Abstract
BackgroundThere is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers.MethodsUsing protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry.ResultsHnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an “individual window of treatment success” in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24–46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients.ConclusionCNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.
Highlights
There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein-DL autoantibodies could be possible biomarkers
Structural citrullination dependent epitopes (SCEs) of heterogeneous nuclear ribonucleoprotein (hnRNP)-DL were detected in 58% of the systemic lupus erythematosus (SLE) patients 98% of these sera were α-CCP-2-negative
It is important to measure other hnRNP autoantibodies and in combination in future studies to evaluate them for personalized medicine. These new data suggest that hnRNP-DL is a novel TLR7/ 9-dependent autoantigen found predominantly in rheumatoid arthritis (RA) and SLE and in mouse models of inflammatory rheumatic diseases
Summary
There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. More than 20 years ago heterogeneous nuclear ribonucleoprotein (hnRNP) complexes were first described as autoimmune targets [1, 2] These complexes associate with DNA and RNA and can stimulate Toll-like receptor (TLR) 7 and 9 [3,4,5,6,7]. Antibodies against these structures are characteristic for autoimmune disorders, such as systemic lupus erythematosus (SLE), progressive systemic sclerosis (scleroderma), primary Sjögren’s syndrome, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), multiple sclerosis (MS) and rheumatoid arthritis (RA) as well as for mouse models of lupus and arthritis [8,9,10]. HnRNP-A2/B1 is citrullinated in the rheumatoid joint, and it can be targeted either as a citrullinated and or native protein in distinct subsets of RA patients [18]
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