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Circulating Helper T-Cell Subsets and Regulatory T Cells in Patients With Common Variable Immunodeficiency Without Known Monogenic Disease

Azizi G1,2,3, Mirshafiey A2,4, Abolhassani H2,3,5, Yazdani R2, Jafarnezhad-Ansariha F4, Shaghaghi M2,6, Mortazavi-Jahromi SS4, Noorbakhsh F7, Rezaei N2,6,7, Aghamohammadi A2,3

1Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
2Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
3Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
4Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
5Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
6Network of Immunology in Infections, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
7Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

J Investig Allergol Clin Immunol 2018; Vol 28(3) : 172-181
doi: 10.18176/jiaci.0231

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
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.

Key words: Common variable immunodeficiency, CVID, Infection, Autoimmunity, Lymphoproliferative disorder, Regulatory T cell, Helper T cell