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Objectives Genetic variation within the human leukocyte antigen (HLA) region influences susceptibility across systemic autoimmune diseases (SADs). We investigated HLA class I and II allelic associations and HLA evolutionary divergence (HED) in systemic lupus erythematosus (SLE) compared to other SADs to identify shared and disease-specific immunogenetic signatures.Methods HLA class I/II genotypes from three SLE cohorts: GWASEUR (n=6,919), SLEGEN (n=3,806), PRECISESADS SLE (n=357), and other SADs [SjS 353, SSc 337, RA 315, UCTD 154, PAPS 89, MCTD 75, controls 486] were analyzed under an additive model. HED was computed using the Grantham distance–based Pierini & Lenz algorithm. Immunopeptidomes for HLA-DQB1 and HLA-DRB1 were predicted with NetMHCIIpan 4.2, and viral/microbial peptide homology was evaluated by blastp with a minimum sequence identity (pident) of 80%.Results Across cohorts, the most significant SLE association was found for HLA-B*08:01, part of the ancestral haplotype AH8.1 including the classical DRB1*03:01 (DR3). The DR2 haplotype (DRB1*15:01–DQB1*06:02) represented an additional independent risk signal. Conversely, DRB1*04:01 predominated in rheumatoid arthritis.HLA-DQB1 showed the highest divergence, markedly increased in SLE (p < 0.00001), suggesting broader peptide presentation, whereas other SADs showed no significant divergence changes. HLA-DRB1 divergence was modestly reduced in some SADs, particularly in Sjögren’s disease, suggesting subtle disease-specific modulation of antigen presentation. HED correlated positively with peptide-binding repertoire size for DQB1 (rho= 0.65) and DRB1 (rho = 0.62). Heterozygotes for DR2-DR3 showed the highest DQB1 divergence.DRB1*03:01 and DRB1*15:01 had enriched sets of exclusive peptides, with 118,424 and 32,417 peptides, respectively (median 15,012). Of these, DRB1*03:01 included 58 peptides homologous to viral proteins (median 4) and 20,130 (17%) to bacterial proteins (median 2,815), while DRB1*15:01 included 28 viral and 11,884 (36.7%) bacterial homologs.Conclusions HLA evolutionary divergence shapes antigen presentation repertoire and autoimmune susceptibility. In SLE, increased DQB1 divergence expands peptide recognition, whereas DR2 and DR3 alleles favor viral and bacterial peptide cross-reactivity. These findings reveal shared and disease-specific immunogenetic mechanisms, suggesting that HED-driven antigen broadening and peptide pathogen mimicry may predispose to autoimmunity.