RESUMEN
CD4+ T follicular helper cells (TFH) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). TFH lymphocytes were characterized by expression of CXCR5 and PD-1. TFH were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and TFH reg were similar in both CVID groups and in N. TFH responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of TFH cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that TFH are functional in CVID and highlight the association of increased circulating TFH with AI and GD manifestations.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Regulación de la Expresión Génica/inmunología , Enfermedad Granulomatosa Crónica/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Autoinmunidad , Ligando de CD40/genética , Ligando de CD40/inmunología , Estudios de Casos y Controles , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/patología , Femenino , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/patología , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-2/farmacología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucinas/genética , Interleucinas/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Cultivo Primario de Células , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptores CCR7/genética , Receptores CCR7/inmunología , Receptores CXCR5/genética , Receptores CXCR5/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patologíaRESUMEN
Peripheral blood mononuclear cells with T(FH) phenotype from two asymptomatic XLP patients were studied. Normal/high numbers of CXCR5+, CD4+ T cells coexpressing PD-1 were demonstrated. Peripheral blood mononuclear cells (PBMC) from these patients responded to sub-optimal PHA/IL-2 stimulation upregulating ICOS and CD40L and increasing intracellular expression of IL-10, IL-21 and IL-4 by CD4+ T(FH) cells. However when compared to N, the time profile of activation and cytokine synthesis was different in XLP and N. While ICOS and CD40L expression in N decreased after 6-8 days, it continued to increase or was maintained in XLP cultures. Intracellular IL-10, IL-21 and IL-4 reached higher values in XLP than N after 8 days. Rather than the absence of T(FH) cells or their intrinsic inability to respond to stimuli, differences in the time profile of their response could contribute to impair their role as helpers of B lymphocytes.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Trastornos Linfoproliferativos/inmunología , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Ligando de CD40/biosíntesis , Ligando de CD40/inmunología , Células Cultivadas , Exones , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Proteína Coestimuladora de Linfocitos T Inducibles/biosíntesis , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Interleucina-2/inmunología , Interleucina-2/farmacología , Interleucinas/inmunología , Interleucinas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Leucocitos Mononucleares/inmunología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/genética , Persona de Mediana Edad , Mutación , Fitohemaglutininas/inmunología , Fitohemaglutininas/farmacología , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria , Linfocitos T Colaboradores-Inductores/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
Survival of lymphocytes after prolonged culture was studied in two asymptomatic XLP patients. Viability of XLP PBMC after 30 days of non-stimulated culture was higher than that of normal controls (N), mainly due to the persistence of CD8 memory lymphocytes. IFNgamma high CD8 T lymphocytes remained higher in XLP than in N after 30 days. The number of perforin+ CD8 lymphocytes was markedly reduced after 30 days in XLP and in N. Increased viability was not related to CD127, PD-1, CD27, or CD62L expression. Concerning B lymphocytes, memory CD27+ CD19+ cells prevailed over CD27- cells after 30 days in both XLP and N, with far more surviving cells in XLP. In N, few CD19+ B lymphocytes were viable after prolonged culture. In XLP, these cells were also IgD+, IgM+ and EBNA2+. These results demonstrate that IFNgamma-positive memory CD8 T cells persist in XLP after prolonged culture in association with a subset of viable memory CD27+ B cells expressing latent EBV antigens. The survival advantage of XLP cells might be related to increased frequency of extranodal lymphoma in XLP patients.