Somatic mutations and T-cell clonality in patients with immunodeficiency

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Savola , P , Martelius , T , Kankainen , M , Huuhtanen , J , Lundgren , S , Koski , Y , Eldfors , S , Kelkka , T , Keränen , M A I , Ellonen , P , Kovanen , P E , Kytölä , S , Saarela , J , Lahdesmaki , H , Seppänen , M R J & Mustjoki , S 2020 , ' Somatic mutations and T-cell clonality in patients with immunodeficiency ' , Haematologica , vol. 105 , no. 12 , pp. 2757-2768 .

Title: Somatic mutations and T-cell clonality in patients with immunodeficiency
Author: Savola, Paula; Martelius, Timi; Kankainen, Matti; Huuhtanen, Jani; Lundgren, Sofie; Koski, Yrjö; Eldfors, Samuli; Kelkka, Tiina; Keränen, Mikko A. I.; Ellonen, Pekka; Kovanen, Panu E.; Kytölä, Soili; Saarela, Janna; Lahdesmaki, Harri; Seppänen, Mikko R. J.; Mustjoki, Satu
Contributor organization: Medicum
HUS Comprehensive Cancer Center
Department of Oncology
Hematologian yksikkö
University of Helsinki
TRIMM - Translational Immunology Research Program
Research Programs Unit
Infektiosairauksien yksikkö
Department of Medicine
HUS Inflammation Center
Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
Department of Medical and Clinical Genetics
Helsinki University Hospital Area
Department of Pathology
Janna Saarela / Principal Investigator
Children's Hospital
HUS Children and Adolescents
Department of Clinical Chemistry and Hematology
Date: 2020-12
Language: eng
Number of pages: 12
Belongs to series: Haematologica
ISSN: 0390-6078
Abstract: Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is, however, implicated. To study whether somatic mutations in CD4(+) and CD8(+) T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset CVID and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2,533 immune-associated genes from CD4(+) and CD8(+) cells. Deep T-cell receptor b-sequencing was used to characterize CD4(+) and CD8(+) T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in CVID, and 48% in controls. Clonal hematopoiesis-associated variants in both CD4(+)and CD8(+) cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immuneand proliferative functions, such as STAT5B (2 patients), C5AR1 (2 patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, CVID patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4(+) and CD8(+) cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.
3111 Biomedicine
3122 Cancers
Peer reviewed: Yes
Rights: cc_by_nc
Usage restriction: openAccess
Self-archived version: publishedVersion

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