
4. T cell help for self-reactive B cells — e.g. drug-induced hemolytic anemia (drug alters RBC surface → new epitope → TH help → autoantibody).
5. Release of sequestered antigens — trauma/surgery → sperm/ocular Ag release → post-vasectomy orchitis, post-traumatic uveitis.
6. Molecular mimicry — microbial epitope resembles self-Ag → cross-reactive response.
   • Acute rheumatic fever: anti-strep M protein Ab cross-reacts cardiac glycoprotein
   • Multiple sclerosis: T cells vs myelin basic protein (viral mimicry)
7. Polyclonal lymphocyte activation — bypasses antigen specificity.
   • T cell: superantigens (S. aureus) bind Vβ region of TCR directly
   • B cell: EBV, HIV
8. Exposure of cryptic self-epitopes — never processed/presented during development (“molecular sequestration” > anatomic sequestration) → not deleted → released by inflammation/injury.
9. Epitope spreading — persistent inflammation → self-peptides processed WITH microbial peptides → T cell recognition shifts to self-epitope.
10. Bystander activation — nonspecific TH1 activation from cytokine influx at infection site.

Autoimmune Diseases

Single Organ/Cell Type

Systemic

Laboratory Diagnosis

AIHA: Coombs test (anti-human IgG antiserum → agglutination if IgG on RBC). Goodpasture: fluorescent anti-IgG/anti-C3b → LINEAR basement membrane deposits. SLE: ANA (IIF, screening, >90% positive) → Anti-dsDNA (highly specific, confirmation) → Anti-Sm. Lupus band test (direct IF, skin). LE cell test = OBSOLETE (only 50-75% positive). Scleroderma: Anti-Scl-70 (IIF). Sjögren: SS-A/anti-Ro + SS-B/anti-La (IIF). RA: RA factor (latex agglutination, IgM anti-Fc-IgG, sensitive-negative only 15%, but NOT specific-false positives in other autoimmune disease) + Anti-CCP (86% RF+ RA, 25% RF- RA, HIGHLY specific 96%). Rose-Waaler test = OBSOLETE.

Definition

Autoimmunity is a condition where the body’s own immunologically competent cells or antibodies act against self-antigens, producing structural or functional damage. Paul Ehrlich first named the concept “horror autotoxicus.” The immune system normally does not attack its own tissue because of tolerance — understanding tolerance is the necessary starting point for understanding how it fails.

Immunological Tolerance

Tolerance is the state of being unable to mount an immune response against one’s own tissue antigens, achieved through two layered mechanisms.

Central Tolerance

This deletes self-reactive T and B lymphocytes during maturation in the central lymphoid organs — thymus for T cells, bone marrow for B cells. In the thymus, a developing T cell whose receptor recognizes a self-antigen (presented by thymic APCs with self-MHC) is negatively selected and deleted by apoptosis, leaving a self-reactive-free peripheral T cell pool. In bone marrow, a developing B cell encountering self-antigen undergoes receptor editing first (reactivating light-chain gene rearrangement to produce a differently-specific receptor) and, if that edited receptor still recognizes self-antigen, negative selection by apoptosis.

Central tolerance is imperfect — many self-reactive T and B cells escape to the periphery — which is why peripheral tolerance exists as a backup.

Peripheral Tolerance

Several mechanisms counteract escaped self-reactive lymphocytes:

• Ignorance — the self-reactive T cell simply never encounters its target self-antigen.
• Anergy — unresponsiveness from incomplete activation: the self-antigen is presented without costimulation (B7 binds CTLA-4 instead of CD28), delivering a negative rather than activating signal.
• Phenotypic skewing — full activation occurs, but the cell secretes nonpathogenic cytokines and fails to drive an autoimmune response despite being technically activated.
• Apoptosis by AICD (activation-induced cell death) — activation itself upregulates Fas ligand, which engages the Fas death receptor and triggers apoptosis.
• Regulatory T cells (Treg) — suppress self-reactive T cells via cytokines (IL-10, TGF-β) or direct cell contact.
• Dendritic cells — immature/tolerogenic DCs capturing self-antigen downregulate costimulatory molecules (CD40, B7) or induce Treg cells instead of activating effector responses.
• Sequestration — certain self-antigens (corneal proteins, testicular antigens, brain antigens) sit in immunologically privileged sites the immune system never encounters under normal circumstances.

B cells get a parallel peripheral check: the roughly 10% of self-reactive B cells that escape bone-marrow central tolerance are further culled in the spleen, partly via downregulation of B cell activating factor (BAFF).

Mechanisms of Autoimmunity

Autoimmunity results from a breakdown of one or more tolerance mechanisms:

• Breakdown of T cell anergy — tissue necrosis and local inflammation can induce normal cells to express B7 they wouldn’t normally carry, removing the anergy block. Postulated in multiple sclerosis, rheumatoid arthritis, psoriasis.
• Failure of AICD — autoreactive activated T cells fail to undergo Fas-Fas-ligand apoptosis, seen in SLE.
• Loss of Treg cells — removes the suppression of self-reactive lymphocytes.
• T cell help for self-reactive B cells — self-reactive B cells only produce autoantibody if they receive T cell help; e.g. in drug-induced hemolytic anaemia, a drug alters the RBC surface enough to create a novel epitope that TH cells can recognize and help against.
• Release of sequestered antigens — trauma or surgery releasing spermatozoa or ocular antigens (never previously exposed to tolerance mechanisms) can trigger post-vasectomy orchitis or post-traumatic uveitis.
• Molecular mimicry — a microbial epitope resembles a self-antigen closely enough that the antibody/T cell response raised against the microbe cross-reacts with self tissue. Acute rheumatic fever (anti-streptococcal-M-protein antibody cross-reacting with cardiac glycoprotein) is the classic example; multiple sclerosis (T cells against myelin basic protein, potentially primed by viral peptide mimicry) is a T-cell-epitope example.
• Polyclonal lymphocyte activation — microbial products activate lymphocytes nonspecifically, bypassing normal antigen-specificity checks: superantigens (e.g. from Staphylococcus aureus) polyclonally activate T cells by binding the antigen-nonspecific Vβ region of the TCR directly; EBV, HIV, and other agents can polyclonally activate B cells.
• Exposure of cryptic self-epitopes — some epitopes of a self-antigen are never effectively processed/presented during immune development (“molecular sequestration,” more common than true anatomic sequestration), so T cell clones against them are never deleted; tissue injury and inflammation can release and differentially process these previously-hidden epitopes.
• Epitope spreading — persistent inflammation and tissue damage cause self-peptides to be processed alongside microbial peptides, and T cell recognition can shift (“spread”) from the microbial epitope to the co-presented self-epitope.
• Bystander activation — nonspecific activation of self-reactive TH1 cells simply by being present amid the cytokine influx generated by a genuinely microorganism-specific TH1 response at an infection site.

Autoimmune Diseases

Autoimmune diseases split into those confined to a single organ/cell type and those causing systemic, multi-organ disease.

Single Organ or Cell Type

Systemic

Laboratory Diagnosis

• Autoimmune hemolytic anaemia — Coombs test: red cells incubated with anti-human-IgG antiserum; agglutination confirms surface IgG.
• Goodpasture syndrome — biopsy with fluorescent-labelled anti-IgG/anti-C3b shows linear basement-membrane deposits.
• SLE — antinuclear antibody (ANA) by indirect immunofluorescence is the standard screen (positive in >90%); anti-dsDNA is highly specific and used for confirmation; anti-Sm antibodies also seen. The lupus band test (direct immunofluorescence of skin) detects Ig/complement deposits; the LE cell test is obsolete (positive in only 50–75% of cases).
• Scleroderma — anti-Scl-70 by indirect immunofluorescence.
• Sjögren syndrome — SS-A/anti-Ro and SS-B/anti-La by indirect immunofluorescence.
• Rheumatoid arthritis — RA factor by latex agglutination (IgM anti-Fc-IgG; sensitive — negative in only 15% of true RA — but not specific, since other autoimmune diseases can be falsely positive) and anti-cyclic citrullinated peptide (anti-CCP, positive in ~86% of RF-positive and ~25% of RF-negative RA, but highly specific at 96%). The Rose-Waaler test for RA factor is now obsolete.

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