Background: Genetic variation within the human leukocyte antigen (HLA) region influences susceptibility across systemic autoimmune diseases (SADs). HLA evolutionary divergence (HED) may influence the breadth of antigen presentation, while pathogen-driven molecular mimicry could contribute to disease heterogeneity.

Objectives: To evaluate HLA class I and II alleles, their evolutionary divergence, and peptide-binding profiles in SLE compared to other systemic autoimmune diseases (SADs), focusing on potential pathogen-driven autoimmunity and clinical relevance.

Methods: HLA class I/II genotypes were analyzed 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) under an additive model. HED was calculated using the Grantham-based Pierini & Lenz algorithm. Predicted immunopeptidomes for HLA-DQA1-DQB1 and HLA-DRB1 were analyzed with NetMHCIIpan 4.2, and viral, bacterial, and archaeal peptide homology was assessed using blastp (≥80% sequence identity).

Results: DRB1*03:01 (DR3 haplotype) and DRB1*15:01–DQB1*06:02 (DR2 haplotype) were confirmed as independent SLE risk alleles, while DRB1*04:01 predominated in RA. SLE patients exhibited significantly higher DQB1 divergence (p<10 ⁻⁵ ), consistent with broader predicted peptide presentation, whereas DRB1 divergence was modestly reduced in SjS and other SADs. HED correlated with predicted peptide-binding repertoire size (DQB1 ρ=0.65; DRB1 ρ=0.62). Heterozygotes for DR2-DR3 showed the highest DQB1 divergence. Importantly, DRB1*03:01 and DRB1*15:01 alleles presented a relatively small total peptide repertoire but a high number of allele-specific peptides exhibiting homology to viral, bacterial, and archaeal proteins, compared to other alleles, suggesting a potential mechanism of pathogen-driven autoimmunity. By contrast, DQA1-DQB1 alleles in the risk haplotypes lacked enrichment of allele-specific peptides homologous to viral, bacterial, or archaeal proteins, emphasizing the allele-specific role of DRB1 in shaping immune recognition and SLE susceptibility.

Conclusions: HLA evolutionary divergence shapes antigen presentation and may contribute to SLE susceptibility. DRB1*03:01 and DRB1*15:01 appear to promote autoimmunity through recognition of peptides homologous to pathogens, whereas DQB1 alleles in the same haplotypes do not show this pattern.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.