Triggering type 1 diabetes post-covid: molecular mimicry?

Abstract

Objective To evaluate the possible similarity between the AA sequences of human insulin and human glutamic acid decarboxylase-65 (GAD65) with the SARS-CoV-2/COVID proteins to explain the possible trigger of DM1. Methods AA sequences of human insulin, GAD65 and SARS-CoV-2 were obtained from the Protein Data Bank archive information database (RCSB PDB). NetMHCpan v4.1 was used for epitope prediction. Sequences were compared using BLAST for epitope comparison and Pairwise Structure Alignment to assess protein similarity. The AA sequences of human insulin (4F0N) and GAD65 (2OKK) were compared with the sequences of the following SARS-CoV-2 proteins: SARS-Cov2 S protein at open state (7DDN), SARS-Cov2 S protein at close state (7DDD), SARS CoV-2 Spike protein (6ZB5), Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain (6M3M), Crystal structure of SARS-CoV-2 nucleocapsid protein C-terminal RNA binding domain (7DE1), Crystal structure of NSP1 from SARS-CoV-2 (7K3N), and SARS-CoV-2 S trimer (7DK3)). Results The percent similarity between epitopes ranged from 45 to 60% (P 0.048) between both human insulin and SARS-CoV2 and for GAD 65 and SARS-CoV2, while the AA similarity of the evaluated samples ranged from 5.00–45.45% between human insulin and SARS-CoV2 and from 10.45–22.22% between GAD65 and SARS-CoV2. Conclusion Immunoinformatics data suggest a potential pathogenic link between SARS-CoV-2/COVID and DM1. Thus, by molecular mimicry, we found that sequence similarity between epitopes and AA sequence between SARS-CoV-2 / COVID and human insulin and GAD65 could lead to the production of an immune cross-response to self-antigens, with self-tolerance breakdown, which could thus trigger DM1.

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“…The molecular mimicry hypothesis is the most appealing pathophysiological pattern mediating beta cells autoimmune injury as suggested by Andrade et al. in a study published in October 2022 where amino-acid sequences of human insulin and GAD65 as long as their epitopes were compared with the sequences of the SARS-CoV-2 proteins (S protein, Spike protein) ( 29 ). Epitope similarity between human insulin and SARS-CoV-2 and between GAD65 and SARS-CoV-2 ranged between 45 to 60%.…”

“…Epitope similarity between human insulin and SARS-CoV-2 and between GAD65 and SARS-CoV-2 ranged between 45 to 60%. This would plausibly result in the development of an immune cross-reaction to self-antigens, thus triggering T1D ( 29 ). However, without clinical data from individuals with T1D or COVID-19, it is difficult to establish a direct causal relationship between SARS-CoV-2 and the triggering of T1D.…”