Chemokine, cytokine and type I interferon production induced by Toll-like receptor activation in common variable immune deficiency.

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.

[Common variable immunodeficiency: Clinical and immunological characterization of patients and homogeneous subgroup definition by means of B lymphocyte subpopulation typing]. / Inmunodeficiencia común variable: caracterización clínica e inmunológica de pacientes e identificación de subgrupos homogéneos con base en la tipificación de subpoblaciones de linfocitos B.

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.

Higher Cardiovascular Risk in Common Variable Immunodeficiency and X-Linked Agammaglobulinaemia Patients.

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.

Inmunodeficiencia común variable: caracterización clínica e inmunológica de pacientes e identificación de subgrupos homogéneos con base en la tipificación de subpoblaciones de linfocitos B / Common variable immunodeficiency: Clinical and immunological characterization of patients and homogeneous subgroup definition by means of B lymphocyte subpopulation typing

Introducción. La inmunodeficiencia común variable es un síndrome heterogéneo caracterizado por infecciones recurrentes, hipogammaglobulinemia y producción deficiente de anticuerpos específicos. Las anormalidades en subpoblaciones de linfocitos en sangre periférica, particularmente de linfocitos B, permiten la clasificación de los pacientes en grupos homogéneos. Objetivo. Caracterizar clínica e inmunológicamente los linfocitos B y tipificar sus subpoblaciones en doce pacientes colombianos con inmunodeficiencia común variable, para clasificarlos en grupos homogéneos. Materiales y métodos. Se revisaron las historias clínicas de los pacientes y se evaluaron las inmunoglobulinas séricas, la proliferación de linfocitos y la hipersensibilidad retardada, así como las subpoblaciones de linfocitos y de linfocitos B mediante citometría de flujo. Resultados. Todos los pacientes presentaron infecciones respiratorias o gastrointestinales recurrentes y, algunos, infecciones en otros sistemas. Además, todos presentaban disminución de la IgG, en tanto que la IgA y la IgM fueron bajas en nueve y diez pacientes, respectivamente. En todos hubo disminución de la proliferación de linfocitos inducida por mitógenos, pero fue normal frente a antígenos específicos. La tipificación de subpoblaciones reveló valores elevados de linfocitos T en tres pacientes; siete presentaron disminución en la relación CD4+/CD8+ y, cuatro, linfocitos NK bajos. El conteo de linfocitos B fue normal en once pacientes, ocho de los cuales presentaron linfocitos B de memoria bajos, en tanto que cuatro presentaron aumento de linfocitos B de transición o de linfocitos B CD21 low . Conclusión. La tipificación de subpoblaciones de linfocitos solo permitió asignar a 11 de los pacientes a grupos homogéneos según los esquemas de clasificación internacionales, lo que indica la necesidad de agregar más criterios hasta lograr una clasificación ideal. Este estudio permitirá establecer mejores seguimientos médicos para pacientes con inmunodeficiencia común variable en grupos con alto riesgo de desarrollar complicaciones clínicas.

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.

Impaired number and function of lymphocytes in patients with common variable immunodeficiency: a consequence of activation-induced cell death / Alteração do número e da função de linfócitos em pacientes com imunodeficiência comum variável: uma consequência da morte celular induzida por alteração

Introduction: Common variable immunodeficiency (CVID) is an immunological disorder characterized by defective antibody production. Objectives: To study lymphocytes number, surface activation molecules, cell markers, lymphoproliferative response, cytokine production, and cell death. Methods: A study was led on thirty four patients with CVID selected from the Division of Clinical Immunology and Allergies of the Faculty of Medicine of São Paulo University (FMUSP), Brazil. Peripheral mononuclear blood cells (PBMC) of CVID patients and healthy individuals were evaluated in regard to the expression of cell surface markers, activation molecules, lymphoproliferative response, cytokine synthesis and apoptosis. Results: CVID patients showed decrease in T and B lymphocyte counts, CD25, CD69, CD40L, and CD70 expression, and low synthesis levels of IL-4 and IL-5. Furthermore, their lymphocytes were more susceptible to apoptosis following activation. Conclusion: The higher susceptibility to apoptosis following activation may also be responsible for the decrease in the expression of activation molecules and CD40L, in cytokine synthesis, and in levels of circulating T and B cells.

Introdução: A imunodeficiência comum variável (CVID) é uma enfermidade imune caracterizada pela produção deficiente de anticorpos. Objetivo: Avaliar o número de linfócitos, moléculas de ativação, resposta linfoproliferativa, produção de citocinas e morte celular. Métodos: Foram selecionados 34 pacientes com CVID na Divisão de Imunologia Clínica e Alergia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Brasil. Células mononucleares obtidas a partir de sangue periférico (PBMC) foram isoladas para avaliação de marcadores de superfície celular, moléculas de ativação, resposta linfoproliferativa, quantificação de citocinas e apoptose. Resultados: Os pacientes analisados apresentaram diminuição na contagem de linfócitos T e B, expressão de CD25, CD69, CD40L, CD70, e baixa produção de IL-4 e IL-5. Os linfócitos se apresentaram mais suscetíveis à apoptose pós-ativação. Conclusão: A maior susceptibilidade à apoptose pós-ativação pode ser responsável pela diminuição na expressão de moléculas de ativação e CD40L, síntese de citocinas e linfócitos T e B circulantes.

A decreased frequency of regulatory T cells in patients with common variable immunodeficiency.

INTRODUCTION: Common variable immunodeficiency disorder (CVID) is a heterogeneous syndrome, characterized by deficient antibody production and recurrent bacterial infections in addition abnormalities in T cells. CD4(+)CD25(high) regulatory T cells (Treg) are essential modulators of immune responses, including down-modulation of immune response to pathogens, allergens, cancer cells and self-antigens. OBJECTIVE: In this study we set out to investigate the frequency of Treg cells in CVID patients and correlate with their immune activation status. MATERIALS AND METHODS: Sixteen patients (6 males and 10 females) with CVID who had been treated with regular intravenous immunoglobulin and 14 controls were enrolled. Quantitative analyses of peripheral blood mononuclear cells (PBMC) were performed by multiparametric flow cytometry using the following cell markers: CD38, HLA-DR, CCR5 (immune activation); CD4, CD25, FOXP3, CD127, and OX40 (Treg cells); Ki-67 and IFN-gamma (intracellular cytokine). RESULTS: A significantly lower proportion of CD4(+)CD25(high)FOXP3 T cells was observed in CVID patients compared with healthy controls (P<0.05). In addition to a higher proportion of CD8(+) T cells from CVID patients expressing the activation markers, CD38(+) and HLA-DR(+) (P<0.05), we observed no significant correlation between Tregs and immune activation. CONCLUSION: Our results demonstrate that a reduction in Treg cells could have impaired immune function in CVID patients.

Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: a link to autoimmunity?

Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease characterized by defective immunoglobulin production and often associated with autoimmunity. We used flow cytometry to analyze CD4(+)CD25(HIGH)FOXP3(+) T regulatory (Treg) cells and ask whether perturbations in their frequency in peripheral blood could underlie the high incidence of autoimmune disorders in CVID patients. In this study, we report for the first time that CVID patients with autoimmune disease have a significantly reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells in their peripheral blood accompanied by a decreased intensity of FOXP3 expression. Notably, although CVID patients in whom autoimmunity was not diagnosed had a reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells, FOXP3 expression levels did not differ from those in healthy controls. In conclusion, these data suggest compromised homeostasis of CD4(+)CD25(HIGH)FOXP3(+) cells in a subset of CVID patients with autoimmunity, and may implicate Treg cells in pathological mechanisms of CVID.

Leptin and the immune response: an active player or an innocent bystander?

Leptin is involved in the control of energy storage by the body. Low serum leptin levels, as seen in starvation, are associated with impaired inflammatory T cell responses that can be reversed by exogenous leptin. Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Several defects in T cell function have also been described, and allergy, autoimmune disease, and lymphomas or other malignancies can be present. Previous studies in Brazilian CVID patients have shown that, in contrast with mononuclear cells from healthy controls, CVID cells cultured with phytohemagglutinin and added leptin increased the proliferative response and decreased activation-induced apoptosis. Interleukin (IL)-2 and especially IL-4 production also increased significantly, although the effects of exposure to leptin were not observed uniformly in CVID patients. The majority, however, responded in some degree, and some exhibited completely restored values of the four parameters.These remarkable results indicate leptin could be used to improve immune function in these patients. On the other hand, we found no specific correlation between serum leptin levels and the number of infectious events over a 24-month period, presence of autoimmunity, allergies, or cancer in these patients. The results suggest that the absolute value of serum leptin does not determine the clinical behavior of patients or responses to leptin in vitro. Of note is the divergence between serum leptin, response to leptin in vitro, and the presence of autoimmunity, indicating the need to identify the cellular and molecular players involved in the regulation of the immune response by leptin in CVID.

Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency.

OBJECTIVE: Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross-talk and by direct action on pancreatic beta-cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance. PATIENTS: Thirteen CVI patients (39 +/- 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender-, age-, body weight- and body mass index (BMI)-matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies. MEASUREMENTS: Serum leptin and insulin levels, homeostasis model assessment - insulin resistance (HOMA-IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one-way analysis of variance (anova) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls. RESULTS: No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0.05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients' serum leptin levels did not correlate with BMI (r = 0.074, P = 0.8) and their high HOMA-IR indicated insulin resistance. CONCLUSIONS: CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.

Necrotizing ulcerative periodontitis associated with severe congenital immunodeficiency in a prepubescent subject: clinical findings and response to intravenous immunoglobulin treatment.

Common variable immunodeficiency (CVID) is a rare multifactorial congenital disease of genetic origin caused by an impairment in the secretion of specific immunoglobulins. It manifests systemically through recurrent respiratory infections, gastrointestinal disorders and autoimmune diseases. Oral manifestations may include gingivitis and lichenoid lesions with Wickham's striae. The treatment for CVID is supported by using intravenous infusion of immunoglobulins (IVIG) that allows for control of the disease and avoidance of recurrent opportunistic infections. This report presents a case of necrotizing ulcerative periodontitis (NUP) in a young patient with CVID, and correlates his periodontal status with systemic conditions before and after IVIG administration during 1 year of evaluation.