A novel class of somatic mutations in blood detected preferentially in CD8 + cells

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2017-02, Vol.175, p.75-81
• Main Authors: Valori, Miko, Jansson, Lilja, Kiviharju, Anna, Ellonen, Pekka, Rajala, Hanna, Awad, Shady Adnan, Mustjoki, Satu, Tienari, Pentti J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Allergy and Immunology; Autoimmune disease; Autoimmune Diseases of the Nervous System - blood; Autoimmune Diseases of the Nervous System - immunology; Autoimmunity - immunology; CD4-Positive T-Lymphocytes - immunology; CD8; CD8-Positive T-Lymphocytes - immunology; Female; Humans; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - immunology; Mutation - genetics; Myasthenia Gravis - blood; Narcolepsy - blood; Narcolepsy - immunology; Somatic mutation; STAT3; Young Adult
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2016.11.018

Abstract Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4 +, CD8 +, CD19 + and CD4 −/CD8 −/CD19 − cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune-related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%–4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8 + cells (85% of mutations). In follow-up after a median time of 2.3 years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity ( ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA , RPA1 and STAT3 ). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies.