human leukocyte antigen

**Genetics** - Located on chromosome 6p21; genes are highly polymorphic, codominantly expressed, and inherited as a haplotype (one from each parent). Siblings have a 25% chance of being a full HLA match. - Class I: HLA-A, -B, -C. Class II: HLA-DP, -DQ, -DR. Class III genes (not true HLA molecules) encode complement components (C2, C4, factor B), TNF-α, and lymphotoxin.

**Class I vs Class II** - Class I: expressed on all nucleated cells and platelets (not RBCs). Structure is a heavy α chain plus β2-microglobulin. It presents endogenous (intracellular, e.g., viral or tumor) peptides to CD8+ cytotoxic T cells (CD8 binds α3). Peptides are loaded in the ER after TAP transport and proteasomal degradation. Also inhibits NK cell killing (NK cells attack cells lacking MHC I). - Class II: expressed on antigen-presenting cells (dendritic cells, macrophages, B cells). Structure is an α and β chain. It presents exogenous antigens, taken up by phagocytosis or endocytosis, to CD4+ helper T cells (CD4 binds β2). The invariant chain blocks the groove in the ER and is cleaved in the endosome, leaving CLIP. HLA-DM then exchanges CLIP for the antigenic peptide.

**Clinical significance** - Transplant: HLA matching reduces rejection. Hyperacute rejection is mediated by preformed antibodies. Acute cellular rejection is mediated by T cells against donor HLA. Graft-versus-host disease occurs when donor T cells attack host HLA. - Mismatch of HLA between donor and recipient drives alloreactivity. Cross-matching detects preformed anti-HLA antibodies.

**High-yield HLA–disease associations** - HLA-A3: hemochromatosis - HLA-B27: Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis (PAIR) - HLA-B57:01: abacavir hypersensitivity (screen before starting) - HLA-B15:02: carbamazepine-induced SJS/TEN (Asian ancestry) - HLA-B58:01: allopurinol hypersensitivity - HLA-DR2: multiple sclerosis, hay fever, SLE, Goodpasture syndrome - HLA-DR3: diabetes mellitus type 1, SLE, Graves disease, Hashimoto thyroiditis, Addison disease - HLA-DR4: rheumatoid arthritis (shared epitope), diabetes mellitus type 1, Addison disease - HLA-DR5: pernicious anemia, Hashimoto thyroiditis - HLA-DQ2/DQ8: celiac disease - HLA-DQ6 (DQB1*06:02): protective against type 1 diabetes. HLA-DQB1*06:02 is associated with narcolepsy type 1. - HLA-C: psoriasis (HLA-Cw6)

**Other key points** - Mnemonic for class I: "1 × 3 = 3" – Class I has 1 chain (heavy chain) plus β2-microglobulin, and a CD8 interaction (8 = 2 × 4... commonly "MHC × CD = 8", so MHC I × CD8 = 8; MHC II × CD4 = 8). - Bare lymphocyte syndrome: deficient MHC II expression causes severe immunodeficiency. MHC I deficiency (TAP defect) causes milder, recurrent respiratory infections. - Viruses (e.g., CMV, HSV) can downregulate MHC I to evade CD8+ T cells, though NK cells compensate. - Thymic selection: positive selection on cortical epithelial cells (MHC restriction) and negative selection in the medulla (AIRE-dependent self-antigen presentation).