Human leukocyte antigen DR4 (HLA-DR4) receptor (HLA-DR4)

The Human leukocyte antigen DR4 (HLA-DR4) receptor is a Major Histocompatibility Complex (MHC) class II cell surface glycoprotein essential for the adaptive immune response (UniProt: P01911). It consists of an alpha and a beta chain that form a specialized peptide-binding groove, which captures and presents exogenous antigens to CD4+ T-helper cells (PubMed: 25238596). This specific groove is a major genetic risk factor for rheumatoid arthritis, particularly when it contains the "shared epitope"—a conserved pentapeptide sequence that preferentially binds citrullinated self-antigens (PubMed: 12851210). The presentation of these self-antigens triggers the activation of autoreactive T cells, leading to chronic inflammation and joint destruction (PubMed: 29063305). Therapeutic strategies targeting the HLA-DR4 peptide-binding groove aim to block this presentation using small molecules, peptide mimetics, or altered peptide ligands (PubMed: 24335000). While drugs like hydroxychloroquine modulate this process by altering endosomal pH, novel inhibitors are being developed to provide more specific immunosuppression by directly masking the shared epitope (PubMed: 31439477).

Other names

HLA-DRB1*04MHC class II antigen DR4Shared Epitope-containing HLA-DRDR4

The primary mechanism involves the competitive inhibition of the peptide-binding groove to prevent the presentation of arthritogenic self-peptides to CD4+ T cells, thereby inhibiting the activation of the autoimmune cascade (PubMed: 24335000). Additionally, some drugs like hydroxychloroquine interfere with the endosomal loading of peptides onto the HLA-DR4 molecule by increasing lysosomal pH (PubMed: 23023703).