RESUMO
Peripheral monocytes from patients with common variable immunodeficiency (CVID) had on average a 2 fold greater tendency to form giant cells in medium without additional cytokines. Giant cell formation was faster and 3 to 5 fold higher in most CVID cells compared to normal. Addition of IL4, GMCSF, IFNγ, TNFa and both T cell and monocyte conditioned media promoted monocyte fusion of some CVID individuals over 5 fold the normal average level, with combinations of cytokines and monokines acting synergistically. The reduction of normal giant cell formation by anti-IFNγ antibody and a greater tendency of CVID cells to fuse in immunoglobulin conditioned media suggests that standard IVIg treatment contributes to granuloma formation. CVID and normal giant cells expressed similar levels of phenotypic molecules and had similar phagocytic activity. Monocytes from many CVID patients have an elevated tendency to fuse which may explain the high incidence of granulomatous complications in CVID.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Células Gigantes/imunologia , Granuloma/imunologia , Doença Granulomatosa Crônica/imunologia , Adulto , Idoso , Feminino , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunological phenotypes. The recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID. RESULTS: The exonic, protein coding regions of the genes encoding: APRIL, BCMA, IL10, IL10Ralpha, IL10Rbeta, IL21, IL21R, and CCL18, were analyzed primarily in familial CVID cases, who showed evidence of genetic linkage to the respective candidate gene loci and CVID families with a recessive pattern of inheritance. Two novel SNPs were identified in exon 5 and exon 8 of the IL21R gene, which segregated with the disease phenotype in one CVID family. Eleven additional SNPs in the genes encoding BCMA, APRIL, IL10, IL10Ralpha, IL21 and IL21R were observed at similar frequencies as in healthy donors. CONCLUSION: We were unable to identify obvious disease causing mutations in the protein coding regions of the analyzed genes in the studied cohort.
Assuntos
Imunodeficiência de Variável Comum/genética , Testes Genéticos , Antígeno de Maturação de Linfócitos B/genética , Quimiocinas CC/genética , Família , Feminino , Humanos , Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/genética , Interleucinas/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-21/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
Common variable immunodeficiency (CVID) is a heterogeneous disorder that is associated with low serum-immunoglobulin concentrations, defective specific-antibody production and an increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts. In spite of the identification of genes that are associated with several known primary immunodeficiencies, the basic immunologic and molecular defects of the majority of patients with CVID have remained obscure. Most of the studies aimed at understanding the immunopathogenesis of CVID suggest that this condition is primarily a T-cell disorder, although renewed attention on the genetic linkage and haplotype analysis in families of patients with CVID and on the role of dendritic cells and B cells has revealed several interesting features. This new information should assist in understanding the pathogenesis of CVID and improving the therapeutic strategies.
