Tolerance and Autoimmunity Study Notes

Immunologic Tolerance: Specific unresponsiveness to self-antigens induced by exposure of lymphocytes to those antigens.
Key Functions:
- Prevents immune attack against the body's own tissues.
- Active tolerance mechanisms prevent inflammatory reactions to harmless airborne and food antigens at mucosal surfaces.

Definition: Takes place in generative (central) lymphoid organs (thymus and bone marrow) during lymphocyte maturation.
T Cell Selection:
- Positive Selection: Occurs in the thymic cortex on immature double-positive ( $CD4^+CD8^+$ ) thymocytes. Cells recognizing self-MHC presenting self-peptides with low-to-moderate affinity receive survival signals.
- Negative Selection: High-affinity TCR binding to self-peptide-MHC complexes triggers apoptosis. Medullary thymic epithelial cells (MTECs), regulated by the Autoimmune Regulator (AIRE) protein, express peripheral tissue-restricted antigens to eliminate autoreactive T cells. Mutations in AIRE cause Autoimmune Polyglandular Syndrome Type 1 (APS-1).
B Cell Selection:
- Positive Selection: Based on expression of functional antigen receptor complexes (pre-BCR and complete membrane IgM).
- Negative Selection: Immature B cells recognizing self-antigens with high affinity undergo receptor editing (re-rearranging light-chain genes). If editing fails or strong reactivity persists, the cell undergoes apoptotic deletion.

Definition: Silences mature T and B cells that escape central tolerance upon encountering self-antigens in peripheral tissues or secondary lymphoid organs.

Mechanisms for Autoreactive T-Cell Silencing:
- Clonal Deletion: Activation-induced cell death.
- Clonal Anergy: Prolonged unresponsiveness induced when a T cell recognizes self-antigen without co-stimulation (e.g., B7-CD28 interaction) or through engagement of inhibitory receptors (CTLA-4, PD-1).
- Peripheral Suppression: Mediated by regulatory T ( $\text{T}_{\text{reg}}$ ) cells ( $CD4^+$ T cells).
Clinical Context:
- Applications: Can be induced to prevent organ transplant rejection and treat autoimmune or allergic diseases.
- Negative Impacts: Allows certain pathogens to evade elimination and provides a microenvironment survival strategy for tumors.

Autoimmunity: Chronic, progressive tissue damage resulting from an overactive immune response against host self-antigens, driven by genetic susceptibility and environmental triggers.
Immunologic Mechanisms of Tolerance Breakdown:
- Defective Self-Tolerance: Autoreactive lymphocytes escape deletion, $\text{T}_{\text{reg}}$ suppression, or inhibitory receptor control (e.g., AIRE mutations).
- Abnormal Self-Antigen Display: Modified self-antigens become immunogenic (e.g., citrullinated proteins in RA).
- Innate Inflammation: Cytokine imbalances disrupt tolerance (e.g., Type I interferons in SLE).
- Polyclonal B-Cell Activation: Microbes directly stimulate self-reactive B cells (e.g., EBV).
- Exposure of Sequestered Antigens: Hidden antigens enter circulation (e.g., lens proteins, sperm antigens after mumps).
- Molecular Mimicry: Microbial epitopes cross-react with self-antigens (e.g., Streptococcus M protein and cardiac tissue in rheumatic fever).
- Aberrant Class II MHC Expression: Non-APCs express Class II MHC and present self-peptides to helper T cells.

Characterized by autoantibody-mediated destruction of blood components (RBCs, platelets, or leukocytes).

Warm Autoimmune Hemolytic Anemia (WAHA):
- Hemolysis Temperature: $98.6^\circ\text{F}\,(37^\circ\text{C})$ .
- Antibody Class: IgG.
- Clinical Features: Dizziness, palpitations, dark urine, pale skin, jaundice, fatigue, enlarged spleen, or deep vein thrombosis (DVT).
- Treatment: Prednisone (may include Rituximab), blood transfusions in severe cases, immunosuppressive agents.
Cold Agglutinin Disease (CAD):
- Hemolysis Temperature: $37\text{--}39^\circ\text{F}\,(3\text{--}4^\circ\text{C})$ .
- Antibody Class: IgM.
- Clinical Features: Raynaud phenomenon alongside general hemolytic manifestations.
- Treatment: Chemotherapy agents.
Diagnosis: Blood tests and Coombs test.

Directed against ubiquitous self-antigens (e.g., nuclear DNA, nucleoproteins, IgG Fc regions), causing widespread multisystem damage driven by Type III or multi-tissue Type II/IV reactions.
Systemic Lupus Erythematosus (SLE):
- Pathogenesis: Characterized by pathogenic autoantibodies against nucleic acids, defective clearance of apoptotic bodies, endosomal TLR engagement, and elevated Type 1 interferons. Leads to vasculopathy, vasculitis, immune complex deposition, and severe renal involvement.
- Demographics: Primarily affects females; $5\%$ of cases present around puberty.
- Diagnostics: Antinuclear Antibody (ANA) test ( $95\%$ sensitivity); Extractable Nuclear Antigen (ENA) test to identify specific binding targets.
Rheumatoid Arthritis (RA):
- Pathogenesis: Autoimmune destruction targeting joints, tendons, and bones. Interaction of HLA susceptibility genes, environmental factors (e.g., smoking), and citrullination of self-proteins activates $\text{Th}17$ and $\text{Th}1$ cells, driving synoviocyte activation, cytokine production, and bone/cartilage destruction.
- Demographics: Prevalence is $2\text{--}3\text{ times}$ greater in women than men.
- Serology: Rheumatoid Factor (RF; IgM anti-antibody targeting the Fc region of IgG, forming immune complexes that deposit in joints) and Anti-Citrullinated Protein Antibodies (ACCP; specific diagnostic marker). ESR and CRP measure general inflammation.

Directed against autoantigens with restricted tissue distribution in a single organ or cell type; driven by Type II or Type IV mechanisms.
Type 1 Diabetes Mellitus (T1DM / IDDM):
- Autoimmune destruction of pancreatic beta cells causing absolute insulin deficiency.
- Genetics: Associated with HLA-DR3 and HLA-DR4.
- Serology: Islet cell cytoplasmic antibodies (ICA) and insulin autoantibodies (IAA).
Hashimoto's Thyroiditis:
- Chronic lymphocytic thyroiditis resulting in thyroid gland destruction by Th1 cells and autoantibodies.
- Demographics: $4\text{--}10\text{ times}$ more common in women; typically develops between ages $30\text{--}50$ .
Graves' Disease:
- Autoimmune hyperthyroidism caused by activating TSH-receptor autoantibodies (TSHR-Ab) that stimulate thyroid hormone production and gland growth (diffuse goiter).
- Demographics: $7.5\text{ times}$ more common in women; peak onset between ages $30\text{--}40$ .
- Genetics: Associated with HLA-DR3 in Caucasians, and HLA Bw35 / HLA Bw36 in Asians.