Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

P. Savola, T. Kelkka, H. L. Rajala, A. Kuuliala, K. Kuuliala, S. Eldfors, P. Ellonen, S. Lagström, M. Lepistö, T. Hannunen, E. I. Andersson, R. K. Khajuria, T. Jaatinen, R. Koivuniemi, H. Repo, J. Saarela, K. Porkka, M. Leirisalo-Repo and S. Mustjoki ()
Additional contact information
P. Savola: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
T. Kelkka: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
H. L. Rajala: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
A. Kuuliala: Bacteriology and Immunology, Medicum, University of Helsinki
K. Kuuliala: Bacteriology and Immunology, Medicum, University of Helsinki
S. Eldfors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
P. Ellonen: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
S. Lagström: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
M. Lepistö: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
T. Hannunen: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
E. I. Andersson: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
R. K. Khajuria: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
T. Jaatinen: Histocompatibility Testing Laboratory, Finnish Red Cross Blood Service
R. Koivuniemi: University of Helsinki and Helsinki University Hospital
H. Repo: Bacteriology and Immunology, Medicum, University of Helsinki
J. Saarela: Institute for Molecular Medicine Finland (FIMM), University of Helsinki
K. Porkka: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre
M. Leirisalo-Repo: University of Helsinki and Helsinki University Hospital
S. Mustjoki: Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Centre

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

Date: 2017
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DOI: 10.1038/ncomms15869

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