In common variable immunodeficiency (CVID), autoimmune diseases and lymphoproliferative disorders (LPD) often develop in addition to recurrent infections due to hypogammaglobulinemia and the decreased number of antigen-specific memory B cells.1,2 While various T-cell abnormalities, such as CD8+ T-cell expansion and suppressed regulatory T cells have been observed in CVID,3 their pathophysiological backgrounds are unknown.
In this issue of Haematologica, Savola et al.4 investigated the somatic mutations of T cells from patients with congenital immunodeficiency, including CVID, using deep amplicon sequencing with 2,355 gene panels and a T-cell receptor (TCR) b gene analysis to seek possible relationships between genetic alterations and T-cell abnormalities in these diseases. They found that 6 of 8 patients with CIVD harbored somatically mutated T cells and, in total, 59% of patients with congenital immunodeficiency were positive for somatic mutations in CD4+ or CD8+ T cells, which would be expected to have deleterious effects on the cellular functions of T cells (Figure 1). Clonal hematopoiesis-related gene mutations, including DNMT3A, were found in CD3+ T cells from 24% of the patients. T-cell somatic mutations were also identified, albeit less frequently, in age-matched heathy controls. Patients with immunodeficiency had more convergent, namely restricted, TCR b chain CDR3 sequences, although these were not specific to previously known antigens. In CD8+ T cells, the somatically mutated gene burden was correlated with the T-cell clone size.
The germline mutations of the genes associated with CVID are heterogenous, and only 30-50% of patients with CVID were positive for germline mutations, such as NFKB1 in B-cell-signaling pathways,5,6 while genetic abnormalities are still unknown in a significant proportion of CVID patients. In this study, Savola et al.4 identified germline TAC1 mutations in CVID patients, and STAT3 and ADA2 mutations in other immunodeficient patients. What role the somatically mutated T cells play in CVID and other immunodeficient states associated with these genetic backgrounds remains unclear. Furthermore, it is not known how or to what extent these identified mutations affect T-cell function. Further steps are needed to clarify the pathophysiology of a population of somatically mutated clonal T cells in whole T-cell networks in the settings of autoimmune diseases, LPD, and hypogammaglobulinemia in CVID or related immunodeficiency. The results presented in this paper provide new insights into the T-cell abnormalities of CVID and immunodeficiency, suggesting that clonal T cells with somatic mutations may contribute to the development of B-cell LPD, and that they may be attributed to B-cell abnormalities, such as decreased numbers of isotypeswitched memory B cells, leading to hypogammaglobulinemia in CVID. To date, B-cell dysfunction and reduced concentrations of immunoglobulins have been considered fundamental characteristics of CVID.1,7 Emerging evidence on T-cell abnormalities,3,8,9 including clonal T cells with somatic mutations, in addition to frequent complication of autoimmune diseases and LPD, together with a variety of germline gene mutations, underlies the heterogeneity and complex nature of CVID and related immunodeficiencies.
Beyond this work, recent evidence shows that somatic mutations of non-neoplastic cells are indeed relevant in various diseases.10-12 Clonal hematopoiesis of myeloid lineage cells in association with bone marrow failure, the development of hematologic neoplasms and arteriosclerosis is one of the issues in the field of hematology.13-15 Now congenital immunodeficiency has been added to the list. Approaches such as a single cell analysis would provide further insight into the inherent genetic instability of T cells in association with the mechanism of TCR rearrangement, clonal hematopoiesis, or any other novel system pertinent to somatic mutations in T cells.
- Bonilla FA, Barlan I, Chapel H. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016; 4(1):38-59. https://doi.org/10.1016/j.jaip.2015.07.025PubMedPubMed CentralGoogle Scholar
- Yakaboski E, Fuleihan RL, Sullivan KE, Cunningham-Rundles C, Feuille E.. Lymphoproliferative disease in CVID: a report of types and frequencies from a US patient registry. J Clin Immunol. 2020; 40(3):524-530. https://doi.org/10.1007/s10875-020-00769-8PubMedPubMed CentralGoogle Scholar
- Wong GK, Huissoon AP. T-cell abnormalities in common variable immunodeficiency: the hidden defect. J Clin Pathol. 2016; 69(8):672-676. https://doi.org/10.1136/jclinpath-2015-203351PubMedPubMed CentralGoogle Scholar
- Savola P, Martelius T, Kankainen M. Somatic mutations and Tcell clonality in patients with immunodeficiency. Haematologica. 2020; 105(12):2757-2768. Google Scholar
- Abolhassani H, Hammarstrom L, Cunningham-Rundles C.. Current genetic landscape in common variable immune deficiency. Blood. 2020; 135(9):656-667. https://doi.org/10.1182/blood.2019000929PubMedPubMed CentralGoogle Scholar
- Seidel MG, Kindle G, Gathmann B. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019; 7(6):1763-1770. https://doi.org/10.1016/j.jaip.2019.02.004PubMedGoogle Scholar
- Ameratunga R, Lehnert K, Woon ST. Review: diagnosing common variable immunodeficiency disorder in the era of genome sequencing. Clin Rev Allergy Immunol. 2018; 54(2):261-268. https://doi.org/10.1007/s12016-017-8645-0PubMedGoogle Scholar
- Ramesh M, Hamm D, Simchoni N, Cunningham-Rundles C.. Clonal and constricted T cell repertoire in common variable immune deficiency. Clin Immunol. 2017; 178:1-9. https://doi.org/10.1016/j.clim.2015.01.002PubMedPubMed CentralGoogle Scholar
- Le Saos-Patrinos C, Loizon S, Blanco P, Viallard JF, Duluc D.. Functions of Tfh cells in common variable immunodeficiency. Front Immunol. 2020; 11:6. https://doi.org/10.3389/fimmu.2020.00006PubMedPubMed CentralGoogle Scholar
- Jaiswal S, Fontanillas P, Flannick J. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014; 371(26):2488-2498. https://doi.org/10.1056/NEJMoa1408617PubMedPubMed CentralGoogle Scholar
- Vijg J, Dong X.. Pathogenic mechanisms of somatic mutation and genome mosaicism in aging. Cell. 2020; 182(1):12-23. https://doi.org/10.1016/j.cell.2020.06.024PubMedPubMed CentralGoogle Scholar
- Savola P, Kelkka T, Rajala HL. Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis. Nat Commun. 2017; 8:15869. https://doi.org/10.1038/ncomms15869PubMedPubMed CentralGoogle Scholar
- Jaiswal S, Natarajan P, Silver AJ. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017; 377(2):111-121. https://doi.org/10.1056/NEJMoa1701719PubMedPubMed CentralGoogle Scholar
- Yoshizato T, Dumitriu B, Hosokawa K. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015; 373(1):35-47. https://doi.org/10.1056/NEJMoa1414799PubMedPubMed CentralGoogle Scholar
- Shen W, Clemente MJ, Hosono N. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest. 2014; 124(10):4529-4538. https://doi.org/10.1172/JCI74747PubMedPubMed CentralGoogle Scholar
Figures & Tables
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.