MHC class I

**Structure** - Heterodimer: one transmembrane α (heavy) chain with 3 domains (α1, α2, α3) plus non-covalently associated β2-microglobulin (β2m; encoded on chromosome 15, not in the MHC locus). - Peptide-binding groove is formed by α1 and α2 and holds peptides of about 8-10 amino acids. - The α3 domain binds CD8 (CD8 × MHC I = 8; 2 × 4 = 8 for MHC II/CD4 is a common mnemonic: "MHC 1 × CD8 = 8", "MHC 2 × CD4 = 8"). - Genes: HLA-A, HLA-B, HLA-C (classical), on chromosome 6p. They are codominantly expressed, so each person has up to 6 different class I alleles. Nonclassical: HLA-E, -F, -G (HLA-G protects fetal trophoblast from NK cells).

**Antigen processing (endogenous pathway)** 1. Cytosolic proteins (viral, tumor, self) are degraded by the proteasome (the immunoproteasome is induced by IFN-γ). 2. Peptides are transported into the ER by TAP (transporter associated with antigen processing). 3. In the ER, the peptide-loading complex (calreticulin, tapasin, ERp57, TAP) loads the peptide onto the α chain/β2m. ERAP trims peptides. 4. The stable peptide-MHC I complex travels via the Golgi to the cell surface. - IFN-α, -β, and -γ upregulate MHC I expression.

**Function and immune interactions** - The TCR on CD8+ T cells recognizes peptide-MHC I, leading to cytotoxic killing through perforin/granzyme and Fas-FasL. - NK cells use inhibitory receptors (KIRs, CD94/NKG2A) that bind MHC I and so spare healthy cells. Cells that lose MHC I (viruses, tumors) are killed by NK cells ("missing self"). - Cross-presentation: certain dendritic cells present exogenous antigen on MHC I to prime naive CD8+ T cells. - Positive selection in the thymic cortex: T cells that bind MHC I become CD8+. - Alloreactivity: MHC mismatch drives graft rejection. Donor MHC is recognized by direct and indirect pathways.

**Clinical associations** - Viral immune evasion: HSV (ICP47 inhibits TAP), CMV (US2/US11 degrade MHC I), adenovirus, and HIV Nef downregulate MHC I. - Bare lymphocyte syndrome type I: TAP or tapasin deficiency causes absent MHC I surface expression, with recurrent respiratory bacterial infections and sometimes necrotizing granulomatous skin lesions. - Tumor escape: loss of β2m or MHC I downregulation helps tumors evade CD8+ T cells. - HLA-B27: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and IBD-associated arthropathy (PAIR). - HLA-B51: Behçet disease. - HLA-B57:01: abacavir hypersensitivity (screen before use). HLA-B15:02: carbamazepine SJS/TEN in Asian patients. HLA-B58:01: allopurinol hypersensitivity. - HLA-A3 (and the C282Y mutation in HFE, which is MHC I-like): hereditary hemochromatosis. HFE is an MHC I-like protein. - Congenital adrenal hyperplasia (21-hydroxylase deficiency) is linked to the nearby MHC III region.

**MHC I vs MHC II (high-yield comparison)** - MHC I: HLA-A, -B, -C; all nucleated cells and platelets; endogenous antigen; CD8+ T cells; peptides loaded in the ER; β2m is required. - MHC II: HLA-DP, -DQ, -DR; APCs only (dendritic cells, macrophages, B cells, and activated endothelium/thymic epithelium); exogenous antigen; CD4+ T cells; loaded in endosomes after the invariant chain is replaced by CLIP and HLA-DM acts. - Disorders of MHC II include bare lymphocyte syndrome type II (CIITA/RFX mutations) and associations such as HLA-DR3/DR4 (type 1 diabetes), DR2 (MS, Goodpasture, SLE), DR5 (pernicious anemia, Hashimoto), DQ2/DQ8 (celiac), and DR4 (rheumatoid arthritis).