Frontiers in Immunology (Nov 2020)
Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature
- Tiina Kelkka,
- Tiina Kelkka,
- Tiina Kelkka,
- Tiina Kelkka,
- Paula Savola,
- Paula Savola,
- Paula Savola,
- Paula Savola,
- Dipabarna Bhattacharya,
- Dipabarna Bhattacharya,
- Dipabarna Bhattacharya,
- Dipabarna Bhattacharya,
- Jani Huuhtanen,
- Jani Huuhtanen,
- Jani Huuhtanen,
- Jani Huuhtanen,
- Tapio Lönnberg,
- Matti Kankainen,
- Matti Kankainen,
- Matti Kankainen,
- Kirsi Paalanen,
- Mikko Tyster,
- Mikko Tyster,
- Mikko Tyster,
- Mikko Tyster,
- Maija Lepistö,
- Pekka Ellonen,
- Johannes Smolander,
- Samuli Eldfors,
- Bhagwan Yadav,
- Bhagwan Yadav,
- Bhagwan Yadav,
- Bhagwan Yadav,
- Sofia Khan,
- Riitta Koivuniemi,
- Christopher Sjöwall,
- Laura L. Elo,
- Laura L. Elo,
- Harri Lähdesmäki,
- Yuka Maeda,
- Hiroyoshi Nishikawa,
- Marjatta Leirisalo-Repo,
- Tuulikki Sokka-Isler,
- Tuulikki Sokka-Isler,
- Satu Mustjoki,
- Satu Mustjoki,
- Satu Mustjoki,
- Satu Mustjoki
Affiliations
- Tiina Kelkka
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Tiina Kelkka
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Tiina Kelkka
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Tiina Kelkka
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Paula Savola
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Paula Savola
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Paula Savola
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Paula Savola
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Dipabarna Bhattacharya
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Dipabarna Bhattacharya
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Dipabarna Bhattacharya
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Dipabarna Bhattacharya
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Jani Huuhtanen
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Jani Huuhtanen
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Jani Huuhtanen
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Jani Huuhtanen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Tapio Lönnberg
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Matti Kankainen
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Matti Kankainen
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Matti Kankainen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Kirsi Paalanen
- Rheumatology, Jyväskylä Central Hospital, Jyväskylä, Finland
- Mikko Tyster
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Mikko Tyster
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Mikko Tyster
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Mikko Tyster
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Maija Lepistö
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Pekka Ellonen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Johannes Smolander
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Samuli Eldfors
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Bhagwan Yadav
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Bhagwan Yadav
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Bhagwan Yadav
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Bhagwan Yadav
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Sofia Khan
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Riitta Koivuniemi
- Rheumatology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
- Christopher Sjöwall
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden
- Laura L. Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Laura L. Elo
- 0Institute of Biomedicine, University of Turku, Turku, Finland
- Harri Lähdesmäki
- 1Department of Computer Science, Aalto University School of Science, Espoo, Finland
- Yuka Maeda
- 2Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan
- Hiroyoshi Nishikawa
- 2Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo, Japan
- Marjatta Leirisalo-Repo
- Rheumatology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
- Tuulikki Sokka-Isler
- Rheumatology, Jyväskylä Central Hospital, Jyväskylä, Finland
- Tuulikki Sokka-Isler
- 3University of Eastern Finland, Faculty of Health Sciences, Kuopio, Finland
- Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland
- Satu Mustjoki
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Satu Mustjoki
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
- Satu Mustjoki
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- DOI
- https://doi.org/10.3389/fimmu.2020.578848
- Journal volume & issue
-
Vol. 11
Abstract
Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCRβ) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCRβ signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients’ repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.
Keywords
