Abstract
Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the immune system. Over the years, contribution of unstable defective ribosomal products (DRiPs) in immunosurveillance has gained prominence. A class of unstable products emerge from non-canonical translation and processing of unannotated mammalian and viral ORFs and their peptides are cryptic in nature. Indeed, high throughput sequencing and proteomics have revealed that a substantial portion of our genomes comprise of non-canonical ORFs, whose generation is significantly modulated during disease. Many of these ORFs comprise short ORFs (sORFs) and upstream ORFs (uORFs) that resemble DRiPs and may hence be preferentially presented. Here, we discuss how such products, normally “hidden” from the immune system, become abundant in viral infections activating autoimmune T-cells, by discussing their emerging role in infection and disease. Finally, we provide a perspective on how these mechanisms can explain several autoimmune disorders in the wake of the COVID-19 pandemic.
Highlights
One of the salient features of autoimmunity lies in the recognition of MHC class I associated self-peptides by T-cells that have escaped self-tolerance during their development and selection in the thymus
While peptides derived from exogenous proteins, Cryptic Peptides in Virus-Induced Autoimmunity acquired externally through the endo-lysosomal pathway are loaded on MHC-II molecules, peptides derived from endogenously synthesized proteins are presented on MHC-I (Vyas et al, 2008)
We provide a perspective on how non-canonical translation and generation of cryptic epitopes can improve our understanding of autoimmune disorders in the context of viral infections
Summary
One of the salient features of autoimmunity lies in the recognition of MHC class I associated self-peptides by T-cells that have escaped self-tolerance during their development and selection in the thymus. Given the immunological role of non-canonical gene products under infection and disease, we speculate that these peptides may play a role in autoimmunity, where they would be absent or weakly presented during T-cell selection, mediating their escape.
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