Dataset Information

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

ABSTRACT: OBJECTIVE:The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA. METHODS:Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects. Samples were evaluated using a bead-based array for IgG reactivity to 29 citrullinated proteins/peptides and 21 noncitrullinated proteins/peptides. Cutoff levels for antibody positivity were established in a separate control group. NET levels in the sputum were measured using sandwich enzyme-linked immunosorbent assays that quantitate DNA-myeloperoxidase and DNA-neutrophil elastase complexes. RESULTS:In at-risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline-specific antibodies in the sputum of at-risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at-risk subjects and subjects with RA. In at-risk subjects, increasing sputum NET levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities. CONCLUSION:These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins/peptides is specific for RA and for subjects at risk of RA, and the association of these proteins/peptides with NETs may be a key feature of early RA-related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early RA-related autoimmunity.

SUBMITTER: Demoruelle MK

PROVIDER: S-EPMC5876113 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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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.

Demoruelle M Kristen MK Bowers Emily E Lahey Lauren J LJ Sokolove Jeremy J Purmalek Monica M Seto Nickie L NL Weisman Michael H MH Norris Jill M JM Kaplan Mariana J MJ Holers V Michael VM Robinson William H WH Deane Kevin D KD

Arthritis & rheumatology (Hoboken, N.J.) 20180302 4

<h4>Objective</h4>The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA.<h4>Met ...[more]

PMID: 29266801

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Project description:OBJECTIVE:Because of its association with joint destruction, anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is considered to be more severe than ACPA-negative RA. Clinically relevant joint destruction is now infrequent thanks to adequate disease suppression. According to patients, important outcomes are pain, fatigue, and independence. We evaluated whether ACPA-positive RA patients diagnosed during or after 2000 have more severe self-reported limitations and impairments, including restrictions at work, than ACPA-negative RA patients. METHODS:A total of 492 ACPA-positive and 450 ACPA-negative RA patients who fulfilled the 2010 criteria and were included in the Leiden Early Arthritis Clinic cohort during or after 2000 were compared for self-reported pain, fatigue, disease activity, general well-being (measured by numerical rating scales), physical function (measured by the Health Assessment Questionnaire), and work restrictions, including absenteeism at baseline and during the 4-year followup. Linear mixed models were used. RESULTS:At disease presentation, ACPA-negative patients had more severe pain, fatigue, self-reported disease activity scores, and functional disability (P < 0.05), although absolute differences were small. During followup, ACPA-negative patients remained somewhat more fatigued (P = 0.002), whereas other patient-reported impairments and limitations were similar. Thirty-eight percent of ACPA-negative and 48% of ACPA-positive patients reported absenteeism (P = 0.30), with median 4 days missed in both groups in the last 3 months. Also, restrictions at work among employed patients and restrictions with household work were not statistically different at baseline and during followup. CONCLUSION:In current rheumatology practice, ACPA-positive RA is not more severe than ACPA-negative RA in terms of patients' relevant outcomes, including physical functioning and restrictions at work. This implies that efforts to further improve the disease course should be proportional to both disease subsets.

Project description:ObjectiveAnti-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.MethodsAn 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.ResultsBroadly, 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.ConclusionDisordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for RA autoantibodies.

Dataset Information

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

Publications

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

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