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Rheumatoid Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Brent A. Luedders, Ted R. Mikuls, James R. O’Dell, Bryant R. England
RF and ACPA are the most clinically relevant autoantibodies in RA. RF targets the Fc region of IgG,40 whereas ACPAs target citrullinated peptides resulting from the posttranslational modification of arginine facilitated by peptidyl arginine deiminase (PAD) enzymes.41 While enzymatically mediated protein citrullination is not specific to RA, tolerance loss to these peptides is. Several antigen-specific citrullinated proteins have been found to be the targets of ACPAs in RA, including α-enolase, fibrinogen, filaggrin, vimentin, and type II collagen, among others.42 Studies leveraging biobanked blood samples of RA patients from the prediagnostic period have shown that RF and ACPA antibodies are detectable in the serum years before the development of clinical signs or symptoms of inflammatory arthritis.43–45 In the absence of joint inflammation, it is hypothesized that RA-related autoimmunity may originate at mucosal sites, such as the lung, intestine, or oral mucosa.46 Evidence suggests that RF and ACPA antibodies may be pathogenic through the ability to stimulate pro-inflammatory cytokine production, an effect that is synergistic among those dual positive for RF and ACPA,47 as well as through direct activation of osteoclasts and pain receptors.48
Biochemical Markers in Ophthalmology
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Abdus Samad Ansari, Pirro G. Hysi
Proteomic analysis of retinal and vitreous tissue has also shown 122 identified proteins linked with the pathophysiology of Alzheimer’s disease. A pathway analysis of these differentially regulated proteins highlighted the possibility of defects in mitochondrial oxidative phosphorylation [154]. Proteomics analyses have also implicated peptidyl arginine deiminase 2 (PAD2) and optic nerve citrullination as pressure-related proteins [153].
Autoimmune Disorders across the Lifespan
Published in Michelle Tollefson, Nancy Eriksen, Neha Pathak, Improving Women's Health Across the Lifespan, 2021
Chronic exposure to tobacco smoke either primary or secondary is an independent risk factor clearly associated with disease susceptibility. Tobacco smoke triggers the development of autoantibodies favoring citrullination and alters the lung environment, resulting in a pro-inflammatory response. RA lung autoimmunity is an important extracellular manifestation and a major cause of RA-associated mortality.1
Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies
Published in Expert Review of Respiratory Medicine, 2022
Auto-immunity and inflammation cooperate in inducing signals resulting in the infiltration of the lung by numerous cell types. As compared to typical UIP, RA-UIP presents with more infiltrating CD4+ lymphocytes and dendritic cells. The appearance of myofibroblasts also differs between the two diseases [58,59]. Infiltration of the lungs by T-cells and B-cells is increased in lung biopsies of RA-ILD patients as compared to patients with IIPs, and some data suggest that this increase is emphasized in lung areas with high citrullination [47,59,60]. Whether citrullination is a marker or a cause of increased inflammation remains unclear. Inducible bronchus-associated lymphoid tissue (iBALT) is found in the lungs of patients suffering from a variety of ILD but is more developed in RA-ILD patients. Furthermore, well-formed iBALT correlates with increased mediators implicated in RA pathogenesis and tissue damage in the lung, suggesting a role of iBALT in the incidence of RA-ILD [61]. Regulatory B cells (Bregs) may be key players in RA-related inflammation. This subtype of LB is characterized by its immunosuppressive properties and the secretion of IL-10, IL-35, TGF-β [62]. Circulating Bregs are decreased in number and in function in RA patients (as well as in other CTDs) and correlates negatively with disease severity [63,64]. The phenotype of B cells infiltrating the lung remains largely undetermined. Additionally, infiltrating mast cells are increased in both RA-ILD and IPF, consistent with their supposed role in fibrogenesis [65].
Advances in the diagnosis of autoimmune diseases based on citrullinated peptides/proteins
Published in Expert Review of Molecular Diagnostics, 2021
Mohammed F. Alghamdi, Elrashdy M. Redwan
Citrullination is a post-translation modification process of proteins induced by a catalytic enzyme called peptidylarginine deiminase (PAD). PADs are a family of five calcium-dependent enzymes (PAD1-4 and PAD6) that converts the arginine residue of certain proteins to citrulline (Figure 1) [18]. Citrullination is involved in many physiological and pathological processes. During the last years, citrullination has attracted the great attention of many researchers. Although citrullination is essential for certain physiological processes; hence, it plays an important role in the terminal differentiation of the epidermis, gene regulation, central nervous system’s (CNS) plasticity, and the formation of neutrophil extracellular traps (NETs) [19–21], it is found implicated in human pathologies such as carcinogenesis and autoimmunity (such as RA, MS, and psoriasis) [22,23]. Several studies have successfully correlated this process to the immunopathogenesis of such ADs [23,24].
Objective and noninvasive biochemical markers in rheumatoid arthritis: where are we and where are we going?
Published in Expert Review of Proteomics, 2021
Anne C. Bay-Jensen, Anne Sofie Siebuhr, Dres Damgaard, Patryk Drobinski, Christian Thudium, Joachim Mortensen, Claus H Nielsen
Citrullination (or deimination) is the post-translational conversion of peptidyl-arginine into peptidyl-citrulline, as catalyzed by peptidylarginine deiminases (PADs). Citrullination affects charge distribution and protein folding and may introduce neo-epitopes that break T- or B-cell tolerance and thereby induce autoimmunity. Moreover, alterations in protein–protein interactions caused by citrullination and aberrant proteolytic degradation may lead to the release of autoantigenic peptides that increase inflammatory responses [21]. Citrullination occurs during inflammatory processes, in general, and macrophages and neutrophils are the main sources of the PADs (PAD2 and PAD4) that are considered to play the most important role in the pathogenesis of RA; the affected proteins may be of intra- as well as extra–cellular origin [59-62]. Although citrullination occurs in a number of inflammatory diseases, e.g. ankylosing spondylitis and inflammatory bowel disease [63,64], the presence of ACPAs is rather specific to RA [54]. The detection of citrullinated proteins, let alone the detection of specific citrullinated sites in any given protein, remains a challenge and as such has not been implemented as an established diagnostic tool. PAD inhibition is a promising therapeutic concept for the treatment of RA [65]. Assays showing abundant citrullination, or revealing a specific citrullination profile, are potentially important tools for patient segmentation in that respect.