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Mechanism of autoimmunity Robbins based md pathology exam answer

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autoimmunity mechanisms breakdown self tolerance current review

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Mechanisms of Autoimmunity

Autoimmunity is an immune response against self-antigens due to a failure of self-tolerance. It produces tissue injury through autoantibodies, immune complexes, and autoreactive T cells.

Normal self-tolerance

Self-reactive lymphocytes are normally controlled at two levels:
  1. Central tolerance - in thymus for T cells and bone marrow for B cells
    • Strongly self-reactive immature lymphocytes undergo negative selection (clonal deletion) by apoptosis.
    • Self-reactive B cells may undergo receptor editing.
    • The thymic protein AIRE enables expression of peripheral self-antigens in the thymus, allowing deletion of T cells reactive to them. AIRE deficiency causes autoimmune polyendocrine syndrome.
  2. Peripheral tolerance - controls self-reactive cells that escape central tolerance
    • Anergy: antigen recognition without adequate co-stimulation renders T cells functionally unresponsive.
    • Suppression by regulatory T cells (Tregs): Tregs suppress autoreactive lymphocytes, mainly through IL-10, TGF-beta, and inhibitory surface molecules.
    • Inhibitory receptors: CTLA-4 and PD-1 inhibit lymphocyte activation.
    • Deletion/apoptosis: repeated stimulation by self-antigen can eliminate autoreactive lymphocytes.
Robbins & Kumar Basic Pathology, p. 175.

Etiopathogenesis: Why self-tolerance fails

Autoimmune diseases develop from the interaction of genetic susceptibility and environmental triggers.

1. Genetic susceptibility

Autoimmune disease is usually polygenic. The important genetic factors are:
  • HLA genes: strongest association in many diseases. Certain MHC alleles present self-peptides more efficiently to T cells.
    • Examples: HLA-B27 in ankylosing spondylitis; HLA-DR3/DR4 in type 1 diabetes mellitus.
  • Genes regulating immune tolerance and lymphocyte activation
    • AIRE defects impair central T-cell tolerance.
    • CTLA-4 polymorphisms reduce inhibitory signaling.
    • Defects affecting Treg development/function, such as FOXP3-related abnormalities, impair peripheral tolerance.
    • Variants in genes involved in cytokine signaling, antigen receptor signaling, apoptosis, and clearance of immune complexes or apoptotic cells can promote autoreactivity.
Thus, genetic defects permit survival or activation of self-reactive T and B cells.

2. Failure of central tolerance

Self-reactive T or B cells may not be deleted during maturation because:
  • Self-antigen is absent or inadequately expressed in thymus/bone marrow.
  • AIRE-dependent expression of tissue antigens is defective.
  • Negative selection or B-cell receptor editing is ineffective.
These lymphocytes then enter peripheral tissues.

3. Failure of peripheral tolerance

Autoreactive mature lymphocytes are activated because of:
  • Defective Treg-mediated suppression
  • Failure of anergy due to excess co-stimulation
  • Reduced inhibitory signals through CTLA-4 or PD-1
  • Failure of activation-induced apoptosis
  • Abnormal activation of B cells, including excessive survival signals
This allows autoreactive helper T cells to activate B cells and cytotoxic T cells.

4. Infections and tissue injury

Infections are important triggers in genetically susceptible persons.

A. Increased co-stimulation and bystander activation

Microbial infection causes inflammation. APCs then express more co-stimulatory molecules and produce cytokines. A self-reactive T cell encountering self-antigen in this inflammatory setting may become activated rather than anergic.

B. Molecular mimicry

Microbial antigens may resemble self-antigens. The immune response generated against the pathogen cross-reacts with host tissue.
  • Example: antibodies against streptococcal M protein cross-react with cardiac tissue in rheumatic fever.

C. Release or altered presentation of self-antigens

Tissue injury may expose normally sequestered or poorly available self-antigens. It can also alter self-proteins, creating neoantigens recognized as foreign.
  • Examples include exposure of ocular antigens after eye trauma and release of nuclear antigens during cell injury.

D. Innate immune activation

Microbial products activate innate immune receptors, including Toll-like receptors, generating cytokines and APC activation. In predisposed individuals this can enhance autoreactive T- and B-cell responses.

5. Defective clearance of apoptotic cells and immune complexes

Persistence of apoptotic cellular material exposes nuclear antigens to the immune system. Failure to remove immune complexes may also sustain inflammation and autoantibody production.
This is especially relevant in systemic lupus erythematosus, in which nuclear antigens, nucleic-acid sensing TLRs, and type I interferons contribute to loss of tolerance.

Mechanisms of tissue injury in autoimmune disease

Once autoimmunity develops, injury occurs by the same mechanisms as hypersensitivity reactions:
  1. Autoantibody-mediated disease
    • Antibodies may opsonize cells and cause phagocytosis or complement-mediated lysis.
    • Antibodies may cause inflammation by complement activation.
    • Antibodies may alter receptor function.
    • Examples: autoimmune hemolytic anemia, Goodpasture syndrome, Graves disease, myasthenia gravis.
  2. Immune-complex-mediated injury
    • Circulating autoantigen-autoantibody complexes deposit in tissues and activate complement.
    • Example: SLE.
  3. T-cell-mediated injury
    • CD4+ Th1 and Th17 cells recruit and activate macrophages and other leukocytes through cytokines.
    • CD8+ cytotoxic T cells directly kill self-antigen-expressing cells.
    • Examples: type 1 diabetes mellitus and multiple sclerosis.

Flowchart for exam

Genetic susceptibility
+
Environmental trigger: infection, inflammation, tissue damage
↓
Defect in central or peripheral self-tolerance
↓
Survival and activation of autoreactive T cells and B cells
↓
Autoantibodies, immune complexes, helper T-cell inflammation, CTL-mediated killing
↓
Organ-specific or systemic autoimmune disease

Conclusion

Autoimmunity results from a breakdown of central and peripheral tolerance to self-antigens. Its pathogenesis requires a susceptible genetic background together with environmental triggers, particularly infections and tissue injury. The resulting autoreactive lymphocytes cause disease through autoantibodies, immune complexes, inflammatory T cells, and cytotoxic T cells.
Robbins & Kumar Basic Pathology, p. 175.
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