@article{Paula Savola_Timi Martelius_Matti Kankainen_Jani Huuhtanen_Sofie Lundgren_Yrjö Koski_Samuli Eldfors_Tiina Kelkka_Mikko A.I. Keränen_Pekka Ellonen_Panu E. Kovanen_Soili Kytölä_Janna Saarela_Harri Lähdesmäki_Mikko R.J. Seppänen_Satu Mustjoki_2020, place={Pavia, Italy}, title={Somatic mutations and T-cell clonality in patients with immunodeficiency}, volume={105}, url={https://haematologica.org/article/view/9576}, DOI={10.3324/haematol.2019.220889}, abstractNote={<p>Common variable immunodeficiency 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 common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta 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 common variable immunodeficiency 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 (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency 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.</p&gt;}, number={12}, journal={Haematologica}, author={Paula Savola and Timi Martelius and Matti Kankainen and Jani Huuhtanen and Sofie Lundgren and Yrjö Koski and Samuli Eldfors and Tiina Kelkka and Mikko A.I. Keränen and Pekka Ellonen and Panu E. Kovanen and Soili Kytölä and Janna Saarela and Harri Lähdesmäki and Mikko R.J. Seppänen and Satu Mustjoki}, year={2020}, month={Dec.}, pages={2757-2768} }