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Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints, characterized by the presence of the highly disease-specific anti-citrullinated protein antibodies (ACPA) in approximately 70% of patients. Epstein-Barr virus (EBV) has previously been suggested to be involved in the pathophysiology of RA. However, given the high incidence of EBV in the general population and the difficulty of detecting initial infection, providing a direct link between EBV infection and RA development has remained elusive. We hypothesized that primary EBV infection may be a trigger for the development of the ACPA response in vivo. Using a unique cohort of 26 kidney transplant patients with a primary EBV infection, the presence of ACPA before and following infection was determined. No increase in IgG anti-CCP2 titers was detected following EBV infection. IgG anti-CCP2 antibodies were present in two patients and borderline positive in another. These three patients were HLA-DR4 negative. To test whether EBV infection may trigger a non-class switched anti-CCP2 response, IgM anti-CCP2 antibodies were analyzed. No general trend in the IgM anti-CCP2 response was observed following EBV infection. Since two out of the three IgG anti-CCP2 (borderline) positive patients were diagnosed with IgA nephropathy, 23 additional IgA nephropathy patients were tested for IgG anti-CCP2, regardless of their EBV status. All of these patients were IgG anti-CCP2 negative, indicating that IgG anti-CCP2 is not commonly present in IgA nephropathy patients. Collectively, these data do not support the hypothesis that EBV does trigger the highly RA specific ACPA response.

SUBMITTER: Kraal LJN

PROVIDER: S-EPMC5945038 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients.

Kraal Lianne J N LJN Nijland Marieke L ML Germar Kristine L KL Baeten Dominique L P DLP Ten Berge Ineke J M IJM Fehres Cynthia M CM

PloS one 20180510 5

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints, characterized by the presence of the highly disease-specific anti-citrullinated protein antibodies (ACPA) in approximately 70% of patients. Epstein-Barr virus (EBV) has previously been suggested to be involved in the pathophysiology of RA. However, given the high incidence of EBV in the general population and the difficulty of detecting initial infection, providing a direct link between EBV infection and RA developme ...[more]

PMID: 29746558

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Project description:The presence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) indicates a breach in immune tolerance. Recent studies indicate that this breach extends to homocitrullination of lysines with the formation of anti-carbamylated protein (anti-CarP) antibodies. We analyzed the clinical and serologic relationships of anti-CarP in 2 RA cohorts.Circulating levels of immunoglobulin G anti-CarP antibodies were determined by ELISA in established (Dartmouth-Hitchcock Medical Center) and early (Sherbrooke University Hospital Center) cohorts and evaluated for anticyclic citrullinated peptide antibodies (anti-CCP), specific ACPA, and rheumatoid factor (RF) levels using the Student t test and correlation analysis.We identified elevated anti-CarP antibodies titers in 47.0% of seropositive patients (Dartmouth, n = 164), with relationships to anti-CCP (p < 0.0001) and IgM-RF (p = 0.001). Similarly, 38.2% of seropositive patients from the Sherbrooke cohort (n = 171) had elevated anti-CarP antibodies; titers correlated to anti-CCP (p = 0.01) but not IgM-RF (p = 0.09). A strong correlation with anti-Sa was observed: 47.9% anti-Sa+ patients were anti-CarP antibodies+ versus only 25.4% anti-Sa- in the Sherbrooke cohort (p = 0.0002), and 62.6% anti-Sa+ patients versus 26.9% anti-Sa- were anti-CarP antibodies+ in Dartmouth (p < 0.0001). We found a more variable response for reactivity to citrullinated fibrinogen or to citrullinated peptides from fibrinogen and ? enolase.In 2 North American RA cohorts, we observed a high prevalence of anti-CarP antibody positivity. We also describe a surprising and unexpected association of anti-CarP with anti-Sa antibodies that could not be explained by cross-reactivity. Further, considerable heterogeneity exists between anti-CarP reactivity and other citrullinated peptide reactivity, raising the question of how the pathogenesis of antibody responses for carbamylated proteins and citrullinated proteins may be linked in vivo.

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.

Dataset Information

Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients.

Publications

Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients.

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