HLA-DRB5 is an MHC class II beta chain that presents exogenous peptide antigens to CD4+ T cells, functioning as a critical component of adaptive immune responses 1. The protein forms heterodimers with HLA-DRA, binding peptides of 10-30 residues in endosomal/lysosomal compartments after antigen processing by proteases. HLA-DRB5 associates with the HLA-DR15 haplotype (containing DRB1*15:01 and DRB5*01:01), presenting a complementary peptide repertoire distinct from DRB1 alone 1. Disease associations include multiple sclerosis risk, where the DR15 haplotype confers increased MS susceptibility, and rheumatoid arthritis, where the HLA-DR15 haplotype increases risk of active disease in anti-citrullinated peptide antibody-positive patients 2. HLA-DRB5 expression is downregulated in several inflammatory conditions: moderate-high disease activity rheumatoid arthritis 3, anti-citrullinated peptide antibody-negative rheumatoid arthritis 2, COPD monocyte/macrophages 4, and membranous nephropathy 5. HLA-DRB5 elevation is associated with left-sided colon cancer 6 and primary Sjögren's syndrome 7, and has been identified as an Alzheimer's disease risk gene 8. These findings suggest HLA-DRB5 variants and expression levels modulate autoimmune disease susceptibility and progression.