Somatic mutations and T-cell clonality in patients with immunodeficiency

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Journal Title
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Volume Title
A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
Date
2020-12
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Language
en
Pages
12
2757-2768
Series
Haematologica, Volume 105, issue 12
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 immune- and 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.
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| openaire: EC/H2020/647355/EU//M-Imm
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Citation
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, Lähdesmäki, 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 . https://doi.org/10.3324/haematol.2019.220889