Citrullinated mouse collagen administered to DBA/1J mice in the absence of adjuvant initiates arthritis

Thiele, Geoffrey M.; Duryee, Michael J.; Dusad, Anand; Hunter, Carlos D.; Lacy, Jordan; Anderson, Daniel R.; Wang, Dong; O'Dell, James Robert; Mikuls, Ted R.; Klassen, Lynell Warren

doi:10.1016/j.intimp.2012.05.007

Cited by 23 publications

(15 citation statements)

References 32 publications

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“…[33], [34]. While not studied in as much detail as other experimental arthritis models, anti-citrullinated protein antibodies have been suggested to play a role in the severity of disease in the collagen antibody induced arthritis model of experimental arthritis [35], [36].…”

Section: Discussionmentioning

confidence: 99%

Porphyromonas gingivalis Peptidylarginine Deiminase, a Key Contributor in the Pathogenesis of Experimental Periodontal Disease and Experimental Arthritis

et al. 2014

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ObjectivesTo investigate the suggested role of Porphyromonas gingivalis peptidylarginine deiminase (PAD) in the relationship between the aetiology of periodontal disease and experimentally induced arthritis and the possible association between these two conditions.MethodsA genetically modified PAD-deficient strain of P. gingivalis W50 was produced. The effect of this strain, compared to the wild type, in an established murine model for experimental periodontitis and experimental arthritis was assessed. Experimental periodontitis was induced following oral inoculation with the PAD-deficient and wild type strains of P. gingivalis. Experimental arthritis was induced via the collagen antibody induction process and was monitored by assessment of paw swelling and micro-CT analysis of the radio-carpal joints. Experimental periodontitis was monitored by micro CT scans of the mandible and histological assessment of the periodontal tissues around the mandibular molars. Serum levels of anti-citrullinated protein antibodies (ACPA) and P. gingivalis were assessed by ELISA.ResultsThe development of experimental periodontitis was significantly reduced in the presence of the PAD-deficient P. gingivalis strain. When experimental arthritis was induced in the presence of the PAD-deficient strain there was less paw swelling, less erosive bone damage to the joints and reduced serum ACPA levels when compared to the wild type P. gingivalis inoculated group.ConclusionThis study has demonstrated that a PAD-deficient strain of P. gingivalis was associated with significantly reduced periodontal inflammation. In addition the extent of experimental arthritis was significantly reduced in animals exposed to prior induction of periodontal disease through oral inoculation of the PAD-deficient strain versus the wild type. This adds further evidence to the potential role for P. gingivalis and its PAD in the pathogenesis of periodontitis and exacerbation of arthritis. Further studies are now needed to elucidate the mechanisms which drive these processes.

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Section: Discussionmentioning

confidence: 99%

Porphyromonas gingivalis Peptidylarginine Deiminase, a Key Contributor in the Pathogenesis of Experimental Periodontal Disease and Experimental Arthritis

et al. 2014

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“…In collagen-induced arthritis (CIA), induction of tolerance with a citrulline-containing peptide led to a significant decrease in susceptibility to CIA, and monoclonal antibodies to citrullinated fibrinogen enhanced arthritis tissue injury when coadministered with anti–type II collagen antibodies (13). In 2 other studies, it was found that citrullinated proteins had increased immunogenicity and arthritogenicity in animal models of arthritis (14,15). In addition, ex vivo studies have shown that ACPAs can activate the complement cascade (16), and ACPA immune complexes stimulate human macrophages to produce proinflammatory cytokines (17,18), providing possible pathogenic mechanisms of ACPAs in RA.…”

mentioning

confidence: 97%

Autoantibodies From Single Circulating Plasmablasts React With Citrullinated Antigens and Porphyromonas gingivalis in Rheumatoid Arthritis

Wang

Yue

et al. 2016

Arthritis & Rheumatology

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Objective Anti–citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA). However, the molecular basis for ACPA production is still unclear. The purpose of this study was to determine if circulating plasmablasts from RA patients produce ACPAs and whether Porphyromonas gingivalis facilitates the generation of ACPAs. Methods Using a single-cell antibody cloning approach, we generated 217 and 110 monoclonal recombinant antibodies from circulating plasmablasts from 7 RA patients and 4 healthy controls, respectively. Antibody reactivity with citrullinated antigens was tested by a second-generation anti–cyclic citrullinated peptide (anti-CCP) kit and by enzyme-linked immunosorbent assays (ELISAs) against citrullinated human antigens. Antibody reactivity with P gingivalis was tested by ELISAs against outer membrane antigens (OMAs) and citrullinated enolase from P gingivalis. Results Approximately 19.5% of plasmablast-derived antibodies from anti-CCP–positive RA patients, but none from 1 anti-CCP–negative RA patient or the healthy controls, specifically recognized citrullinated antigens. The immunoglobulin genes encoding these ACPAs were highly mutated, with increased ratios of replacement mutations to silent mutations, suggesting the involvement of active antigen selection in ACPA generation. Interestingly, 63% of the ACPAs cross-reacted with OMAs and/or citrullinated enolase from P gingivalis. The reactivity of ACPAs against citrullinated proteins from P gingivalis was confirmed by immunoblotting and mass spectrometry. Furthermore, some germline-reverted ACPAs retained their reactivity with P gingivalis antigens but completely lost their reactivity with citrullinated human antigens. Conclusion These results suggest that circulating plasmablasts in RA patients produce ACPAs and that this process may be facilitated by anti–P gingivalis immune responses.

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“…However, it has been described that silica treatment induces apoptosis in macrophages, which in turn increase citrullination due to elevated intracellular calcium concentrations [4, 12]. An increase in citrullination may aggravate arthritis as described for the administration of citrullinated collagen [13]. On the other side, it is known that silica treatment can recruit CD4 + Foxp3+ regulatory T cells to the lungs which may counteract immune activation [14].…”

Section: Discussionmentioning

confidence: 99%

Experimental silicosis does not aggravate collagen-induced arthritis in mice

Engelmann

Müller‐Hilke

2017

J Negat Results BioMed

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ObjectivesTo investigate the effect of chronic lung inflammation on the incidence and severity of collagen-induced arthritis in mice.MethodsChronic lung inflammation in the form of silicosis was induced via intranasal application of silica particles. Immunization with collagen Type II commenced one week later and mice were sacrificed six weeks after booster immunization. Thereafter, silicosis was confirmed via flow cytometry and arthritis was evaluated performing knee and paw histology.ResultsPronounced lung inflammation in the silica-treated compared to PBS-treated control mice was demonstrated by significantly elevated broncho-alveolar lavage (BAL) cell count, attributable to increased numbers of macrophages and granulocytes. Inflammation in the lungs was not associated with elevated PAD2 and PAD4 expression, yet silica treated animals had significantly higher aCCP serum titers. However, lung inflammation did not lead to an increase in the incidence of arthritis, nor did it exacerbate the macroscopic or histologic joint scores.ConclusionsChronic lung inflammation resulting from silicosis does not aggravate collagen-induced arthritis in mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12952-017-0071-6) contains supplementary material, which is available to authorized users.

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Citrullinated mouse collagen administered to DBA/1J mice in the absence of adjuvant initiates arthritis

Cited by 23 publications

References 32 publications

Porphyromonas gingivalis Peptidylarginine Deiminase, a Key Contributor in the Pathogenesis of Experimental Periodontal Disease and Experimental Arthritis

Porphyromonas gingivalis Peptidylarginine Deiminase, a Key Contributor in the Pathogenesis of Experimental Periodontal Disease and Experimental Arthritis

Autoantibodies From Single Circulating Plasmablasts React With Citrullinated Antigens and Porphyromonas gingivalis in Rheumatoid Arthritis

Experimental silicosis does not aggravate collagen-induced arthritis in mice

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