RESUMEN
LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.
Asunto(s)
Dominios Proteicos , Humanos , Dominios Proteicos/genética , Fenotipo , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Agammaglobulinemia/diagnóstico , Niño , Edad de Inicio , Mutación , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
BACKGROUND: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. OBJECTIVE: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. METHOD: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. RESULTS: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. CONCLUSION: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.
ANTECEDENTES: Las deficiencias de anticuerpos abarcan un amplio espectro de patologías y constituyen aproximadamente 50 % de las inmunodeficiencias primarias; con la citometría es posible evaluar el estado inmunológico de forma rápida, efectiva y a bajo costo. OBJETIVO: Evaluar mediante citometría de flujo, las células de pacientes con tres tipos de inmunodeficiencias primarias humorales. MÉTODO: Mediante citometría de flujo se analizaron muestras de sangre de pacientes y sujetos sanos con distintos anticuerpos monoclonales. RESULTADOS: Mediante diversas tinciones se demostró disminución severa de linfocitos B en pacientes con agammaglobulinemia ligada al cromosoma X, la falta de expresión de CD154 en pacientes con síndrome de hiperinmunoglobulina M y heterogeneidad de subpoblaciones de linfocitos B en pacientes con inmunodeficiencia común variable. CONCLUSIÓN: Con la citometría de flujo es posible realizar el diagnóstico temprano de inmunodeficiencias primarias con un nivel de confianza elevado y, en muchos casos, identificar los genes implicados.
Asunto(s)
Agammaglobulinemia/inmunología , Inmunodeficiencia Variable Común/inmunología , Citometría de Flujo , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Síndromes de Inmunodeficiencia/inmunología , Adolescente , Anticuerpos Monoclonales/inmunología , Linfocitos B/inmunología , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Resumen Antecedentes: Las deficiencias de anticuerpos abarcan un amplio espectro de patologías y constituyen aproximadamente 50 % de las inmunodeficiencias primarias; con la citometría es posible evaluar el estado inmunológico de forma rápida, efectiva y a bajo costo. Objetivo: Evaluar mediante citometría de flujo, las células de pacientes con tres tipos de inmunodeficiencias primarias humorales. Método: Mediante citometría de flujo se analizaron muestras de sangre de pacientes y sujetos sanos con distintos anticuerpos monoclonales. Resultados: Mediante diversas tinciones se demostró disminución severa de linfocitos B en pacientes con agammaglobulinemia ligada al cromosoma X, la falta de expresión de CD154 en pacientes con síndrome de hiperinmunoglobulina M y heterogeneidad de subpoblaciones de linfocitos B en pacientes con inmunodeficiencia común variable. Conclusión: Con la citometría de flujo es posible realizar el diagnóstico temprano de inmunodeficiencias primarias con un nivel de confianza elevado y, en muchos casos, identificar los genes implicados.
Abstract Background: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. Objective: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. Method: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. Results: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. Conclusion: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Inmunodeficiencia Variable Común/inmunología , Agammaglobulinemia/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Citometría de Flujo , Síndromes de Inmunodeficiencia/inmunología , Linfocitos B/inmunología , Estudios Transversales , Estudios Prospectivos , Anticuerpos Monoclonales/inmunologíaRESUMEN
OBJECTIVE: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. CASE DESCRIPTION: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. COMMENTS: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.
Asunto(s)
Inmunodeficiencia Variable Común/complicaciones , Tumores Neuroendocrinos/diagnóstico , Neumonía/diagnóstico , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Antineoplásicos/uso terapéutico , Niño , Inmunodeficiencia Variable Común/inmunología , Diarrea/diagnóstico , Diarrea/etiología , Resultado Fatal , Humanos , Neoplasias Intestinales/diagnóstico por imagen , Neoplasias Intestinales/patología , Neoplasias Intestinales/cirugía , Masculino , Metástasis de la Neoplasia/patología , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Neumonía/etiología , Recurrencia , Pérdida de PesoRESUMEN
ABSTRACT Objective: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. Case description: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. Comments: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.
RESUMO Objetivo: Relatar um caso de criança portadora de imunodeficiência primária que, aos oito anos, desenvolveu sintomas digestivos, culminando com o diagnóstico de tumor neuroendócrino aos dez anos de idade. Descrição do caso: Menino, com um ano de idade, começou a apresentar pneumonias de repetição em diferentes lobos pulmonares. Aos quatro anos, a investigação imunológica mostrou diminuição dos níveis séricos de IgG e IgA. Após exclusão de outras causas de hipogamaglobulinemia, teve diagnóstico de imunodeficiência comum variável, passando a receber reposição mensal de imunoglobulina humana. Evoluiu bem, porém, aos oito anos, começou com epigastralgia e, aos dez anos, diarreia crônica persistente e perda de peso. O quadro culminou com o diagnóstico de tumor neuroendócrino intestinal, de rápida progressão, com óbito do paciente. Comentários: A literatura tem chamado a atenção para tumores gástricos em adultos com imunodeficiência comum variável, alertando para a importância do diagnóstico precoce e da pesquisa de neoplasias digestivas. Até o momento, não há descrição de tumor neuroendócrino em pacientes pediátricos portadores de imunodeficiência comum variável. Acredita-se ser importante a hipótese de neoplasia digestiva diante de crianças com imunodeficiência comum variável e com manifestações clínicas semelhantes ao caso descrito, na tentativa de melhorar o prognóstico para pacientes pediátricos.
Asunto(s)
Humanos , Masculino , Niño , Neumonía/diagnóstico , Inmunodeficiencia Variable Común/complicaciones , Tumores Neuroendocrinos/diagnóstico , Neumonía/etiología , Recurrencia , Pérdida de Peso , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Inmunodeficiencia Variable Común/inmunología , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Resultado Fatal , Diarrea/diagnóstico , Diarrea/etiología , Neoplasias Intestinales/cirugía , Neoplasias Intestinales/patología , Neoplasias Intestinales/diagnóstico por imagen , Metástasis de la Neoplasia/patología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.
Asunto(s)
Linfocitos B/inmunología , Diferenciación Celular/inmunología , Inmunodeficiencia Variable Común/inmunología , Endotoxemia/inmunología , Deficiencia de IgA/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Linfocitos B/patología , Niño , Preescolar , Inmunodeficiencia Variable Común/patología , Endotoxemia/patología , Femenino , Humanos , Deficiencia de IgA/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies defined by marked reductions in serum IgG, IgA and/or IgM levels and recurrent bacterial infections. Some patients are associated with defects in T cells and regulatory T cells (Tregs), resulting in recurrent viral infections and early-onset autoimmune disease. METHODS: We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127low and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21low B cells (CD19+CD38lowCD21low); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry. RESULTS: Fourteen patients presented with autoimmune diseases (AI) (39%), including 11 with autoimmune thrombocytopenia (ITP) (31%); two with vitiligo (6%); one with systemic lupus erythematosus (LES) (3%); and one with multiple sclerosis (MS) (3%). CVID patients with AI had a reduced proportion of Tregs (both CD4+CD25+CD127low and FoxP3+ cells) compared with healthy controls. CVID patients with AI had expanded CD21low B cell populations compared with patients who did not have AI. A correlation between increased CD4+CD45RO T cell populations and reduced Tregs was also observed. CONCLUSIONS: Our results showed that 39% of patients with CVID had AI and reduced Tregs populations. Research in this area might provide noteworthy data to better understand immune dysfunction and dysregulation related to CVID.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Linfocitos T Reguladores/inmunología , Subgrupos de Linfocitos B/inmunología , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunofenotipificación , Antígenos Comunes de Leucocito/metabolismo , Masculino , Receptores de Complemento 3d/metabolismo , Adulto JovenRESUMEN
Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency in adulthood. CVID diagnosis is by exclusion and should be considered in patients of any age who have hypogammaglobulinemia of unknown origin. Numerous patients with CVID show alterations in the development of B lymphocytes, both in plasma cells and memory cells. The absence of memory B cells suggests an insufficient germinal reaction, which can be associated with a blockade of the transition of T1 cells into T2 in patients with IDCV, owing to B-cell activating factor (BAFF) receptor deficiency. In patients with IDCV, memory B cell alterations with isotype change favor the development of concomitant comorbidities such as lymphadenopathy, splenomegaly, autoimmunity and granulomatous disease, and multiple classifications that use memory B cells in common have therefore been made trying to generate a classification of patients with IDCV, as well as to establish prognostic factors.
La inmunodeficiencia común variable (IDCV) es la inmunodeficiencia sintomática más común en la edad adulta. El diagnóstico de IDCV es de exclusión y debe considerarse en pacientes de cualquier edad que presenten hipogammaglobulinemia sin causa conocida. Numerosos pacientes con IDCV presentan alteraciones en el desarrollo de los linfocitos B, tanto en las células plasmáticas como de memoria. La ausencia de células B de memoria sugiere una reacción germinal insuficiente que puede asociarse con bloqueo de la transición de células T1 a T2 en pacientes con IDCV, debido a deficiencia del receptor BAFF (factor activador de linfocitos B). En pacientes con IDCV, las alteraciones en las células B de memoria con cambio de isotipo favorecen el desarrollo de comorbilidades concomitantes como linfadenopatía, esplenomegalia, autoinmunidad y enfermedad granulomatosa, por lo que se han realizado múltiples clasificaciones de IDCV que utilizan en común a las células B de memoria para intentar establecer factores pronósticos.
Asunto(s)
Linfocitos B/inmunología , Inmunodeficiencia Variable Común/inmunología , Humanos , Memoria InmunológicaRESUMEN
La inmunodeficiencia variable común (IDVC) es una inmunodeficiencia primaria por déficit de anticuerpos, relativamente frecuente. Es considerada un trastorno genético debido a la presencia de mutaciones en genes que codifican para determinado componente del sistema inmune adaptativo. Se caracteriza por disminución de los niveles séricos de IgG, IgA y, en ocasiones, de IgM. El cuadro clínico es muy variable y se describen cuatro fenotipos clínicos. Presentación del caso: Paciente de 16 años de edad, que desde el primer año de vida presentó múltiples cuadros infecciosos respiratorios altos y bajos, complicados y no complicados, principalmente de etiología bacteriana, los cuales requirieron ingresos y tratamientos antimicrobianos de amplio espectro. Se reportaron antecedentes personales y familiares de asma, dermatitis atópica y eczemas recurrentes. Además, presentó trastornos gastrointestinales de diferentes causas e intolerancia a la leche. En una ocasión fue ingresado por un síndrome adénico, que se interpretó como una mononucleosis infecciosa. Se le realizaron estudios inmunológicos a raíz de una neumonía complicada encontrando disminución de los niveles séricos de IgG y se corroboró por citometría de flujo disminución de la población linfocitaria CD19 positiva. Recibió tratamiento con inmunoglobulinas por vía intravenosa con una buena respuesta. Ante cuadros infecciosos que se repiten, principalmente de origen bacterianos, es importante pensar en esta enfermedad, pues el diagnóstico y el tratamiento oportuno mejoran la calidad de vida del paciente (AU)
Asunto(s)
Humanos , Masculino , Femenino , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Linfocitos T , Linfocitos B , Infecciones del Sistema Respiratorio/genéticaRESUMEN
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by impaired antibody production and recurrent infections. In the last 20 years, several groups have reported that B cells from CVID patients have an impaired somatic hypermutation (SHM). The reported frequency of this defect among CVID patient cohorts is highly variable and so is the methodology used to evaluate this process. Interestingly, the low level of SHM on B cells from CVID patients has been correlated with the presence of infectious and non-infectious complications. In this review, an overview of the studies regarding SHM in CVID patients is presented. We highlight the importance of SHM studies in CVID patients as a clinical tool due to the reported association with clinical complications by several groups. We also considered SHM measurement useful to guide future investigations in order to identify genetic defects involved in the development of the disease.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Animales , Linfocitos B/inmunología , Secuencia de Bases , Inmunodeficiencia Variable Común/inmunología , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Humanos , Mutación , Hipermutación Somática de InmunoglobulinaRESUMEN
Common variable immunodeficiency (CVID) is a syndrome with predominantly defective B cell function. However, abnormalities in the number and function of other lymphocyte subpopulations in peripheral blood (PB) have been described in most patients. We have analysed the distribution of iNKT cell subpopulations in the PB of CVID patients and the ability of these cells to provide in vitro cognate B cell help. The total of iNKT cells was reduced in the PB of CVID patients, especially CD4+, CD4-/CD8- and CCR5+/CXCR3+. These findings were associated with an enrichment of memory-like and a tendency towards a reduction in TNF-α-expressing effector iNKT cells in the peripheral blood mononuclear cells (PBMC) of CVID patients. Moreover, an accumulation of follicular helper iNKT cells in the PB of CVID patients was demonstrated. CVID αGalCer-pulsed iNKT cells are not able to induce autologous B cell proliferation although they do induce proliferation to healthy donor B cells. Interestingly, autologous and heterologous co-cultures did not differ in the amount of immunoglobulin secreted by B cells in vitro. Finally, reduced intracellular SAP expression in iNKT cells and other lymphocytes in the blood from CVID patients was observed. These results provide further insights into the immunological mechanisms underlying the iNKT cell defects and the potential targets to improve B cell help in CVID.
Asunto(s)
Linfocitos B/inmunología , Comunicación Celular , Inmunodeficiencia Variable Común/inmunología , Células T Asesinas Naturales/inmunología , Saposinas/metabolismo , Adolescente , Adulto , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Femenino , Galactosilceramidas/inmunología , Humanos , Inmunoglobulinas/metabolismo , Memoria Inmunológica , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
Common variable immunodeficiency (CVID) is the largest group of symptomatic primary immune deficiencies; it is characterized by hypogammaglobulinemia, poor response to vaccines and increased susceptibility to infections. Cellular phenotypes and abnormalities have been described both in adaptive and innate immune response. Several classifications of common variable immunodeficiency are based on defects found on T and B cells, which have been correlated with clinical manifestations. In recent years, significant progress has been made in elucidating the genetic mechanisms that result in a IDCV phenotype. Massive sequencing technologies have favored the description of mutations in several genes, but only in 2 % to 10 % of patients. These monogenetic defects are: ICOS, TNFRSF13B (TACI), TNFRS13C (BAFFR), TNRFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), (CD27), LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R, VAV1, RAC1, BLK, IKZF1 (IKAROS) and IRF2BP2. These findings have provided a possible explanation for the pathogenesis of IDCV, since these molecules play an important role in the co-operation between B and T cells in the germinal center, as well as in intrinsic signaling pathways of both.
La inmunodeficiencia común variable constituye el mayor grupo de inmunodeficiencias primarias sintomáticas; se caracterizan por hipogammaglobulinemia, pobre respuesta a las vacunas y susceptibilidad aumentada a las infecciones. Se han descrito fenotipos celulares y anormalidades tanto en la respuesta inmune adaptativa como en la innata. Varias de las clasificaciones se basan en los defectos encontrados en las células T y B, que se han correlacionado con las manifestaciones clínicas. En los últimos años se ha progresado significativamente en el desentrañamiento de los mecanismos genéticos que resultan en un fenotipo de inmunodeficiencia común variable. Las tecnologías de secuenciación masiva han favorecido la descripción de mutaciones en varios genes, pero solo en 2 a 10 % de los pacientes. Estos defectos monogénicos son ICOS, TNFRSF13B (TACI), TNFRS13C (BAFFR), TNRFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R, VAV1, RAC1, BLK, IKZF1 (IKAROS) y IRF2BP2. Los anteriores hallazgos han proporcionado una posible explicación para la patogénesis de la inmunodeficiencia común variable, ya que esas moléculas desempeñan un papel importante en la cooperación entre las células B y T en el centro germinal, así como en las vías de señalización intrínseca de ambas.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Inmunidad Adaptativa , Autoinmunidad , Inmunodeficiencia Variable Común/clasificación , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/genética , Susceptibilidad a Enfermedades , Enfermedades Gastrointestinales/etiología , Estudios de Asociación Genética , Humanos , Inmunidad Innata , Cooperación Linfocítica , Subgrupos Linfocitarios/inmunología , Infecciones del Sistema Respiratorio/etiologíaRESUMEN
Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on γδ T cells in CVID patients. Newly diagnosed CVID patients (nâ=â15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study γδ T cells and CVID patients were compared to healthy controls (nâ=â22). The frequency and absolute count of Vδ1 γδ T cells was found to be increased in CVID (median 0.60% vs 2.64%, Pâ<0.01 and 7.5 vs 39, Pâ<0.01 respectively), while they were decreased for Vδ2 γδ T cells (median, 2.36% vs 0.74%, Pâ<0.01 and 37.8 vs 13.9, Pâ<0.01 respectively) resulting in an inversion of the Vδ1 to Vδ2 ratio (0.24 vs 1.4, Pâ<0.001). Markers of immune activation were elevated on all subsets of γδ T cells, and HLA-DR expression was associated with an expansion of Vδ1 γδ T cells (râ=â0.73, Pâ=â0.003). Elevated PD-1 expression was found only on Vδ2 γδ T cells (median 1.15% vs 3.08%, Pâ<0.001) and was associated with the decrease of Vδ2 γδ T cells (râ=â-0.67, Pâ=â0.007). IVIg had no effect on the frequency of Vδ1 and Vδ2 γδ T cells or HLA-DR expression, but alleviated CD38 expression on Vδ1 γδ T cells (median MFI 965 vs 736, Pâ<0.05). These findings suggest that immunological perturbations of γδ T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Inmunodeficiencia Variable Común/tratamiento farmacológico , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/uso terapéutico , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficiency and is associated with recurrent infections and chronic inflammatory diseases. We evaluated the ability of Toll-like receptor (TLR) ligands to induce secretion of chemokines, cytokines and type I interferons by peripheral blood mononuclear cells (PBMCs) from CVID patients. High levels of CXCL10, CCL2, CXCL9, CCL5, CXCL8, and IL-6 were detected in sera of CVID patients compared with healthy controls. Increased chemokine levels were observed in unstimulated PBMCs, but after stimulation with TLR2 and TLR4 agonists, equivalent chemokine and pro-inflammatory cytokine secretion, as in healthy controls, was observed, whereas TLR4 agonist induced a decreased secretion of CCL2 and CXCL8 and increased secretion of TNF. Decreased IFN-α secretion induced by TLR7/TLR8 activation was observed in CVID, which was recovered with TLR9 signaling. Our findings revealed that TLR9 activation has an adjuvant effect on the altered type I response in CVID.
Asunto(s)
Quimiocinas/inmunología , Inmunodeficiencia Variable Común/inmunología , Citocinas/inmunología , Interferón Tipo I/inmunología , Receptores Toll-Like/inmunología , Adulto , Anciano , Células Cultivadas , Quimiocinas/sangre , Quimiocinas/metabolismo , Inmunodeficiencia Variable Común/sangre , Inmunodeficiencia Variable Común/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Femenino , Humanos , Imidazoles/farmacología , Interferón Tipo I/biosíntesis , Interferón Tipo I/sangre , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ligandos , Lipopolisacáridos/farmacología , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos/farmacología , Poli I-C/farmacología , Quinolinas/farmacología , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/inmunología , Receptor Toll-Like 8/metabolismo , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Infections caused by bacteria or viruses are frequent in common variable immunodeficiency (CVID) patients due to antibody deficiencies, which may be associated with altered T cell function. CVID patients are frequently in contact with pathogen-associated molecular patterns (PAMPs), leading to the activation of innate immunity through Toll-like receptors (TLR) affecting T cell activation. We evaluated the effect of TLR activation on T cells in CVID patients undergoing intravenous immunoglobulin (IVIg) replacement using synthetic ligands. METHODS: Expression of exhaustion, activation and maturation markers on T cells from peripheral blood as well as regulatory T cells and follicular T cells in peripheral blood mononuclear cells (PBMCs) from CVID and healthy individuals were evaluated by flow cytometry. PBMCs cultured with TLR agonists were assessed for intracellular IFN-γ, TNF, IL-10, IL-17a or IL-22 secretion as monofunctional or polyfunctional T cells (simultaneous cytokine secretion) by flow cytometry. RESULTS: We found increased expression of the exhaustion marker PD-1 on effector memory CD4(+) T cells (CD45RA(-)CCR7(-)) in the peripheral blood and increased expression of CD38 in terminally differentiated CD8(+) T cells (CD45RA(+)CCR7(-)). Furthermore, a decreased frequency of naïve regulatory T cells (CD45RA(+)Foxp3(low)), but not of activated regulatory T cells (CD45RA(-)Foxp3(high)) was detected in CVID patients with splenomegaly, the non-infectious manifestation in this CVID cohort (43.7 %). Moreover, the frequency of peripheral blood follicular helper T cells (CD3(+)CD4(+)CXCR5(+)PD-1(+)ICOS(+)) was similar between the CVID and control groups. Upon in vitro TLR3 activation, a decreased frequency of CD8(+) T cells secreting IFN-γ, IL-17a or IL-22 was detected in the CVID group compared to the control group. However, a TLR7/TLR8 agonist and staphylococcal enterotoxin B induced an increased Th22/Tc22 (IL-22(+), IFN-γ(-), IL-17a(-)) response in CVID patients. Both TLR2 and TLR7/8/CL097 activation induced an increased response of CD4(+) T cells secreting three cytokines (IL-17a, IL-22 and TNF)in CVID patients, whereas CD8(+) T cells were unresponsive to these stimuli. CONCLUSION: The data show that despite the unresponsive profile of CD8(+) T cells to TLR activation, CD4(+) T cells and Tc22/Th22 cells are responsive, suggesting that activation of innate immunity by TLRs could be a strategy to stimulate CD4(+) T cells in CVID.
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Linfocitos T CD8-positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Receptores Toll-Like/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Biomarcadores/metabolismo , Citocinas/metabolismo , Demografía , Femenino , Humanos , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Receptores Toll-Like/agonistas , Adulto JovenRESUMEN
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.
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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
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.
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Linfocitos B Reguladores/inmunología , Inmunodeficiencia Variable Común/inmunología , Interleucina-10/metabolismo , Autoinmunidad , Inmunodeficiencia Variable Común/metabolismo , Citometría de Flujo , Humanos , Activación de Linfocitos , Linfocitos T Reguladores/inmunologíaRESUMEN
La inmunodeficiencia común variable(IDCV) es una inmunodeficiencia humoral primaria caracterizada por la disminución de inmunoglobulina G y al menos otra inmunoglobulina, la presencia de infecciones recurrentes y complicaciones no infecciosas como enfermedades autoinmunes, linfoproliferativas o neoplásicas
Summary: Common variable immunodeficiency is a humoral primary immunodeficiency characterized by low LgG levels and of at least another immunoglobulin, recurrent infections, and moninfectious complications, as autoimmune, lymphoproliferative or neoplastic diseases
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Masculino , Femenino , Humanos , Inmunodeficiencia Variable Común/inmunología , Infecciones/inmunología , Inmunidad AdaptativaRESUMEN
INTRODUCTION: Common variable immunodeficiency is a heterogeneous syndrome characterized by recurrent infections, hypogammaglobulinemia and defective production of specific antibodies. Abnormalities in peripheral blood lymphocyte subpopulations, in particular of B lymphocytes, allow the classification of patients into homogeneous groups. OBJECTIVE: To perform a clinical and immunological characterization and to evaluate lymphocyte subpopulations of twelve Colombian patients with common variable immunodeficiency in order to define homogeneous groups. MATERIALS AND METHODS: We reviewed medical records and evaluated serum immunoglobulins (Ig), lymphoproliferation, delayed hypersensitivity and used flow cytometry to quantify peripheral blood total lymphocyte and B cell populations. RESULTS: All patients had recurrent respiratory and/or gastrointestinal infections, while some also had infections affecting other systems. All patients had abnormally low serum IgG levels, while IgA and IgM levels were reduced in nine and ten patients, respectively. Lymphoproliferation to mitogen was lower in patients than in healthy controls but lymphoproliferation to specific antigen was normal in all. Flow cytometry revealed high numbers of T cells in three patients, while seven had a low CD4+/CD8+ ratio and four had reduced NK cells . Eleven patients had normal B cell counts, and eight of them also showed decreased memory B lymphocytes, and four had increased transitional or CD21 low B lymphocytes. CONCLUSION: Lymphocyte typing allowed assigning all but one patient to homogeneous groups according to international classification schemes, indicating the necessity of including more criteria until an ideal classification is achieved. This study will lead to a better medical monitoring of common variable immunodeficiency patients in groups at high risk of developing clinical complications.
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Subgrupos de Linfocitos B , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/inmunología , Adolescente , Adulto , Anciano , Niño , Preescolar , Inmunodeficiencia Variable Común/sangre , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: Common variable immunodeficiency and X-linked agammaglobulinaemia are primary immunodeficiencies classified as antibody deficiencies, and they both result in hypogammaglobulinaemia. OBJECTIVE: Evaluate the lipid profile and other cardiovascular risk biomarkers in CVID and XLA patients. METHODS: In total, 24 patients and 12 healthy controls matched by age and gender were included in the study. We evaluated anthropometric measurements, and seric total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apo A-I, small dense LDL (sdLDL), C-reactive protein (CRP), and tumour necrosis factor alpha (TNF-alpha), myeloperoxidase (MPO), cholesteryl ester transfer protein (CETP), and lecithin cholesterol acyltransferase (LCAT) were assessed. RESULTS: CRP (p = 0.008) and TNF-alpha (p < 0.001) concentrations were significantly higher, whereas HDL-c (p = 0.025) and apo A-I (p = 0.013) levels were significantly lower in patients than in the controls. In the patient group, a negative and significant correlation was observed between HDL-c and TNF-alpha (r = -0.406; p = 0.049) and between HDL-c and TG (r = -0.641; p = 0.001). CONCLUSION: Common variable immunodeficiency and X-linked agammaglobulinaemia patients presented themselves with increased inflammatory markers associated with a decreased HDL-c and apo A-I levels, which can predispose to a high cardiovascular risk.