Notably, the HLA-DRB1-shared epitope alleles (e.g., *04:01, *04:04, and DR4/DRx heterozygotes) demonstrate strong RA association through three principal mechanisms: (1) shaping thymic selection by altering T-cell receptor (TCR) affinity thresholds, permitting escape of autoreactive clones (8); (2) facilitating post-translational citrullination of bound peptides through local microenvironment modifications (9); and (3) enabling cross-reactivity between microbial and self-peptides via conserved binding grooves (9). Here, HLA-DRB1 is linked to rheumatoid arthritis.