Costimulatory molecules and cytokine production by T lymphocytes in common variable immunodeficiency disease.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by hypogammaglobulinaemia and recurrent infections. Although early works pointed to a primary B-lymphocyte defect as a cause of the disease, a failure in T-lymphocyte cooperation has also been suggested. T cells exert their costimulatory function through either membrane costimulatory molecules or secreted cytokines, both having an influence in the development of the humoral response. The aim of our study was to evaluate whether an abnormal expression and induction of costimulatory molecules or alterations in the production of cytokines by T cells cause deficient T/B cooperation in CVID patients. We studied the expression and upregulation of costimulatory molecules (CD28, CD40L/CD154 and CTLA-4/CD152) and production of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF-alpha) in purified T lymphocytes from CVID patients stimulated with optimal doses of anti-CD3 or suboptimal doses of anti-CD3 and anti-CD28. Stimulated T cells from CVID patients expressed normal levels of CD28, CD40L/CD154 and CTLA-4/CD152 when compared with controls. Except for higher production of IL-4 after stimulation with anti-CD3, T cells of CVID patients produced similar amounts of cytokines compared with controls. An imbalance between costimulatory molecules expression (CD28, CD40L/CD154 and CTLA-4/CD152) and cytokine production by T cells does not explain a deficient cooperation between T and B cells in this group of CVID patients.

Molecular studies and NK cell function of a new case of TAP2 homozygous human deficiency.

In this paper we describe the clinical and molecular features of a new case (GOR) of homozygous human TAP2 deficiency, analysing the phenotype and function of NK cells. The patient presented from infancy with recurrent sinopulmonary infections; a selective IgG2 deficiency, negative antibody response to polysaccharide vaccination and low level of cell surface expression of HLA class I antigens were found. The sequence of TAP2 gene identified a single mutation, a C to T substitution changing the CGA arg codon at amino acid 220 into TGA stop codon in exon 3. By using MoAbs for KIRs, CD94, CD94/NKG2A and ILT2 we observed, in agreement with others, that the latter two receptors were overexpressed on TAP2-deficient NK cells. The inhibitory CD94/NKG2A and triggering CD94/NKG2C NK receptors, specific for HLA-E, appeared to be functional in a limited number of NK clones that could be expanded in vitro. Expression of HLA-E was virtually undetectable in GOR B-LCL and very faint in PBMC, further supporting that interactions of class I leader sequence nonamers with HLA-E in the ER depend on a functional TAP complex.

[Common variable immunodeficiency. Review]. / Inmunodeficiencia variable común. Revisión.

Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by deficient antibody production. The cause of this immunodeficiency is unknown; several in vitro studies have revealed a significant number of alterations that could explain the hypogammaglobulinemia present in this syndrome. Among those described are primary B cell alterations, numerical and functional T cell abnormalities, and defects in the interaction between accessory cells. The alteration typical of CVI is the failure of B lymphocytes to differentiate from antibody-producing cells, resulting in deficient immunoglobulin secretion. Among the T cell abnormalities described are a diminished proliferative response to mitogens and antigens, alterations in the level of production of several cytokines, especially reduction in the production of IL-2, diminished antigen-specific T cells and increase basal apoptosis after stimulation. Antigen presenting cells, monocytes and dendritic cells can also present alterations and contribute to deficient antigen response. The clinical manifestations of these patients is variable; most present recurrent bacterial infections due to encapsulated bacteria, especially sinusitis, otitis, bronchitis, and pneumonias. A few patients can present mycobacterial or fungal infection and occasionally Pneumocystis carinii. Viral infection is uncommon in these patients although some suffer recurrent herpes zoster infection. Clinical features of septicemia and central nervous system infections are less frequent. The incidence of digestive tract infections in these patients is high. The most common cause of diarrhea is Giardia lamblia; Salmonella, Shigella and Campylobacter are also common pathogens. Autoimmune disease is also more prevalent in these patients than in the general population. The most frequently associated diseases are hemolytic anemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia. Cancer is also frequently associated with CVI, the most common forms being lymphoproliferative syndromes, especially non-Hodgkin's lymphoma. Granulomas are a unusual manifestation in some patients with CVI; their localization varies but the most commonly affected organs are the spleen and lungs. Some authors have compared these granulomas with those characterizing sarcoidosis, especially when appearing in the lung. Diagnosis of CVI is usually by exclusion of other diseases, such as cystic fibrosis, immotile cilia syndrome or allergic processes. CVI should be suspected in all patients with recurrent bacterial infections especially those localized in the respiratory tract. Other primary immunodeficiencies which present clinical findings similar to CVI and which should be ruled out are selective IgG subclass deficiency, IgA deficiency and selective deficiency in the response to polysaccharide antigens with normal immunoglobulin levels. The serum hypogammaglobulinemia present in all patients with CVI provides the diagnostic key. The age at which clinical manifestations appear, the absence of familial antecedents and the presence of circulating B lymphocytes form the basis of the differential diagnosis between X-linked agammaglobulinemia and autosomal recessive forms. The treatment of choice of patients with CVI is treatment with human gamma-globulin. Currently, the most common route of administration is intravenous; these molecules have a half-life of approximately 21 days and a high degree of safety concerning the possible transmission of viral infections. Adverse reactions are generally few and clinically unimportant. The most frequently used doses oscillate between 200 and 400 mg/kg body weight every 2-4 weeks. Both the dose and its frequency should be personalized for each patient. Early diagnosis of patients with CVI, application of treatment with appropriate antibiotics for infections and treatment with gamma-globulins prevent long-term complications of this disease and dramatically improve the quality of life and life expectancy of these patients.

Inmunodeficiencia variable común. Revisión / Common variable immunodeficiency. Review

La inmunodeficiencia variable común (IVC) es una inmunodeficiencia primaria caracterizada por una deficiente producción de anticuerpos. La causa de esta inmunodeficiencia no es conocida; distintos estudios in vitro han puesto de manifiesto un número importante de alteraciones que podrían explicar la hipogammaglobulinemia presente en este síndrome. Entre las descritas se incluyen alteraciones primarias de la célula B, anormalidades numéricas y funcionales de la célula T y defectos de colaboración de las células accesorias. La alteración típica de la IVC es el fallo de diferenciación del linfocito B a célula productora de anticuerpos, del que resulta la deficiente secreción de inmunoglobulinas. Entre las anormalidades descritas en la célula T, se encuentran una respuesta proliferativa disminuida a mitógenos y antígenos, alteraciones en los niveles de producción de distintas citocinas, especialmente reducción en la producción de IL-2, disminución de las células T específicas para antígeno y aumento de la apoptosis basal y tras estimulación. Las células presentadoras de antígeno, monocitos y células dendríticas, también pueden presentar alteraciones y contribuir a una respuesta a antígenos deficitaria.La expresión clínica de estos pacientes es variable; la mayoría presentan infecciones bacterianas de repetición por bacterias encapsuladas, especialmente sinusitis, otitis, bronquitis y neumonías. Un número reducido de pacientes puede presentar infección por micobacterias, hongos y ocasionalmente por Pneumocystis carinii. Los virus no suelen infectar a estos pacientes, aunque algunos sufren herpes zoster de repetición. Cuadros de septicemia e infecciones del sistema nervioso central son menos frecuentes. Las infecciones del aparato digestivo tienen una incidencia alta en estos enfermos. Giardia lamblia es la causa más frecuente de diarrea; Salmonella, Shigella y Campylobacter son también patógenos habituales. La presencia de enfermedad autoinmune es también superior al de la población normal. Las patologías más frecuentemente asociadas son la anemia hemolítica, la púrpura trombocitopénica idiopática y la neutropenia autoinmune. El cáncer también presenta un grado elevado de asociación con la IVC, los más frecuentes son los síndromes linfoproliferativos, en especial los linfomas no Hodgkin. Los granulomas son una manifestación peculiar de algunos pacientes con IVC; su localización es variable pero el bazo y el pulmón suelen ser los órganos más afectados. Algunos autores han comparado estos granulomas con los que caracterizan a la sarcoidosis, especialmente cuando aparecen en el pulmón. El diagnóstico de la IVC se realiza habitualmente por exclusión de otras patologías, como la fibrosis quística, el síndrome de cilio inmóvil o procesos alérgicos y debe sospecharse en todo paciente con infecciones bacterianas de repetición localizadas especialmente en aparato respiratorio. Otras inmunodeficiencias primarias que presentan una patología similar a la IVC y que deben descartarse son la deficiencia selectiva de subclases de IgG, la deficiencia de IgA y la deficiencia selectiva en la respuesta a antígenos polisacáridos con niveles normales de inmunoglobulinas. La hipogammaglobulinemia sérica presente todos los pacientes con IVC dará la clave del diagnóstico. La edad de aparición de las manifestaciones clínicas, la ausencia de historia familiar y la presencia de linfocitos B circulantes servirá para realizar el diagnóstico diferencial con la gammaglobulinemia ligada al cromosoma X y con las formas autosómicas recesivas.El tratamiento de elección de los pacientes con IVC es el sustitutivo con gammaglobulina humana; la forma más común de aplicación actual es la intravenosa; estas moléculas tienen una vida media aproximada de 21 días y un alto grado de seguridad en relación a la posible transmisión de enfermedades víricas; el número de reacciones adversas es por lo general bajo y de poca relevancia. Las dosis más utilizadas oscilan entre los 200-400 mg/kg de peso cada 2-4 semanas, pero es recomendable que tanto la dosis como la frecuencia se indiquen de forma personalizada para cada paciente. El diagnóstico precoz de los pacientes con IVC, la aplicación de los tratamientos con antibióticos adecuados para las infecciones y del sustitutivo con gammaglobulina previene las complicaciones a largo plazo de la enfermedad y mejora drásticamente la calidad y esperanza de vida de estos enfermos (AU)

Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by deficient antibody production. The cause of this immunodeficiency is unknown; several in vitro studies have revealed a significant number of alterations that could explain the hypogammaglobulinemia present in this syndrome. Among those described are primary B cell alterations, numerical and functional T cell abnormalities, and defects in the interaction between accessory cells. The alteration typical of CVI is the failure of B lymphocytes to differentiate from antibody-producing cells, resulting in deficient immunoglobulin secretion. Among the T cell abnormalities described are a diminished proliferative response to mitogens and antigens, alterations in the level of production of several cytokines, especially reduction in the production of IL-2, diminished antigen-specific T cells and increase basal apoptosis after stimulation. Antigen presenting cells, monocytes and dendritic cells can also present alterations and contribute to deficient antigen response. The clinical manifestations of these patients is variable; most present recurrent bacterial infections due to encapsulated bacteria, especially sinusitis, otitis, bronchitis, and pneumonias. A few patients can present mycobacterial or fungal infection and occasionally Pneumocystis carinii. Viral infection is uncommon in these patients although some suffer recurrent herpes zoster infection. Clinical features of septicemia and central nervous system infections are less frequent. The incidence of digestive tract infections in these patients is high. The most common cause of diarrhea is Giardia lamblia; Salmonella, Shigella and Campylobacter are also common pathogens. Autoimmune disease is also more prevalent in these patients than in the general population. The most frequently associated diseases are hemolytic anemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia. Cancer is also frequently associated with CVI, the most common forms being lymphoproliferative syndromes, especially non-Hodgkin's lymphoma. Granulomas are a unusual manifestation in some patients with CVI; their localization varies but the most commonly affected organs are the spleen and lungs. Some authors have compared these granulomas with those characterizing sarcoidosis, especially when appearing in the lung. Diagnosis of CVI is usually by exclusion of other diseases, such as cystic fibrosis, immotile cilia syndrome or allergic processes. CVI should be suspected in all patients with recurrent bacterial infections especially those localized in the respiratory tract. Other primary immunodeficiencies which present clinical findings similar to CVI and which should be ruled out are selective IgG subclass deficiency, IgA deficiency and selective deficiency in the response to polysaccharide antigens with normal immunoglobulin levels. The serum hypogammaglobulinemia present in all patients with CVI provides the diagnostic key. The age at which clinical manifestations appear, the absence of familial antecedents and the presence of circulating B lymphocytes form the basis of the differential diagnosis between X-linked agammaglobulinemia and autosomal recessive forms. The treatment of choice of patients with CVI is treatment with human gamma-globulin. Currently, the most common route of administration is intravenous; these molecules have a half-life of approximately 21 days and a high degree of safety concerning the possible transmission of viral infections. Adverse reactions are generally few and clinically unimportant. The most frequently used doses oscillate between 200 and 400 mg/kg body weight every 2-4 weeks. Both the dose and its frequency should be personalized for each patient. Early diagnosis of patients with CVI, application of treatment with appropriate antibiotics for infections and treatment with gamma-globulins prevent long-term complications of this disease and dramatically improve the quality of life and life expectancy of these patients (AU)