Background: Molecules involved in antigen presentation of intra- and extracellular peptides, are encoded by genes of the human leukocyte antigen (HLA) system located within the Major Histocompatibility Complex (MHC) region in chromosome 6p21; some of these genes are among the most polymorphic in the human genome. According to the allelic divergence advantage hypothesis, an individual’s immunopeptidome is more diverse the more different their two homologous HLA allele sequences are. Although the relationship HLA to autoimmune diseases (ADs) has been widely demonstrated, the effect of evolutionary divergence in ADs is still unknown.

Objectives: To investigate the immunopeptidome of patients with systemic autoimmune diseases through the study of the evolutionary divergence in the HLA region.

Methods: In this study we have analyzed the HLA evolutionary divergence (HED) of the sequences of the HLA-A, B, C, DPB1, DQB1 and DRB1 genes in the European cohort of the PRECISESADS project composed of 460 controls and 1,564 ADs patients. HED value summarizes the physicochemical differences according to Graham’s distance, between the aminoacids of the peptide binding sites of the two homologous alleles of each class I and class II gene of each patient. Additionally, we employed an in silico reference proteome from the bone marrow niche to investigate the binding ability of self-generated peptides potentially implicated in the etiology of ADs.

Results: In comparison to controls (HED = 12.4), patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome (13.8 and 14.4, respectively) showed a significant higher evolutionary divergence for DQB1 while a non-significant decreased HED value was observed in rheumatoid arthritis (RA) patients (11.3). DRB1 gene showed a trend towards lower HED values in ADs compared to controls. The SLE results were replicated in two independent European cohorts.

The in silico analysis of the binding capacities of peptides generated form a bone marrow niche proteomic reference for the DQB1 locus was concordant with the allelic divergence advantage hypothesis, where higher divergence values correlated with larger predicted binding capabilities. SLE patients’ genotypes demonstrated greater binding capacities of the DQB1 gene alleles as well as higher HED values. Instead, DRB1 gene alleles with the highest HED value do not correlated with the greatest self-peptide binding capacities.

Conclusion: This study revealed that HLA evolutionary divergence patterns as well as predicted binding capabilities are not only disease-specific but also gene specific. Whereas DQB1 results were consistent with the allelic divergence advantage hypothesis, DRB1 greater binding capacities were better explained by shared epitope hypothesis.

REFERENCES: NIL.

Acknowledgements: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Disclosure of Interests: None declared.