RESUMEN
INTRODUCTION: Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity. METHODS: The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations. RESULTS: The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3). CONCLUSIONS: The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.
Asunto(s)
Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Homocigoto , Infecciones por Mycobacterium/genética , Familia , Estudio de Asociación del Genoma Completo , Humanos , Escala de LodRESUMEN
Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.
Asunto(s)
Genes Ligados a X , Predisposición Genética a la Enfermedad , Macrófagos/inmunología , Glicoproteínas de Membrana/genética , NADPH Oxidasas/genética , Tuberculosis/genética , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Mutación , NADPH Oxidasa 2 , NADPH Oxidasas/inmunologíaRESUMEN
Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
Asunto(s)
Sudunidad beta 1 del Receptor de Interleucina-12/deficiencia , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Citocinas/sangre , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Sudunidad beta 1 del Receptor de Interleucina-12/genética , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Infecciones por Mycobacterium no Tuberculosas/genética , Mycobacterium bovis/aislamiento & purificación , Mycobacterium tuberculosis/aislamiento & purificación , Micobacterias no Tuberculosas/aislamiento & purificación , Análisis de SupervivenciaRESUMEN
Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon gamma receptor 2 (IFN gamma R2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFN gamma mediated immunity may predispose patients to SCC.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Receptores de Interferón/deficiencia , Neoplasias Cutáneas/metabolismo , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Carcinoma de Células Escamosas/patología , Niño , Preescolar , Análisis Mutacional de ADN , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Receptores de Interferón/química , Receptores de Interferón/genética , Neoplasias Cutáneas/patología , Coloración y EtiquetadoRESUMEN
Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The ß1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.
Asunto(s)
Mycobacterium bovis/patogenicidad , Mutación Puntual , Receptores de Interleucina-12/genética , Tuberculosis/etiología , Adolescente , Vacuna BCG/efectos adversos , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Humanos , Lactante , Interferón gamma/biosíntesis , Masculino , México , Linaje , Tuberculosis/genética , Tuberculosis/inmunología , Tuberculosis/microbiologíaRESUMEN
Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Asunto(s)
Factor de Transcripción STAT1/deficiencia , Factor de Transcripción STAT1/metabolismo , Alelos , Empalme Alternativo/genética , Aminoácidos/genética , Aminoácidos/metabolismo , Secuencia de Bases , Células Cultivadas , Femenino , Humanos , Interferones/genética , Interferones/metabolismo , Masculino , Mutación/genética , Linaje , ARN Mensajero/genética , Factor de Transcripción STAT1/genética , HermanosAsunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Enfermedades Genéticas Congénitas/genética , Síndromes de Inmunodeficiencia/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Interleucina-12/genética , Proteínas Supresoras de Tumor/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/inmunología , Niño , Proteínas de Unión al ADN/inmunología , Femenino , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/inmunología , Enfermedades Genéticas Congénitas/terapia , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Masculino , Linaje , Proteínas Serina-Treonina Quinasas/inmunología , Receptores de Interleucina-12/inmunología , Proteínas Supresoras de Tumor/inmunologíaRESUMEN
The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
Asunto(s)
Diferenciación Celular/inmunología , Enfermedades Genéticas Congénitas/inmunología , Interleucina-17/inmunología , Receptores de Interleucina-12/inmunología , Factor de Transcripción STAT3/inmunología , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Diferenciación Celular/genética , Citocinas/genética , Citocinas/inmunología , Femenino , Enfermedades Genéticas Congénitas/genética , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/genética , Quinasas Asociadas a Receptores de Interleucina-1/inmunología , Interleucina-17/genética , Masculino , Mutación , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Sitios de Carácter Cuantitativo/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Interleucina-12/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/inmunología , Factor de Transcripción STAT3/genética , Transducción de Señal/genéticaRESUMEN
Natural killer (NK) cells have been originally defined by their "naturally occurring" effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-gamma (IFN-gamma) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rbeta1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-gamma production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rbeta1- and IL-12p40-deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56(+) effector memory T cells. The susceptibility of IL-12/23 axis-deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56(+) T cells in the control of these infections in humans.
Asunto(s)
Antígeno CD56 , Interleucina-12/fisiología , Interleucina-23/fisiología , Células Asesinas Naturales/inmunología , Adolescente , Adulto , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Memoria Inmunológica , Subunidad p40 de la Interleucina-12/deficiencia , Masculino , Mutación , Infecciones por Mycobacterium/inmunología , Receptores de Interleucina-12/deficiencia , Receptores de Interleucina-12/genética , Infecciones por Salmonella/inmunología , Linfocitos T/inmunologíaAsunto(s)
Predisposición Genética a la Enfermedad , Receptores de Interleucina-12/deficiencia , Infecciones por Salmonella/genética , Tuberculosis Ganglionar/genética , Bacteriemia/microbiología , Niño , Cromosomas Humanos Par 1 , Enfermedad Crónica , Consanguinidad , Exones , Eliminación de Gen , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Masculino , Receptores de Interleucina-12/genética , Recurrencia , Infecciones por Salmonella/diagnóstico , Tuberculosis Ganglionar/diagnóstico , Tuberculosis Ganglionar/microbiologíaRESUMEN
A few known primary immunodeficiencies confer predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines (regional disease, known as BCG-itis, or disseminated disease, known as BCG-osis), or more virulent mycobacteria, such as Mycobacterium tuberculosis (pulmonary and disseminated tuberculosis). We investigated the clinical and genetic features of a 12-year-old boy with both recurrent BCG-osis and disseminated tuberculosis. The patient's phagocytic cells produced no O(2)(-). A hemizygous splice mutation was found in intron 5 of CYBB, leading to a diagnosis of X-linked chronic granulomatous disease. Chronic granulomatous disease should be suspected in all children with BCG-osis, even in the absence of nonmycobacterial infectious diseases, and in selected children with recurrent BCG-itis or severe tuberculosis.
Asunto(s)
Vacuna BCG/efectos adversos , Enfermedad Granulomatosa Crónica/diagnóstico , Tuberculosis/diagnóstico , Secuencia de Bases , Niño , Diagnóstico Diferencial , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/patología , Humanos , Masculino , Glicoproteínas de Membrana/genética , Datos de Secuencia Molecular , Mutación , NADPH Oxidasa 2 , NADPH Oxidasas/genética , Tuberculosis/etiologíaRESUMEN
BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is associated with infection caused by weakly virulent mycobacteria in otherwise healthy people. Causal germline mutations in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12RB1, IL12B) and one X-linked (NEMO) gene have been described. The gene products are physiologically related, as they are involved in interleukin 12/23-dependent, interferon gamma-mediated immunity. However, no genetic aetiology has yet been identified for about half the patients with MSMD. METHODS: A large kindred was studied, including four male maternal relatives with recurrent mycobacterial disease, suggesting X-linked recessive inheritance. Three patients had recurrent disease caused by the bacille Calmette-Guérin vaccine, and the fourth had recurrent tuberculosis. The infections showed tropism for the peripheral lymph nodes. RESULTS: Known autosomal and X-linked genetic aetiologies of MSMD were excluded through genetic and immunological investigations. Genetic linkage analysis of the X-chromosome identified two candidate regions, on Xp11.4-Xp21.2 and Xq25-Xq26.3, with a maximum LOD score of 2. CONCLUSION: A new X-linked recessive form of MSMD is reported, paving the way for the identification of a new MSMD-causing gene.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos X , Predisposición Genética a la Enfermedad , Infecciones por Mycobacterium/genética , Tuberculosis/genética , Adulto , Vacuna BCG/uso terapéutico , Femenino , Genes Recesivos , Genotipo , Granuloma/genética , Granuloma/patología , Humanos , Ganglios Linfáticos/patología , Enfermedades Linfáticas/genética , Enfermedades Linfáticas/patología , Masculino , Linaje , Recurrencia , Tuberculosis/prevención & controlRESUMEN
Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders. Although genetically different, these conditions are immunologically related, as all result in impaired IL-12/23-IFN-gamma-mediated immunity. These disorders were initially thought to be rare, but have now been diagnosed in over 220 patients from over 43 countries worldwide. We review here the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-gamma circuit.
Asunto(s)
Enfermedades Genéticas Congénitas/inmunología , Interferón gamma/genética , Interleucina-12/genética , Interleucina-23/genética , Animales , Humanos , Interferón gamma/inmunología , Interleucina-12/inmunología , Interleucina-23/inmunología , MutaciónRESUMEN
Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4+ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN-gamma producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4+ T cells to induce IL-12 secretion by DCs. These data suggest that CD4+ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.
Asunto(s)
Células Dendríticas/metabolismo , Interferón gamma/fisiología , Interleucina-12/fisiología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Humanos , Superantígenos/fisiologíaRESUMEN
The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.
Asunto(s)
Infecciones por Mycobacterium/genética , Factor de Transcripción STAT1/genética , Adolescente , Adulto , Alelos , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Proteínas Ligadas a GPI , Regulación de la Expresión Génica , Genes Dominantes , Genes Recesivos , Heterocigoto , Humanos , Inmunidad Activa/genética , Lactante , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Interferón-alfa/metabolismo , Interferón gamma/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Modelos Biológicos , Modelos Moleculares , Proteínas Mutantes/química , Mutación , Infecciones por Mycobacterium/etiología , Linaje , Unión Proteica , Factor de Transcripción STAT1/metabolismo , Transcripción Genética , Transfección/métodosRESUMEN
Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.
Asunto(s)
Antígenos CD40/fisiología , Genes Ligados a X , Predisposición Genética a la Enfermedad , Quinasa I-kappa B/genética , Interleucina-12/biosíntesis , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Cromosoma X , Adolescente , Adulto , Animales , Línea Celular Transformada , Células Cultivadas , Niño , Preescolar , Femenino , Humanos , Lactante , Células L , Masculino , Ratones , LinajeRESUMEN
Amorphic mutations in the NF- kappa B essential modulator (NEMO) cause X-dominant incontinentia pigmenti, which is lethal in males in utero, whereas hypomorphic mutations cause X-recessive anhidrotic ectodermal dysplasia with immunodeficiency, a complex developmental disorder and life-threatening primary immunodeficiency. We characterized the NEMO mutation 110_111insC, which creates the most-upstream premature translation termination codon (at codon position 49) of any known NEMO mutation. Surprisingly, this mutation is associated with a pure immunodeficiency. We solve this paradox by showing that a Kozakian methionine codon located immediately downstream from the insertion allows the reinitiation of translation. The residual production of an NH(2)-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages but was insufficient for the development of protective immune responses.
Asunto(s)
Codón de Terminación , Quinasa I-kappa B/genética , Mutación , Biosíntesis de Proteínas , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos X , ADN , Genes Letales , Humanos , Incontinencia Pigmentaria/genética , Datos de Secuencia MolecularAsunto(s)
Síndromes de Inmunodeficiencia/genética , Sudunidad beta 1 del Receptor de Interleucina-12/deficiencia , Sudunidad beta 1 del Receptor de Interleucina-12/genética , Receptores de Interleucina-12/deficiencia , Receptores de Interleucina-12/genética , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/inmunología , Lactante , Masculino , Mutación , Infecciones por Mycobacterium/inmunología , Infecciones por Salmonella/inmunología , Tuberculosis Ganglionar/inmunología , TurquíaRESUMEN
Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.
Asunto(s)
Vacuna BCG/efectos adversos , Interferón gamma/genética , Interleucina-12/genética , Mycobacterium bovis , Tuberculosis/genética , Adulto , Preescolar , Predisposición Genética a la Enfermedad , Humanos , Subunidad p40 de la Interleucina-12 , Irán , Masculino , Subunidades de Proteína/genética , Receptores de Interferón/genética , Infecciones por Salmonella/genética , Infecciones por Salmonella/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Receptor de Interferón gammaRESUMEN
BACKGROUND: Paracoccidioides brasiliensis is a facultative intracellular dimorphic fungus that causes paracoccidioidomycosis (PCM), the most important deep mycosis in Latin America. Only a small percentage of individuals infected by P. brasiliensis develop clinical PCM, possibly in part because of genetically determined interindividual variability of host immunity. However, no primary immunodeficiency has ever been associated with PCM. METHODS: We describe the first patient, to our knowledge, with PCM and a well-defined primary immunodeficiency in the beta 1 subunit of the interleukin (IL)-12/IL-23 receptor, a disorder previously shown to be specifically associated with impaired interferon (IFN)-gamma production, mycobacteriosis, and salmonellosis. RESULTS: Our patient had a childhood history of bacille Calmette-Guérin disease and nontyphoid salmonellosis and, at the age of 20 years, presented to our clinic with a disseminated (acute) form of PCM. He responded well to antifungal treatment and is now doing well at 24 years of age. CONCLUSIONS: This unique observation supports previous studies of PCM suggesting that IL-12, IL-23, and IFN-gamma play an important role in protective immunity to P. brasiliensis. Tuberculosis and PCM are thus not only related clinically and pathologically, but also by their immunological pathogenesis. Our study further expands the spectrum of clinical manifestations of inherited defects of the IL-12/IL-23-IFN-gamma axis. Patients with unexplained deep fungal infections, such as PCM, should be tested for defects in the IL-12/IL-23-IFN- gamma axis.