Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

University of California San Francisco, United States of America
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(5):e35296. DOI: 10.1371/journal.pone.0035296
Source: PubMed


Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Download full-text


Available from: Jeremy Sokolove,
  • Source
    • "For patients with arthralgias, RF, anti-CCP [27], and anti-carbamylated protein (anti-CarP) antibodies [22] are associated with a higher risk of RA. These studies [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21], with sample sizes for RA ranging from 49 to 183, and a median follow-up time ranging from 1 to 5 years, all reported that various isotypes of autoantibodies were increased in individuals who were free of RA at the time of blood sampling, but developed RA later, as compared with those who did not develop RA during the follow-up period. The positive rates for RF or anti-CCP antibodies in pre-clinical RA patients range from 10% to 60%, which is higher than healthy controls [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The presence of autoantibodies is characteristic of autoimmune diseases. It is widely accepted that autoantibodies provide crucial diagnostic and prognostic information for autoimmune diseases. Indeed, numerous studies have demonstrated that the appearance of autoantibodies precedes the clinical onset of autoimmune diseases. We performed a literature review regarding the appearance of autoantibodies that preceded the clinical onset of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, primary biliary cirrhosis, inflammatory bowel disease, and multiple sclerosis. Herein we review and comment on the major findings of these studies.
    Clinica Chimica Acta 06/2014; 437:14-18. DOI:10.1016/j.cca.2014.06.015 · 2.82 Impact Factor
  • Source
    • "In addition, expansion of anti-citrullinated protein antibodies (ACPA) has strongly predicted increases in many inflammatory cytokines in RA including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, it was observed that the preclinical phase of RA can be characterized by accumulation of multiple autoantibody specificities that reflect the process of antigen spreading [105]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this review, we explore the role of dendritic cell subsets in the development of tissue-specific autoimmune diseases. From the increasing list of dendritic cell subclasses, it is becoming clear that we are only at the beginning of understanding the role of these antigen presenting cells in mediating autoimmunity. Emerging research areas for the study of dendritic cell involvement in the onset and inhibition of tissue-specific autoimmunity are presented. Further, we compare tissue specific to systemic autoimmunity to demonstrate how development of dendritic cell-based therapies may be broadly applicable to both classes of autoimmunity. Continued development of these research areas will lead us closer to clinical assessment of novel immunosuppressive therapy for the reversal and prevention of tissue-specific autoimmunity. Through description of dendritic cell functions in the modulation of tissue-specific autoimmunity, we hope to stimulate a greater appreciation and understanding of the role dendritic cells play in the development and treatment of autoimmunity.
    Research Journal of Immunology 04/2014; 2014(5):857143. DOI:10.1155/2014/857143
  • Source
    • "Potential RA-associated antigens identified from the literature and through proteomic screening [26] were coupled to spectrally distinct beads using the BioPlex multiplex assay platform (Bio-Rad Laboratories, Hercules, CA, USA) for analysis and a Luminex 200 instrument (Luminex, Austin, TX, USA) as previously described [6]. Three preestablished control serum samples consisting of high reactivity, low reactivity and no reactivity were run on each plate as internal controls: negative, low positive and high positive. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles. We identified 192 women in the Nurses' Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated. All ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01). There is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA.
    Arthritis research & therapy 10/2013; 15(5):R159. DOI:10.1186/ar4342 · 3.75 Impact Factor
Show more