Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

Abstract

Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.

Molecular Mimicry of the Rheumatoid Arthritis-Related Immunodominant T-Cell Epitope within Type II Collagen (CII260-270) by the Bacterial L-Asparaginase

“…One of the most common hypotheses is that it involves infection with certain pathogenic microorganisms and subsequent molecular mimicry [ 1 , 2 , 3 , 4 , 5 ]. Molecular mimicry assumes sequence similarity between pathogenic and self-peptides that could provoke the cross-reactivity of the activated T or B cells to self-structures [ 6 ]. T lymphocytes (Th1 and Th17) are leading immune cells in the development of RA [ 6 , 7 , 8 ].…”

“…Molecular mimicry assumes sequence similarity between pathogenic and self-peptides that could provoke the cross-reactivity of the activated T or B cells to self-structures [ 6 ]. T lymphocytes (Th1 and Th17) are leading immune cells in the development of RA [ 6 , 7 , 8 ].…”

“…Cusick et al proposed that this is due to the involvement of multiple infections in the priming of the immune system and they gave examples of bacterial infections initiating or exacerbating autoimmune diseases [ 2 ]. In search of homology between bacterial proteins and RA-related T-cell epitopes using an immunoinformatics analysis, Repac et al were able to retrieve the major RA-triggering candidates among which are Proteus mirabilis , Escherichia coli , Mycobacterium tuberculosis , Klebsiella pneumoniae , Streptococcus pyogenes, and Prevotella species [ 6 ]. A possible role of some oral and gut microbial species ( Porphyromonas gingivalis and Prevotella copri ) in RA pathogenicity has also been discussed [ 9 , 10 ].…”

“…This immunodominant T-cell epitope is restricted by the RA-associated HLA-DRB1*04 and HLA-DRB1*01 alleles [ 11 , 12 , 19 , 20 , 22 ]. Thus, to trigger autoreactive T cells via molecular mimicry, the foreign antigens have to be similar to the RA-related T-cell epitopes and presented within the right HLA molecules [ 6 ].…”

Integration: Gospel for immune bioinformatician on epitope-based therapy

“…Affinity analyses have been widely used in the study of infectious diseases ( 22 – 24 ), neoplasms ( 25 ) and autoimmune diseases ( 26 ). Table 1 lists the current international mainstream epitope analysis algorithms.…”