TY - JOUR
T1 - Somatic mutations and T-cell clonality in patients with immunodeficiency
AU - Savola, Paula
AU - Martelius, Timi
AU - Kankainen, Matti
AU - Huuhtanen, Jani
AU - Lundgren, Sofie
AU - Koski, Yrjö
AU - Eldfors, Samuli
AU - Kelkka, Tiina
AU - Keränen, Mikko A.I.
AU - Ellonen, Pekka
AU - Kovanen, Panu E.
AU - Kytölä, Soili
AU - Saarela, Janna
AU - Lähdesmäki, Harri
AU - Seppänen, Mikko R.J.
AU - Mustjoki, Satu
N1 - | openaire: EC/H2020/647355/EU//M-Imm
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85097038511&partnerID=8YFLogxK
U2 - 10.3324/haematol.2019.220889
DO - 10.3324/haematol.2019.220889
M3 - Article
C2 - 31857367
AN - SCOPUS:85097038511
VL - 105
SP - 2757
EP - 2768
JO - HAEMATOLOGICA: THE HEMATOLOGY JOURNAL
JF - HAEMATOLOGICA: THE HEMATOLOGY JOURNAL
SN - 0390-6078
IS - 12
ER -