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

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.

Two faces of LRBA deficiency in siblings: hypogammaglobulinemia and normal immunoglobulin levels

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Circulating helper T-Cell subsets and regulatory T Cells in patients with common variable immunodeficiency without known monogenic disease

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-gamma, 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

Antecedentes: La inmunodeficiencia variable común (CVID) es la inmunodeficiencia primaria (PID) sintomática más frecuente, caracterizada por manifestaciones clínicas heterogéneas y alteraciones de los linfocitos B y T. En este trabajo, investigamos las poblaciones de linfocitos T cooperadores (Th) y linfocitos T reguladores (Treg), así como sus citocinas y factores de transcripción, en pacientes con CVID sin un diagnóstico genético definitivo. Métodos: Se estudiaron 13 pacientes con CVID y 13 controles sanos (HC). El análisis de las mutaciones se realizó mediante secuenciación del exoma completo en los pacientes con CVID para descartar PID monogénicas. Las poblaciones de linfocitos Th y Treg se examinaron mediante citometría de flujo. Se cuantificaron las citocinas características (IFN-gamma, IL-17, IL-22 e IL-10) y los factores de transcripción específicos de estas subpoblaciones linfocitarias, tanto antes como después de la estimulación. Resultados: Las principales manifestaciones clínicas de estos pacientes fueron las infecciones y los fenotipos linfoproliferativos, pero no se encontraron fenotipos autoinmunes ni de enfermedad alérgica. Los porcentajes de linfocitos T CD4+, Th17 y linfocitos Treg se redujo significativamente en los pacientes con CVID; sin embargo, las poblaciones de Th1, Th1similares a Th17 y Th 22 fueron normales. Después de la estimulación, la expresión de los genes receptor huérfano tipo C del ácido retinoico (RORC) y del factor de transcripción 1 relacionado con Runt (RUNX1), IL-17 e IL-10 fue significativamente menor en los pacientes con IDCV en comparación con los controles sanos. También se objetivó una menor concentración de IL-17 e IL-10 en los sobrenadantes del cultivo de linfocitos T CD4 + estimulados de los pacientes con CVID, respecto a los HC. Conclusiones: Nuestros hallazgos demuestran que en los pacientes con CVID sin un diagnóstico genético definitivo y sin trastornos monogénicos, el desequilibrio de Th17 y Treg podría estar asociado con infecciones y fenotipos linfoproliferativos