This article was originally published here
Front Immunol. June 01, 2021; 12: 678953. doi: 10.3389 / fimmu.2021.678953. eCollection 2021.
ABSTRACT
The generation of post-translational modifications (PTMs) in human proteins is a physiological process that leads to a structural and immunological diversity of proteins with potentially altered biological functions. PTMs often arise from normal responses to cellular stress, including general oxidative changes in the tissue microenvironment and intracellular stress on the endoplasmic reticulum or immune-mediated inflammatory stress. Many studies have now shown the presence of “neoepitopes”, which consist of PTM’s own proteins that induce robust autoimmune reactions. These pathways for inflammatory neoepitopes are commonly seen in many autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (T1D), among others. This review will focus on a specific PTM for self proteins known as citrullination. Citrullination is mediated by calcium-dependent peptidylarginine deiminase (PAD) enzymes, which catalyze the elimination, the conversion of arginine into the non-classical amino acid citrulline. PADs and citrullinated peptides have been implicated in various autoimmune diseases, particularly with prominent roles in the diagnosis and pathology of rheumatoid arthritis. More recently, an important role for PADs and citrullinated self-proteins in T1D has emerged. In this review, we will provide a comprehensive overview of the pathogenic roles of PADs and citrullination in inflammation and autoimmunity, with particular focus on the evidence for their role in T1D. The general role of PADs in epigenetic and transcriptional processes as well as their crucial role in histone citrullination, neutrophil biology and neutrophil extracellular traps (NET) formation are discussed. The latter is important given the increasing evidence that neutrophils and NETosis play a role in the pathogenesis of T1D. In addition, the underlying processes leading to citrullination will be discussed, the genetic susceptibility factors for increased recognition of citrullinated epitopes by T1D HLA susceptibility types and an overview of the reported autoreactive responses to citrullinated epitopes of both T cells and autoantibodies give in T1D patients. Finally, we will discuss recent observations in NOD mice that indicate the prevention of diabetes development through PAD inhibition, and the potential role of PAD inhibitors as a new therapeutic strategy in autoimmunity, and particularly in T1D.
PMID: 34140951 | PMC: PMC8204103 | DOI: 10.3389 / fimmu.2021.678953
