Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Systemic sclerosis (SSc) is a systemic autoimmune disease that manifests as progressive fibrosis of the skin and internal organs. SSc is associated with the presence of several autoantibodies (aab) to intracellular targets, with the three most important SSc-specific being anti-centromere antibodies, anti-Scl70 antibodies and anti-RNA polymerase III antibodies, which occur in over 50% of SSc patients. Autoantibody specificities are strongly associated with pattern of organ involvement and disease outcome, making autoantibodies an essential tool in the clinical management of SSc. This highlights the need for additional specific and sensitive diagnostic and prognostic biomarkers in SSc. We have recently conducted high-content autoantibody profiling studies of SSc, systemic autoimmune diseases (AID), and healthy controls and found novel SSc-associated autoantibodies. These novel SSc-associated autoantibody biomarker candidates and their diagnostic value were evaluated by testing samples derived from 2 different SSc cohorts from the University Hospital Düsseldorf and the University Hospital Zurich.
Three novel identified biomarker candidates, namely Lysine (K)-specific demethylase 6B (KDM6B), Protein Phosphatase Inhibitor 2 (PPP1R2) and Bicaudal Drosophila Homolog 2 (BICD2) were developed into research ELISA Kits using highly purified recombinant antigen and evaluated. Autoantibody specificities were analyzed using an independent and well characterized cohort consisting with sera of patients suffering from SSc (n=198), myositis (n=20), RA (n=20), SLE (n=40) and healthy blood donors (n=132). Assay threshold levels were calculated using a receiver operation characteristic analysis and set for specificities of 90% (KDM6B) and 95% for PPP1R2 and BICD2, respectively.
Using the respective cut off for the ELISA tests we were able to find autoantibody reactivity against BICD2 in 34 of 198 (17.2 %) of SSc patients and 11 of 212 (5.1%) of control samples, against PPP1R2 in 21 of 198 (10.6%) SSc and 11 of 212 controls (5.1%) and against KDM6B in 25 of 198 (12.6%) SSc patients and 21 of 212 controls (9.9%), respectively. Positive results of anti-BICD2 and anti-PPP1R2 aab co-migrated with anti-Centromere aab, but were also found in anti-Centromere and anti-Scl 70 negative samples. Interestingly, both anti- BICD2 and anti-PPP1R2 aab were found in SSc samples tested negative for anti-RNA Polymerase III auto-reactivity. Epitope mapping of KDM6B revealed reactivity against multiple epitopes of which reactivity against an EBNA-2 like polyproline-stretch in the sequence of the protein was strongest and could be blocked by polyproline. Interestingly, this reactivity occurred also in other AID samples.
In this study we were able to confirm the diagnostic value and high specificity of the newly discovered autoantigens using ELISA. While PPP1R2 and BICD2 were found to be elevated in patients suffering from SSc, we found that autoantibodies against KDM6B are at least in part generated through a homology to EBNA-2 and could thus be a key target the suspected link between EBNA infection and autoimmune connective tissue diseases.
To cite this abstract in AMA style:Schulte-Pelkum J, Budde P, Zucht HD, Wirtz D, Schulz-Knappe P, Distler O, Jordan S, Hunzelmann N, Schneider M, Maurer B. Validation of Novel Biomarker Candidates for Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/validation-of-novel-biomarker-candidates-for-systemic-sclerosis/. Accessed March 3, 2021.
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