Somatic Mutations in Clonally Expanded Cytotoxic Lymphocytes in Patients with Newly Diagnosed Rheumatoid Arthritis

Paula Savola¹, Tiina Kelkka¹, Hanna Rajala¹, Antti Kuuliala², Krista Kuuliala², Samuli Eldfors³, Pekka Ellonen³, Sonja Lagstrom³, Rajiv Kumar Khajuria¹, Taina Jaatinen⁴, Riitta Koivuniemi⁵, Heikki Repo², Janna Saarela³, Kimmo Porkka¹, Marjatta Leirisalo-Repo⁶ and Satu Mustjoki¹, ¹Department of Hematology, Hematology Research Unit Helsinki, University of Helsinki, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland, ²Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland, ³Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland, ⁴Clinical Laboratory, Finnish Red Cross Blood Service, Helsinki, Finland, ⁵Department of Medicine, Division of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, ⁶Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: CD8 cells, genetics, pathogenesis and rheumatoid arthritis (RA), T cells

Session Information

Date: Monday, November 9, 2015

Title: T cell Biology and Targets in Autoimmune Disease Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: In rheumatoid arthritis (RA), the mechanisms initiating immune dysregulation leading to joint damage are incompletely understood. Previous studies show that large CD8+ T cell lymphocyte clones occur commonly in RA. We hypothesized that in some RA patients, lymphocytes may have acquired somatic mutations resulting in clonal expansions and abnormal immune reactivity.

Methods: We used flow cytometry and deep T-cell receptor sequencing to assess T-cell clonality in a cohort of 82 newly diagnosed RA patients. These patients fulfilled the ACR/EULAR 2010 criteria for RA. Further, acquired genetic changes either in sorted CD8+ or CD4+ T cells were investigated with a next-generation sequencing panel consisting of 986 known immunoregulatory genes. Mutations discovered with this panel were validated and screened from other patients with the deep Amplicon sequencing method.

Results: Significant (>10%) clonal CD8+ T-cell expansions were present in 51% (34/67) of RA patient peripheral blood samples. In two out of 15 patients (13%) sequenced with the next-generation immunogene panel, somatic, high-confidence missense mutations were discovered. Patient 1 had mutations in PADI4 (peptidyl arginine deiminase, type IV), PROM1 (prominin 1) and C5 (complement component 5) genes, and patient 2 in IRF1 (interferon regulatory factor 1), SLAMF6 (SLAM family member 6) and SEC14L3 (SEC14-like 3 (S. cerevisiae)) genes. These mutations were restricted to the expanded CD8+ T-cell clones and they persisted during immunosuppressive therapy. Functionally, mutated PADI4 led to decreased expression and enzymatic activity of the PADI4, whereas mutated IRF1 resulted in increased STAT1 expression. However, no recurrent mutations in these genes were found in other patients.

Conclusion: Clonal CD8+ T-cell expansions were observed in a significant proportion of RA patients, and in two patients expanded CD8+ T-cell clones harbored acquired somatic mutations in genes (PADI4 and IRF1) known to be causally relevant for the pathogenesis of RA. The mutations in these two genes changed the protein function. Further studies utilizing unbiased sequencing assays are needed to validate the role of somatic mutations as inducers of T-cell activation and autoimmunity in RA.

Disclosure: P. Savola, None; T. Kelkka, None; H. Rajala, None; A. Kuuliala, None; K. Kuuliala, None; S. Eldfors, None; P. Ellonen, None; S. Lagstrom, None; R. K. Khajuria, None; T. Jaatinen, None; R. Koivuniemi, None; H. Repo, None; J. Saarela, Roche Pharmaceuticals, 5; K. Porkka, Pfizer Inc, 9,Bristol-Myers Squibb, 9,Novartis Pharmaceutical Corporation, 9; M. Leirisalo-Repo, None; S. Mustjoki, Pfizer Inc, 9,Novartis Pharmaceutical Corporation, 9,Bristol-Myers Squibb, 9.

To cite this abstract in AMA style:

Savola P, Kelkka T, Rajala H, Kuuliala A, Kuuliala K, Eldfors S, Ellonen P, Lagstrom S, Khajuria RK, Jaatinen T, Koivuniemi R, Repo H, Saarela J, Porkka K, Leirisalo-Repo M, Mustjoki S. Somatic Mutations in Clonally Expanded Cytotoxic Lymphocytes in Patients with Newly Diagnosed Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/somatic-mutations-in-clonally-expanded-cytotoxic-lymphocytes-in-patients-with-newly-diagnosed-rheumatoid-arthritis/. Accessed .

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/somatic-mutations-in-clonally-expanded-cytotoxic-lymphocytes-in-patients-with-newly-diagnosed-rheumatoid-arthritis/