Autoimmunity and Immunological Tolerance
Autoimmunity is an immune response against the body's own (self) antigens, leading to autoimmune diseases.
- Characterized by loss of self-tolerance.
- Can involve antibody-mediated, T-cell-mediated, or combined mechanisms.
Immunological tolerance is the unresponsiveness of the immune system to self-antigens.
- Critical to prevent autoimmunity.
- Maintained through central and peripheral mechanisms.
Mechanisms of Immunological Tolerance
- 1 Central tolerance
Occurs during lymphocyte development in primary lymphoid organs.
- T cells (in thymus):
- Negative selection: self-reactive T cells undergo apoptosis.
- Development of regulatory T cells (some self-reactive T cells differentiate into Tregs).
- B cells (in bone marrow):
- Receptor editing: self-reactive B cells can change their specificity.
- Deletion: strongly self-reactive B cells undergo apoptosis.
- Anergy: functional inactivation without deletion.
- 2 Peripheral tolerance
Controls self-reactive lymphocytes that escape central tolerance.
- Anergy: Functional inactivation when lymphocytes recognize antigen without co-stimulatory signals.
- Suppression by regulatory T cells (Tregs):
- Tregs (CD4+, CD25+, FOXP3+) inhibit activation of other lymphocytes.
- Activation-induced cell death:
- Repeated stimulation leads to expression of death receptors (e.g., Fas) → apoptosis.
Breakdown of Self-Tolerance
Leads to autoimmunity. Factors include:
- 1 Genetic factors
- HLA (MHC) associations:
- HLA-B27 → ankylosing spondylitis.
- HLA-DR3/DR4 → type 1 diabetes mellitus.
- 2 Environmental factors
- Infections (molecular mimicry):
- Example: Streptococcus pyogenes → rheumatic fever (cross-reactive M protein).
- 3 Hormonal factors
- Higher prevalence in females → possible role of estrogen in promoting immune responses.
Mechanisms of Autoimmune Tissue Injury
- 1 Antibody-mediated mechanisms
- Type II hypersensitivity: cytotoxic antibodies destroy cells (e.g., autoimmune hemolytic anemia).
- Type III hypersensitivity: immune complex-mediated injury (e.g., SLE).
- 2 T cell-mediated mechanisms
- Type IV hypersensitivity: direct cellular cytotoxicity and cytokine-mediated inflammation (e.g., type 1 diabetes mellitus, multiple sclerosis).