Citrullination and autoimmunity

Valesini, Guido; Gerardi, Maria Chiara; Iannuccelli, Cristina; Pacucci, Viviana Antonella; Pendolino, Monica; Shoenfeld, Yehuda

doi:10.1016/j.autrev.2015.01.013

Cited by 225 publications

(230 citation statements)

References 88 publications

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“…PADs convert positively charged protein arginine residues to neutral, potentially immunogenic citrulline. In genetically predisposed individuals, protein citrullination poses the potential risk of production of anticitrullinated peptide/protein antibodies (ACPA), which are strongly associated with development of RA [31,32]. In this context, the combination of current smoking and possession of HLA-DRB1 shared epitope (SE) alleles, both of which are independently associated with RA, is closely associated with the appearance of ACPA, an event which precedes, and is predictive of, the development of RA [33][34][35][36][37][38].…”

Section: Smoking and Ramentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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Smoking is now well recognised not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. Recent studies have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smokingrelated RA. These involve release of the enzymes, peptidylarginine deiminases (PADs) 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. PADs, in turn, mediate the conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide/protein pathogenic autoantibodies (ACPA), an event which precedes the development of RA. This review is focused primarily on smoking-mediated harmful chronic inflammatory responses, both local and systemic, which promote the formation of ACPA, as well as the possible involvement of other types of outdoor and indoor pollution in the pathogenesis of RA. This is preceded by a brief overview of the evidence implicating smoking as a risk factor for development of ACPA-positive RA.Keywords: Anti-citrullinated peptide/protein antibodies; airway microbiota; atmospheric pollution; heavy metals; peptidylarginine deiminases; smoking cessation strategies. ImplicationsChronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of rheumatoid arthritis. These mechanistic insights not only reinforce the association between smoking and risk for rheumatoid arthritis, but also the necessity to increase the level of awareness in those at highest risk.

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Section: Smoking and Ramentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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“…PADI enzymes are further involved in a range of auto-inflammatory diseases, including rheumatoid arthritis and multiple sclerosis due to their activation during NETosis, apoptosis, and autophagy (12). A common denominator in these diseases is an increase in enzymatic PADI activity and increased levels of antibodies against citrullinated antigens (1).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

Cantariño

Musulén

Valero

et al. 2016

Molecular Cancer Research

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Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is upregulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently, this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis.Implications: Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points toward a possible role of citrullination in modulating tumor cells and their microenvironment.

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“…6,12,46 Antibodies to citrullinated antigens are detectable in a variety of autoimmune diseases, including RA, indicating that citrullination plays a role in the process of epitope spreading 52 and the emergence of autoepitopes. 35,60,64 Likewise, citrullinated antigens are relevant in animal models of autoimmunity. 9,24,58 Neutrophils represent another example of hitherto underappreciated contributors to the pathogenesis of autoimmune diseases.…”

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confidence: 99%

Mouse Models of Rheumatoid Arthritis

Caplazi¹,

Baca²,

Barck³

et al. 2015

Vet Pathol

117

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Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody-induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFD ARE mouse, in which arthritis results from overexpression of TNF-a, a master proinflammatory cytokine that drives disease in many patients.

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Citrullination and autoimmunity

Cited by 225 publications

References 88 publications

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

Mouse Models of Rheumatoid Arthritis

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