Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis

Demoruelle, M. Kristen; Bowers, Emily; Lahey, Lauren J.; Sokolove, Jeremy; Purmalek, Monica; Seto, Nickie; Weisman, Michael H.; Norris, Jill M.; Kaplan, Mariana J.; Holers, V. Michael; Robinson, William H.; Deane, Kevin D.

doi:10.1002/art.40401

Cited by 54 publications

(47 citation statements)

References 49 publications

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“…Along those lines, Quirk and colleagues found that RA‐free patients with bronchiectasis had autoantibody directed to non‐citrullinated proteins, while in established RA, citrulline‐specific ACPA responses dominated . Demoruelle and colleagues also demonstrated that in the sputum there is a modest antibody response to non‐citrullinated antigens in subjects at‐risk for RA as well as with established RA . Such findings imply that early autoimmune responses at mucosal sites may be directed to non‐citrullinated proteins with epitope spreading to citrullinated proteins over time, and identifying early non‐citrullinated autoantibody responses could provide novel insights into disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, 39% of seronegative at‐risk subjects also had sputum positivity for at least one RA‐related antibody, supporting that RA‐related autoantibodies can be locally generated in the lung. The authors more recently demonstrated that sputum ACPA levels significantly correlate with levels of neutrophil extracellular traps (NETs) in subjects at‐risk for RA and that multiple citrulline‐specific ACPA responses are increased in the sputum of subjects at‐risk for RA and in established RA . Because NET formation can externalize RA‐associated citrullinated proteins, increased citrullinated protein containing NET formation in the lung could be a mechanism by which ACPA are triggered in the lung during the pre‐RA period.…”

Section: The Lung In Pre‐ramentioning

confidence: 99%

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Lung inflammation in the pathogenesis of rheumatoid arthritis

Demoruelle

Wilson

Deane

2020

Immunological Reviews

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The primary manifestation of rheumatoid arthritis (RA) is articular disease; however, extra‐articular disease can also occur. In particular, pulmonary disease is a leading cause of morbidity and mortality in individuals with RA. Herein, we will review the types, prevalence, risk factors, and potential pathophysiology of lung disease in individuals with established RA. We will also discuss the emerging understanding of potential role of the lung in the generation of RA‐related autoantibodies during a period of disease development termed “pre‐RA.” Finally, we will discuss a research agenda outlining the next steps to improve our understanding and management of lung inflammation and lung disease throughout the natural history of RA.

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Section: Discussionmentioning

confidence: 99%

Section: The Lung In Pre‐ramentioning

confidence: 99%

Lung inflammation in the pathogenesis of rheumatoid arthritis

Demoruelle

Wilson

Deane

2020

Immunological Reviews

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“…Several tissue sources have been studied to examine this hypothesis including bronchoalveolar lavage (BAL), bronchial mucosa, lung tissue, and/or sputum from a variety of individuals including healthy non‐smokers and smokers, patients with RA‐associated interstitial lung disease (RA‐ILD), RA‐associated interstitial pneumonia (RA‐IP), idiopathic IP, non‐RA patients with chronic obstructive pulmonary disease (non‐RA COPD), RA patients without pulmonary symptoms, and RA‐free subjects at risk for RA . Among these studies, only two addressed citrullination in the lung by MS.…”

Section: The Ra Citrullinome In Extraarticular Sitesmentioning

confidence: 99%

“…GrB, granzyme B; APC, antigen-presenting cell and RA-free subjects at risk for RA. 57,[133][134][135][136][137][138][139][140][141][142] Among these studies, only two addressed citrullination in the lung by MS. In lung tissue from non-RA COPD, MS was only applied to study citrullination of α-enolase and vimentin, but only confirmed citrullination in vimentin.…”

Section: Citrullination In the Lungmentioning

confidence: 99%

“…136 In the majority of the studies, however, the analysis of citrullination in lung samples (ie, BAL and tissue) was done indirectly by immunodetection of citrullinated proteins, 133,135,137,138 rather than MS, which provides no information regarding the protein identity, extent of citrullination, or identify of citrullination sites. In addition, cellular expression of PAD enzymes, detection of ACPAs, and/or the presence of markers of neutrophil lysis (denoted as NETs) in lung samples (ie, BAL, tissue, and/or sputum) have been used as indirect evidence to support dysregulated citrullination in the lung, 133,134,137,[140][141][142] suggesting that detailed MS analysis of the lung citrullinome is needed.…”

Section: Citrullination In the Lungmentioning

confidence: 99%

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Insights into the study and origin of the citrullinome in rheumatoid arthritis

Fert-Bober

Darrah

Andrade

2019

Immunological Reviews

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The presence of autoantibodies and autoreactive T cells to citrullinated proteins and citrullinating enzymes in patients with rheumatoid arthritis (RA), together with the accumulation of citrullinated proteins in rheumatoid joints, provides substantial evidence that dysregulated citrullination is a hallmark feature of RA. However, understanding mechanisms that dysregulate citrullination in RA has important challenges. Citrullination is a normal process in immune and non‐immune cells, which is likely activated by different conditions (eg, inflammation) with no pathogenic consequences. In a complex inflammatory environment such as the RA joint, unique strategies are therefore required to dissect specific mechanisms involved in the abnormal production of citrullinated proteins. Here, we will review current models of citrullination in RA and discuss critical components that, in our view, are relevant to understanding the accumulation of citrullinated proteins in the RA joint, collectively referred to as the RA citrullinome. In particular, we will focus on potential caveats in the study of citrullination in RA and will highlight methods to precisely detect citrullinated proteins in complex biological samples, which is a confirmatory approach to mechanistically link the RA citrullinome with unique pathogenic pathways in RA.

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Disordered Antigens and Epitope Overlap Between Anti–Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis

Zheng

Mergaert

Fahmy

et al. 2019

Arthritis & Rheumatology

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Objective. Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly present in rheumatoid arthritis (RA) without a clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive RA to identify novel features of reactivity.Methods. An array was created using a total of 172,828 native peptides, citrulline-containing peptides, and homocitrulline-containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide (CCP)-positive RF+, CCP+RF−, CCP−RF+, and CCP−RF− serum from RA patients (n = 48) and controls (n = 12). IgG-bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3-dimensional structure. Binding to IgG-derived peptides was specifically evaluated. Enzyme-linked immunosorbent assay confirmed key results.Results. Broadly, CCP+RF+ patients had high citrulline-specific IgG binding to array peptides and CCP+RF− and CCP−RF+ patients had modest citrulline-specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; P < 0.0001). All RA groups had low homocitrulline-specific binding. CCP+RF+ patients had moderate IgG binding to native peptides (median Z score 2.38; P < 0.0001). The highest IgG binding was to citrulline-containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP+RF+ patients targeted citrulline-containing IgG-derived peptides.Conclusion. Disordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for RA autoantibodies.

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Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis

Cited by 54 publications

References 49 publications

Lung inflammation in the pathogenesis of rheumatoid arthritis

Lung inflammation in the pathogenesis of rheumatoid arthritis

Insights into the study and origin of the citrullinome in rheumatoid arthritis

Disordered Antigens and Epitope Overlap Between Anti–Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis

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