RESUMO
The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.
Assuntos
Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Interferon Tipo I/farmacologia , Interferon gama/farmacologia , Transativadores/deficiência , Transativadores/genética , Viroses/etiologia , Substituição de Aminoácidos , Antivirais/farmacologia , Sequência de Bases , Consanguinidade , DNA/genética , Feminino , Humanos , Técnicas In Vitro , Lactente , Masculino , Infecções por Mycobacterium/tratamento farmacológico , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/fisiopatologia , Linhagem , Proteínas Recombinantes , Fator de Transcrição STAT1 , Deleção de Sequência , Transdução de Sinais , Viroses/tratamento farmacológico , Viroses/genética , Viroses/fisiopatologiaRESUMO
Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.
Assuntos
Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/microbiologia , Interleucina-12 , Interleucinas/deficiência , Interleucinas/genética , Mutação/genética , Adolescente , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular Transformada , Criança , Pré-Escolar , Consanguinidade , Feminino , Efeito Fundador , Haplótipos/genética , Herpesvirus Humano 4/fisiologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/fisiopatologia , Índia , Lactente , Subunidade p40 da Interleucina-12 , Interleucinas/metabolismo , Masculino , Mutagênese Insercional/genética , Paquistão , Linhagem , Fenótipo , Polimorfismo Genético/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Arábia Saudita , Deleção de Sequência/genéticaRESUMO
Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.