The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients
Abstract Background 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 autoant...
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2021-09-01
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Online Access: | https://doi.org/10.1186/s13075-021-02603-x |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bianka Marklein Madeleine Jenning Zoltán Konthur Thomas Häupl Franziska Welzel Ute Nonhoff Sylvia Krobitsch Debbie M. Mulder Marije I. Koenders Vijay Joshua Andrew P. Cope Mark J. Shlomchik Hans-Joachim Anders Gerd R. Burmester Aase Hensvold Anca I. Catrina Johan Rönnelid Günter Steiner Karl Skriner |
spellingShingle |
Bianka Marklein Madeleine Jenning Zoltán Konthur Thomas Häupl Franziska Welzel Ute Nonhoff Sylvia Krobitsch Debbie M. Mulder Marije I. Koenders Vijay Joshua Andrew P. Cope Mark J. Shlomchik Hans-Joachim Anders Gerd R. Burmester Aase Hensvold Anca I. Catrina Johan Rönnelid Günter Steiner Karl Skriner The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients Arthritis Research & Therapy Rheumatoid arthritis ACPA Anti-CCP Rheumatoid factor Shared epitope Systemic lupus erythematosus |
author_facet |
Bianka Marklein Madeleine Jenning Zoltán Konthur Thomas Häupl Franziska Welzel Ute Nonhoff Sylvia Krobitsch Debbie M. Mulder Marije I. Koenders Vijay Joshua Andrew P. Cope Mark J. Shlomchik Hans-Joachim Anders Gerd R. Burmester Aase Hensvold Anca I. Catrina Johan Rönnelid Günter Steiner Karl Skriner |
author_sort |
Bianka Marklein |
title |
The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients |
title_short |
The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients |
title_full |
The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients |
title_fullStr |
The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients |
title_full_unstemmed |
The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients |
title_sort |
citrullinated/native index of autoantibodies against hnrnp-dl predicts an individual “window of treatment success” in ra patients |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2021-09-01 |
description |
Abstract Background 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. Methods Using 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. Results HnRNP-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. Conclusion CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA. |
topic |
Rheumatoid arthritis ACPA Anti-CCP Rheumatoid factor Shared epitope Systemic lupus erythematosus |
url |
https://doi.org/10.1186/s13075-021-02603-x |
work_keys_str_mv |
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doaj-6e28ab54dbcf4c858aedc3ba90e27fcf2021-09-19T11:05:52ZengBMCArthritis Research & Therapy1478-63622021-09-0123111610.1186/s13075-021-02603-xThe citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patientsBianka Marklein0Madeleine Jenning1Zoltán Konthur2Thomas Häupl3Franziska Welzel4Ute Nonhoff5Sylvia Krobitsch6Debbie M. Mulder7Marije I. Koenders8Vijay Joshua9Andrew P. Cope10Mark J. Shlomchik11Hans-Joachim Anders12Gerd R. Burmester13Aase Hensvold14Anca I. Catrina15Johan Rönnelid16Günter Steiner17Karl Skriner18Department of Rheumatology and Clinical Immunology, Charité — Universitätsmedizin BerlinDepartment of Rheumatology and Clinical Immunology, Charité — Universitätsmedizin BerlinMax Planck Institute for Molecular GeneticsDepartment of Rheumatology and Clinical Immunology, Charité — Universitätsmedizin BerlinMax Planck Institute for Molecular GeneticsMax Planck Institute for Molecular GeneticsMax Planck Institute for Molecular GeneticsDepartment of Experimental Rheumatology, Radboud University Medical CenterDepartment of Experimental Rheumatology, Radboud University Medical CenterDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalCentre for Rheumatic Diseases, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College LondonDepartment of Immunology, University of Pittsburgh School of MedicineMedical Clinic and Policlinic IV, Nephrological Center, Ludwig-Maximilian-University HospitalDepartment of Rheumatology and Clinical Immunology, Charité — Universitätsmedizin BerlinDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDivision of Rheumatology, Medical University of ViennaDepartment of Rheumatology and Clinical Immunology, Charité — Universitätsmedizin BerlinAbstract Background 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. Methods Using 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. Results HnRNP-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. Conclusion CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.https://doi.org/10.1186/s13075-021-02603-xRheumatoid arthritisACPAAnti-CCPRheumatoid factorShared epitopeSystemic lupus erythematosus |