Interaction between extracellular matrix molecules and microbial pathogens: evidence for the missing link in autoimmunity with rheumatoid arthritis as a disease model

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation followed by tissue rebuilding or fibrosis. A failure by the body to regulate inflammation effectively is one of the hallmarks of RA. The interaction between the external environment and the human host plays an important role in the development of autoimmunity. In RA, the observation of anti-cyclic citrullinated peptide antibodies (ACPA) to autoantigens is well recognized. Citrullination is a post-translational modification mediated by peptidyl arginine deiminases, which exist in both mammalian and bacterial forms. Previous studies have shown how proteins expressed in the human extracellular matrix (ECM) acquire properties of damage-associated molecular patterns (DAMPs) in RA and include collagens, tenascin-C, and fibronectin (FN). ECM DAMPs can further potentiate tissue damage in RA. Recent work has shown that citrullination in RA occurs at mucosal sites, including the oral cavity and lung. Mucosal sites have been linked with bacterial infection, e.g., periodontal disease, where exogenous pathogens are implicated in the development of autoimmunity via an infectious trigger. Proteases produced at mucosal sites, both by bacteria and the human host, can induce the release of ECM DAMPs, thereby revealing neoepitopes which can be citrullinated and lead to an autoantibody response with further production of ACPA. In this perspectives article, the evidence for the interplay between the ECM and bacteria at human mucosal surfaces, which can become a focus for citrullination and the development of autoimmunity, is explored. Specific examples, with reference to collagen, fibrinogen, and FN, are discussed.

Urinary metabolite profiling provides potential differentiation to explore the mechanisms of adjuvant‐induced arthritis in rats

“…Between them, the secondary inflammatory period caused by autoimmune disorders reached a peak between days 19 and 21 following arthritis induction. Paw swelling and arthritis index are the main indicators of AA rats (Sofat et al, 2014). This study found that secondary paw swelling and arthritis index significantly increased in the experimental group.…”

Protein Posttranslational Modifications: Roles in Aging and Age‐Related Disease

“…Moreover, several studies have begun uncovering the broad spectrum of PTMs involved in key bacterial cellular processes, including redox regulation via reversible S-thiolation [34], posttranslational hydroxylation [35], and the role of citrullination in the interaction between bacteria and human mucosal surfaces [36]. Several experimental studies have been done on the posttranslationally modified antimicrobial peptides known as lantibiotics [37].…”

Periodontal Disease and Autoimmunity: What We Have Learned from Microbiome Studies in Rheumatology

“…It is hypothesized that this citrullination leads to amino acid chains being recognized as autoantigens, which leads to the development of autoantibodies and the subsequent autoimmune damage that is the signature for rheumatoid arthritis. PAD is produced by human cells, for example, in the lung; however, it is also produced by the microbe P. gingivalis [52].…”