PADI2 Is Significantly Associated with Rheumatoid Arthritis

Chang, Xiaotian; Xia, Yifang; Pan, Jihong; Meng, Qingsong; Zhao, Yan; Yan, Xinfeng

doi:10.1371/journal.pone.0081259

Cited by 40 publications

(35 citation statements)

References 47 publications

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“…The phenotypic presentations vary between the patients but clinical presentations are consistent, which [34][35][36][37] WES analysis has therefore provided us with the first steps for determining the impact of these two variants of uncertain significance and whether they have the propensity to be disease causing.…”

Section: Family Patient Gene(s) Genomic Variation Protein Effect Varimentioning

confidence: 99%

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Johnson¹,

Lowe²,

Fütterer³

et al. 2016

Haematologica

123

135

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Section: Family Patient Gene(s) Genomic Variation Protein Effect Varimentioning

confidence: 99%

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Johnson¹,

Lowe²,

Fütterer³

et al. 2016

Haematologica

123

135

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“…Peptidylarginine deiminases (PADs) catalyze citrullination, but which PAD catalyzes inflammation-induced citrullination in rheumatoid arthritis and other diseases is unclear. Single nucleotide polymorphisms (SNPs) in PADI2 and PADI4 , the genes that encode PAD2 and PAD4, have been associated with rheumatoid arthritis [4–12], suggesting that they may both be involved in disease pathogenesis. Further, both PAD2 and PAD4 are found in immune cells [13–15] as well as in the rheumatoid joint [16, 17] and a pan-PAD inhibitor reduces collagen induced arthritis [18].…”

Section: Introductionmentioning

confidence: 99%

Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

Bawadekar

Shim

Johnson

et al. 2017

Journal of Autoimmunity

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Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullination seen in inflammation. PAD4 exacerbates inflammatory arthritis and is critical for neutrophil extracellular traps (NETs). NETs display citrullinated antigens targeted by ACPAs and thus may be a source of citrullinated protein. However, PAD4 is not required for citrullination in inflamed lungs. PAD2 is important for citrullination in healthy tissues and is present in NETs, but its role in citrullination in the inflamed joint, NETosis and inflammatory arthritis is unknown. Here we use mice with TNFα-induced inflammatory arthritis, a model of rheumatoid arthritis, to identify the roles of PAD2 and PAD4 in citrullination, NETosis, and arthritis. In mice with TNFα-induced arthritis, citrullination in the inflamed ankle was increased as determined by western blot. This increase was unchanged in the ankles of mice that lack PAD4. In contrast, citrullination was nearly absent in the ankles of PAD2-deficient mice. Interestingly, PAD2 was not required for NET formation as assessed by immunofluorescence or for killing of Candida albicans as determined by viability assay. Finally, plasma cell numbers as assessed by flow cytometry, IgG levels quantified by ELISA, and inflammatory arthritis as determined by clinical and pathological scoring were all reduced in the absence of PAD2. Thus, PAD2 contributes to TNFα-induced citrullination and arthritis, but is not required for NETosis. In contrast, PAD4, which is critical for NETosis, is dispensable for generalized citrullination supporting the possibility that NETs may not be a major source of citrullinated protein in arthritis.

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“…91 The presence of ACPAs represent a specified subgroup that constitutes 70 to 80% of all RA patients. 74,75 These observations indicate a strong role of ACPAs in development of clinical RA, ACPAs are therefore listed as an important criterion for RA disease classification in American College of Rheumatology/ European League against Rheumatism (ACR-EULAR) guidelines. 92 The discovery of the first citrullinated antigens (filaggrin) and ACPAs (antikeratin factor and antiperinuclear factor) in RA 93,94 led to the development of enzyme-linked immunosorbent assay (ELISA)-based methods for detecting ACPAs.…”

Section: Anti-citrullinated Autoantibodiesmentioning

confidence: 99%

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

Bezuidenhout

Pretorius

2020

Semin Thromb Hemost

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Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

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PADI2 Is Significantly Associated with Rheumatoid Arthritis

Cited by 40 publications

References 47 publications

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease

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