Overview
This lecture covers autoimmune disorders, focusing on how genetic and environmental factors disrupt immunological tolerance, major mechanisms of disease, and specific examples such as myasthenia gravis, SLE, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.
Introduction to Autoimmunity
- Autoimmune disorders occur when adaptive immune responses target self-antigens (βautoβ meaning self).
- These diseases arise from the breakdown of immunological tolerance, leading to tissue damage.
- Both autoreactive T cells and autoantibody-producing B cells can be involved.
- Prevalence is about 5% in western populations.
Mechanisms of Immunological Tolerance
- Central tolerance in primary lymphoid organs (bone marrow, thymus) removes strongly self-reactive lymphocytes.
- The transcription factor AIRE enables thymus expression of tissue-specific antigens for T cell selection.
- Peripheral tolerance occurs after lymphocytes exit primary organs, involving immune-privileged sites, deletion, anergy, activation-induced cell death, and regulatory T cells (Tregs).
- Tregs inhibit inflammation via cytokines and other mechanisms.
Causes of Autoimmunity
- Defects in tolerance mechanisms allow autoreactive lymphocytes to survive or become activated.
- Genetic factors include mutations in key immune regulatory genes (AIRE, CTLA-4, FOXP3, Fas), HLA/MHC alleles, and biological sex (higher incidence in females).
- Environmental triggers include infections/inflammation, tissue injury, antigen release from immune-privileged sites, and molecular mimicry (e.g., rheumatic fever).
Pathogenesis and Classification
- Autoimmunity usually involves loss of tolerance by multiple lymphocyte types.
- Diseases are grouped by primary effector: autoantibody-mediated, immune complex-mediated, or T-cell-mediated.
- Tissue specificity is determined by antigen expression (organ-specific vs. systemic diseases).
- Many disorders show relapsing-remitting symptoms, treated with immunosuppressives.
Example Autoimmune Disorders
Myasthenia Gravis
- Driven by autoantibodies against acetylcholine receptors on muscle cells, blocking nerve signaling and causing muscle weakness.
Systemic Lupus Erythematosus (SLE)
- Caused by autoantibodies against nuclear antigens; immune complexes deposit in tissues (especially kidneys), leading to systemic inflammation.
Type 1 Diabetes Mellitus
- Mediated by CD8 T cells that destroy insulin-producing Ξ²-cells in pancreatic islets, abolishing insulin production.
Rheumatoid Arthritis (RA)
- Involves autoreactive CD4 T cells that activate macrophages and fibroblasts, causing inflammation and joint destruction.
Multiple Sclerosis (MS)
- Th1/Th17 T cells target myelin in the CNS, leading to neuroinflammation, demyelination, and progressive neurological deficits.
Key Terms & Definitions
- Allergen β harmless environmental antigen causing allergy.
- Autoantigen β self-molecule targeted in autoimmunity.
- Central tolerance β deletion of self-reactive lymphocytes in primary lymphoid organs.
- Peripheral tolerance β suppression of autoreactive cells after leaving the primary organs.
- AIRE β transcription factor enabling thymic expression of tissue-specific antigens.
- Treg (Regulatory T cell) β cell suppressing immune responses to maintain tolerance.
- Molecular mimicry β cross-reactivity between pathogen and self-antigens.
- Immune privileged site β tissue protected from immune surveillance (e.g., brain, eye).
- Relapsing-remitting β disease course with alternating flares and remissions.
Action Items / Next Steps
- Respond to the discussion board prompt on autoimmune therapies.
- Prepare for the next lecture on transplantation immunology.