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.

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    • "Therefore , early diagnosis and intervention is important to prevent rapid progression of the disease[1,2]. 98%[6,7,11]and they may precede the clinical appearance of RA by more than 10 years and predict more severe clinical outcomes121314151617. The two major genetic risk factors for RA, the shared epitope (SE) and PTPN22, are both independently associated with smoking and the generation of ACPAs[18,19]. "
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    ABSTRACT: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of Rheumatoid arthritis (RA) and represent an important tool for the serological diagnosis of RA. In this study, we describe ACPA reactivity to overlapping citrullinated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-derived peptides and analyze their potential as substrates for ACPA detection by streptavidin capture enzyme-linked immunosorbent assay. Using systematically overlapping peptides, containing a 10 amino acid overlap, labelled with biotin C-terminally or N-terminally, sera from 160 individuals (RA sera (n=60), healthy controls (n=40), systemic lupus erythematosus (n=20), Sjögren's syndrome (n=40)) were screened for antibody reactivity. Antibodies to a panel of five citrullinated EBNA-1 peptides were found in 67% of RA sera, exclusively of the IgG isotype, while 53% of the patient sera reacted with a single peptide, ARGGSRERARGRGRG-Cit-GEKR, accounting for more than half of the ACPA reactivity alone. Moreover, these antibodies were detected in 10% of CCP2-negative RA sera. In addition, 47% of the RA sera reacted with two or three citrullinated EBNA-1 peptides from the selected peptide panel. Furthermore, a negative correlation between the biotin attachment site and the location of citrulline in the peptides was found, i.e. the closer the citrulline was located to biotin, the lower the antibody reactivity. Our data suggest that citrullinated EBNA-1 peptides may be considered a substrate for the detection of ACPAs and that the presence of Epstein-Barr virus may play a role in the induction of these autoantibodies.
    Full-text · Article · Jan 2016 · Peptides
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    • "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]. "
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    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.
    Full-text · Article · Jun 2014 · Clinica Chimica Acta
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    • "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]. "
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    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.
    Full-text · Article · Apr 2014 · Research Journal of Immunology
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