SARS-CoV-2 Spike Protein and Molecular Mimicry: An Immunoinformatic Screen for Cross-Reactive Autoantigen Candidates

This study investigated the role of molecular mimicry in the context of autoimmunity associated with viral infection, using SARS-CoV-2 as a model system. A bioinformatic analysis was performed to identify sequence homologies between the SARS-CoV-2 Spike (S) protein and the human proteome, with a specific focus on immunogenic regions to assess potential cross-reactivity. The analysis revealed homologous regions between the viral S protein and several human proteins, including DAAM2, CHL1, HAVR2/TIM3, FSTL1, FHOD3, MYO18A, EMILIN3, LAMP1, and αENaC, which are predicted to be recognizable by B-cell receptors. Such recognition could potentially lead to the production of autoreactive antibodies, which can contribute to the development of autoimmune diseases. Furthermore, the study examined potential autoreactive CD4+ T-cell responses to human protein autoepitopes that could be presented by HLA class II molecules. Several HLA class II genetic variants were computationally associated with a higher likelihood of cross-reactive immune reactions following COVID-19, including HLA-DPA1*01:03/DPB1*02:01, HLA-DPA1*02:01/DPB1*01:01, HLA-DPA1*02:01/DPB1*05:01, HLA-DPA1*02:01/DPB1*14:01, HLA-DQA1*01:02/DQB1*06:02, HLA-DRB1*04:01, HLA-DRB1*04:05, HLA-DRB1*07:01, and HLA-DRB1*15:01. Additionally, seven T helper cell autoepitopes (YSEILDKYFKNFDNG, ERTRFQTLLNELDRS, AERTRFQTLLNELDR, RERKVEAEVQAIQEQ, NAINIGLTVLPPPRT, PQSAVYSTGSNGILL, TIRIGIYIGAGICAG) were identified that could be implicated in autoimmune T-cell responses through presentation by class II HLA molecules. These findings highlight the utility of viral B- and T-cell epitope prediction for investigating molecular mimicry as a possible mechanism in virus-associated autoimmunity.