HLA-DRB4 is a major histocompatibility complex class II molecule that presents exogenous peptide antigens to CD4+ T cells, playing a crucial role in adaptive immune responses. The protein binds peptides of 10-30 residues derived from antigens that enter the endocytic pathway of antigen-presenting cells (APCs), including dendritic cells and gastrointestinal epithelial cells. HLA-DRB4 forms a heterodimer with an alpha chain and associates with CD74 in the endoplasmic reticulum before trafficking to endosomal/lysosomal compartments where antigen processing occurs [UniProt]. The peptide-binding cleft exhibits unique structural features: position 81 (Ybeta81) alters P1 pocket specificity, while residues at positions 71, 74, 26, and 13 create a distinctive P4 pocket topology, conferring complementary rather than redundant binding patterns compared to other HLA-DR molecules 1. Clinically, HLA-DRB4 associations have been identified in multiple autoimmune and infectious diseases. HLA-DRB4 presence was nearly universal (100%) in anti-LGI1 encephalitis patients versus 46.5% in controls, supporting an autoimmune mechanism 2. The DRB4*01:01 allele shows positive association with early-onset vitiligo and protects against late-onset disease, possibly through arginine at position 71 affecting antigen presentation 3. HLA-DRB4 also interacts with CTLA-4 polymorphisms to influence thyroid dysfunction severity in Hashimoto's thyroiditis 4. Additionally, HLA-DRB4-containing haplotypes show protective associations against HIV-related Kaposi's sarcoma 5.