HLA

HLA genes are highly polymorphic and divided into Class I (HLA-A, -B, -C) and Class II (HLA-DP, -DQ, -DR) molecules. Class I MHC is expressed on all nucleated cells and presents endogenous (intracellular) antigens via the endogenous pathway (proteasome → TAP → ER) to CD8+ cytotoxic T cells. Class II MHC is expressed on professional antigen-presenting cells (dendritic cells, macrophages, B cells) and presents exogenous antigens via the exocytic/endosomic pathway to CD4+ helper T cells. HLA typing is critical for organ/tissue transplantation matching—mismatches increase risk of graft rejection and graft-versus-host disease (GVHD). Certain HLA alleles show strong disease associations, tested via odds ratio/relative risk: HLA-B27 (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, IBD-associated arthritis, uveitis—remember 'PAIR'), HLA-DR4 (rheumatoid arthritis, type 1 diabetes), HLA-DR3 (Graves disease, SLE, type 1 diabetes, Addison disease), HLA-DQ2/DQ8 (celiac disease), HLA-B8 (Graves, myasthenia gravis), and HLA-Cw6 (psoriasis). Mechanistically, molecular mimicry and abnormal peptide presentation are theorized links between HLA type and autoimmunity. HLA genes are inherited in haplotypes (codominant expression) and are the most polymorphic genes in the human genome, contributing to their role in transplant rejection and population-level diversity in pathogen resistance. Bare lymphocyte syndrome is a rare disorder from defective MHC class I or II expression, leading to immunodeficiency.