G Azizi1,2,3, A Mirshafiey2,4, H Abolhassani2,3,5, R Yazdani2, F Jafarnezhad-Ansariha4, M Shaghaghi2,6, S S Mortazavi-Jahromi4, F Noorbakhsh7, N Rezaei2,6,7, A Aghamohammadi2,3. 1. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran. 2. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 3. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 4. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. 5. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. 6. Network of Immunology in Infections, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 7. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). It is characterized by heterogeneous clinical manifestations and defects in B cells and T cells. In the present study, we investigated helper T (TH) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in CVID patients with no definitive genetic diagnosis. METHODS: The study population comprised 13 CVID patients and 13 healthy controls. Mutation analysis was performed using whole exome sequencing in CVID patients to rule out monogenic PIDs. TH subsets and Treg were analyzed using flow cytometry. The expression of determinant cytokines (IFN-γ, IL-17, IL-22, and IL-10) and cell subset specific transcription factors was evaluated before and after stimulation. RESULTS: The main clinical presentations of these patients were infections only and lymphoproliferative phenotypes. No autoimmune or allergy phenotypes were recorded. The frequencies of CD4+ T cells, TH17, and Treg cells were significantly reduced in CVID patients; however, TH1, TH1-like TH17, and TH22 subsets were normal. After stimulation, expression of retinoic-acid-orphan-receptor-C (RORC), runtrelated transcription factor 1 (RUNX1), IL17, and IL10 was significantly lower in CVID patients than in the healthy controls. Moreover, the concentration of IL-17 and IL-10 in the cell culture supernatants of stimulated CD4+ T cells was lower in CVID patients than in healthy controls. CONCLUSIONS: Our findings demonstrate that the imbalance of TH17 and Tregs could be associated with infection and the lymphoproliferative phenotype in CVID patients without monogenic disorders.
BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). It is characterized by heterogeneous clinical manifestations and defects in B cells and T cells. In the present study, we investigated helper T (TH) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in CVIDpatients with no definitive genetic diagnosis. METHODS: The study population comprised 13 CVIDpatients and 13 healthy controls. Mutation analysis was performed using whole exome sequencing in CVIDpatients to rule out monogenic PIDs. TH subsets and Treg were analyzed using flow cytometry. The expression of determinant cytokines (IFN-γ, IL-17, IL-22, and IL-10) and cell subset specific transcription factors was evaluated before and after stimulation. RESULTS: The main clinical presentations of these patients were infections only and lymphoproliferative phenotypes. No autoimmune or allergy phenotypes were recorded. The frequencies of CD4+ T cells, TH17, and Treg cells were significantly reduced in CVIDpatients; however, TH1, TH1-like TH17, and TH22 subsets were normal. After stimulation, expression of retinoic-acid-orphan-receptor-C (RORC), runtrelated transcription factor 1 (RUNX1), IL17, and IL10 was significantly lower in CVIDpatients than in the healthy controls. Moreover, the concentration of IL-17 and IL-10 in the cell culture supernatants of stimulated CD4+ T cells was lower in CVIDpatients than in healthy controls. CONCLUSIONS: Our findings demonstrate that the imbalance of TH17 and Tregs could be associated with infection and the lymphoproliferative phenotype in CVIDpatients without monogenic disorders.
Entities:
Keywords:
Autoimmunity; CVID; Common variable immunodeficiency; Helper T cell; Infection; Lymphoproliferative disorder; Regulatory T cell