Pathomechanism of autoimmune diseases

1. Definition

Autoimmunity is an immune reaction against self (auto) antigens. Self-antigens exist in healthy people; cell turnover or injury (ischemia/necrosis) generates them. The core pathomechanism is loss of self-tolerance. Disorders are:

• Organ-specific — response against one organ/cell type → localized damage.
• Systemic — multisystem disease with many autoantibodies against many antigens.

2. Immunological tolerance

Self-tolerance = lack of immune response to one’s own antigens, maintained by two mechanisms:

• Central tolerance — deletion of self-reactive T/B lymphocytes during maturation in thymus / bone marrow. Thymic APCs present self-antigens on self-MHC; self-reactive immature T cells undergo apoptosis (negative selection); analogous editing for B cells.
• Peripheral tolerance — eliminates self-reactive cells that escaped:
  • Anergy — inactivation when costimulation (e.g. B7) is absent.
  • Suppression by regulatory T cells (Treg) — cytokines (IL-10, TGF-β) suppress self-reactive responses.
  • Activation-induced cell death — repeated stimulation → Fas/FasL apoptosis.

3. Mechanisms breaking tolerance

• Molecular mimicry — microbial epitopes cross-react with self (e.g. rheumatic heart disease after streptococcus).
• Breakdown of T-cell anergy — infection/necrosis upregulates costimulatory molecules on APCs → ↑ T-cell activation.
• Polyclonal activation (e.g. EBV).
• Modification of self-molecules (drug/hapten, partial digestion) → neoantigens.

4. Effector mechanisms & pathogenic factors

Tissue injury is mediated by autoantibodies (type II / III hypersensitivity) and T cells (type IV); immune-complex deposition is common. Th1/Th17 cytokines (IFN-γ, IL-17) drive chronic inflammation; dysregulated Treg permits autoimmunity.

Pathogenic factors: genetics (familial clustering, HLA association, gene polymorphism — CTLA-4, PTPN22), infections (antigen release), UV radiation, smoking (molecule modification), and gender (hormonal — female predominance).

Organ-specific	Systemic
Autoimmune hemolytic anemia, ITP, pernicious anemia, myasthenia gravis, Graves, Goodpasture, T1DM, MS, Hashimoto, Crohn’s	SLE, rheumatoid arthritis, systemic sclerosis, Sjögren, polyarteritis nodosa, inflammatory myopathies

💡 High-yield: Autoimmunity = loss of self-tolerance. Central tolerance = thymic/marrow negative selection; peripheral = anergy, Treg suppression, Fas apoptosis. Tolerance is broken by molecular mimicry, anergy breakdown, polyclonal activation, molecule modification. Risk: HLA + female sex + infection/UV/smoking. Effectors: autoantibodies (II/III) + T cells (IV).