RESUMO
Hyper IgE syndrome (HIES) is characterized by recurrent skin abscesses, eczema, pneumonia, and high levels of serum IgE. Nonimmunologic manifestations of HIES include a characteristic face, pathologic dentition, scoliosis, bone alterations, hyperextensible joints, and vascular abnormalities. Somatic mosaicism is defined by the presence of two or more populations of cells with different genotypes in one individual. In this report, we describe one patient with classical HIES and another patient with a mild phenotype, both harboring the same genetic mutation. The patient with a mild phenotype did not present the characteristic face, had normal production of IL-17A by T CD4+ cells, but had low phosphorylation of STAT-3 in B cells. Interestingly, the mutation found in B cells was absent in other cell types analyzed, in agreement with the presence of a somatic mosaic genotype. The clinical and functional differences observed between these patients justify the use of complementary tools for a better definition of the cases. These approaches allow for a better understanding of complex phenotypes associated with somatic mosaicisms, and present the possibility to analyze the role of B lymphocytes in the pathophysiology of this disease. This knowledge has an impact on not only the treatment but also the provision of appropriate genetic counseling.
Assuntos
Linfócitos B/fisiologia , Síndrome de Job/imunologia , Mosaicismo , Mutação/genética , Fator de Transcrição STAT3/genética , Células Th17/fisiologia , Adulto , Células Cultivadas , Feminino , Aconselhamento Genético , Genótipo , Humanos , Imunoglobulina E/metabolismo , Memória Imunológica , Interleucina-17/metabolismo , Síndrome de Job/diagnóstico , Masculino , Especificidade de Órgãos , Fenótipo , Fosforilação/genética , Fator de Transcrição STAT3/metabolismo , Adulto JovemRESUMO
NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.
Assuntos
Displasia Ectodérmica/genética , Família , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/genética , Incontinência Pigmentar/genética , Púrpura Trombocitopênica Idiopática/genética , Ubiquitinação/genética , Adolescente , Adulto , Displasia Ectodérmica/imunologia , Feminino , Heterozigoto , Humanos , Quinase I-kappa B/imunologia , Síndromes de Imunodeficiência/imunologia , Incontinência Pigmentar/imunologia , Masculino , Mutação de Sentido Incorreto , Púrpura Trombocitopênica Idiopática/imunologia , Ubiquitinação/imunologiaAssuntos
Mutação com Ganho de Função , Mutação com Perda de Função , Fator de Transcrição STAT3/genética , Substituição de Aminoácidos , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Humanos , Síndrome de Job/genética , Transtornos Linfoproliferativos/genética , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/imunologia , Eletricidade Estática , Domínios de Homologia de src/genéticaRESUMO
BACKGROUND: Colostrum is the primary source of maternal immunoglobulin A (IgA) for the newborn. IgA participates in protection and regulation mechanisms of the immune response at the neonate's mucosa. Several studies have evaluated infectious diseases and vaccine protocols effects during pregnancy on maternal milk IgA levels, with the aim to understand lactation protecting effect on newborn. However, most of their results demonstrated that there were no differences in the total IgA levels. In humans, IgA has two subclasses (IgA1 and IgA2), they have an anatomical distribution among mucosal compartments, their levels vary after antigen stimulation and are also seen to describe differential affinities in colostrum. Although there are differences between IgA subclasses in several compartments, these studies have excluded specific colostrum IgA1 and IgA2 determination. METHODS: We analyzed data from 900 women in Mexico City. With Pearson correlation, we compared the number of infectious episodes during their pregnancy that was associated with mucosal compartments (skin, respiratory and gastrointestinal tracts) and colostrum IgA subclasses. RESULTS: We show a correlation between increased colostrum IgA1 levels and the number of infectious episodes at respiratory tract and the skin. In contrast, infections at the gastrointestinal tract correlated with increased IgA2 amounts. CONCLUSIONS: Infections present during pregnancy at certain mucosal site increase specific IgA subclasses levels in human colostrum. These results will help in understanding infections and immunizations effects on maternal IgA at the mammary gland, and their impact on the development and protection of the newborn.