A liver biopsy from a 40-year-old woman with autoimmune hepatitis shows interface hepatitis (piecemeal necrosis), plasma cell-rich portal infiltrates, rosette formation of hepatocytes, and hepatocyte 'emperipolesis' (lymphocytes penetrating hepatocyte cytoplasm). Serology shows ANA positive 1:640, anti-smooth muscle antibody (SMA) positive 1:320, elevated IgG (3.8 g/dL). Which HLA allele is most strongly associated with Type 1 AIH in European populations, and what is the mechanistic link?
- A HLA-A*02:01; presentation of endogenous hepatocyte antigens via MHC class I to cytotoxic CD8+ T cells drives direct hepatocytolysis
- B HLA-B*27:05; molecular mimicry with HBsAg drives cross-reactive T-cell activation in hepatitis B-triggered autoimmunity
- C HLA-DQ2 (DQB1*02:01); shared with celiac disease, allowing gluten-derived peptides to trigger hepatic inflammation via portal circulation
- D HLA-DR3 (DRB1*03:01) and HLA-DR4 (DRB1*04:01); these MHC class II alleles present hepatocyte-derived autoantigens (e.g., ASGPR, SLA/LP) to CD4+ helper T cells, amplifying Th1/Th17-driven inflammation and B-cell autoantibody production ✓
Explanation
Type 1 autoimmune hepatitis is strongly associated with HLA-DR3 (DRB1*03:01) in younger patients with more aggressive disease, and HLA-DR4 (DRB1*04:01) in older patients with milder disease. Both alleles encode MHC class II molecules that bind and present hepatocyte-derived autoantigenic peptides (ASGPR, CYP2D6 for Type 2, SLA/LP) to CD4+ T helper cells. The resulting Th1 and Th17 responses cause IFN-γ and IL-17 production that attracts cytotoxic lymphocytes and activates B cells to produce ANA and SMA; emperipolesis represents lymphocyte-mediated hepatocyte injury via perforin/granzyme.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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