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1.
Vaccine ; 36(32 Pt B): 4890-4896, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30037479

RESUMO

We have recently demonstrated the effectiveness of an intranasal immunization approach against Neospora caninum infection in immunosufficient mice. Generated evidence indicated that antibodies could be mediating the observed protection. We similarly immunized IL-12/IL-23 p40 chain-deficient (Il12b-/-) mice, which have impaired cellular immunity, to further explore the host protective mechanism conferred by the used immunization strategy. The immunized mice presented lower parasitic burdens after intraperitoneal infection with N. caninum and also had elevated levels of parasite-specific antibodies. However, passive immunization with antibodies purified from immunized donors conferred only limited protection to infected Il12b-/- recipients. Despite their intrinsic IL-12 deficiency, the immunized Il12b-/- mice mounted a parasite-specific immune response that was mediated by interferon-γ (IFN-γ). Neutralization of IFN-γ in the immunized mice abrogated the observed protective effect of the immunization. These results show altogether that the used immunization strategy overcome the cellular immunity defect of Il12b-/- mice and conferred protection from N. caninum infection. The observed protective effect was predominantly mediated by IFN-γ and to a lesser extent but non-negligibly by IgG antibodies. These results also highlight that in a host with compromised cellular immunity, the immune response against intracellular pathogens could be markedly boosted by immunization.


Assuntos
Antígenos de Protozoários/imunologia , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Neospora/imunologia , Receptores de Interleucina-12/deficiência , Animais , Anticorpos Antiprotozoários/imunologia , Feminino , Imunidade nas Mucosas/imunologia , Imunização , Interferon gama/genética , Interleucina-12/genética , Interleucina-23/genética , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-12/genética
2.
Turk J Pediatr ; 60(5): 584-587, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30968642

RESUMO

Dogruel D, Bulut FD, Yilmaz M, Önenli-Mungan N, Altintas DU. Coexistence of 2 rare autosomal recessively inherited disorders manifesting with immune deficiency; IL-12 receptor ß1 and biotinidase deficiencies. Turk J Pediatr 2018; 60: 584-587. In this report, we described an infant with both partial biotinidase and IL-12Rß1 deficiencies as these two entities are rare and unrelated inherited disorders. One-month-old girl was diagnosed as partial biotinidase deficiency with newborn screening programme. Mutation analysis revealed a compound heterozygous mutation BTD: c.1330G > C (p.Val444Leu) / c.196_197dupCATC (p.Leu69HisfsTer24). At the age of 6 months, a nodule on her left axilla with purulent discharge was noticed which was related to BCG vaccination. A mutational analysis revealed a homozygous c.783+1G > A mutation on IL-12Rß1 gene. Interferon-gamma and anti-tuberculosis treatment were initiated together and the nodule with purulent discharge regressed dramatically. Here, we want to emphasize consideration of coexistence of two rare autosomal recessively inherited diseases in a patient due to the high rate of consanguinity in our country.


Assuntos
Deficiência de Biotinidase/complicações , Síndromes de Imunodeficiência/diagnóstico , Receptores de Interleucina-12/deficiência , Antituberculosos/uso terapêutico , Deficiência de Biotinidase/genética , Análise Mutacional de DNA/métodos , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Lactente , Recém-Nascido , Interferon gama/uso terapêutico , Mutação , Triagem Neonatal/métodos , Receptores de Interleucina-12/genética
3.
Pediatrics ; 140(5)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29025965

RESUMO

Tuberculosis is a major worldwide problem, and protection from it is achieved mainly by live attenuated bacille Calmette-Guérin vaccine, which is capable of causing disease in immunocompromised host. Oral thrush is abnormal in healthy children, which suggests an underlying immunodeficiency. Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by a selective predisposition to weakly virulent Mycobacteria and Salmonella and also predisposition to chronic mucocutaneous candidiasis. Interleukin 12 receptor ß1 (IL-12Rß1) deficiency is the most common disease of Mendelian susceptibility to mycobacterial disease, and to date only 50 IL-12Rß1 deficient patients with clinical signs of chronic mucocutaneous candidiasis have been reported. We report a 2.5-year-old daughter of consanguineous parents with both regional bacille Calmette-Guérin lymphadenitis and recurrent oral candidiasis carrying biallelic R175W mutation in the IL12RB1 gene, resulting in complete loss of expression of IL-12Rß1. To our knowledge, this is the first report of bacille Calmette-Guérin lymphadenitis with concurrent oral candidiasis displaying such a mutation. New mutations and wide clinical diversities are the indisputable fact of populations with a high rate of consanguineous marriages.


Assuntos
Vacina BCG/efeitos adversos , Candidíase Bucal/diagnóstico por imagem , Linfadenite/diagnóstico por imagem , Receptores de Interleucina-12/deficiência , Candidíase Bucal/genética , Pré-Escolar , Feminino , Humanos , Linfadenite/induzido quimicamente , Linfadenite/complicações , Linfadenite/genética , Linhagem , Receptores de Interleucina-12/genética
4.
J Clin Immunol ; 37(7): 732-738, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28865061

RESUMO

PURPOSE: Mendelian susceptibility to mycobacterial disease is a rare clinical condition characterized by a predisposition to infectious diseases caused by poorly virulent mycobacteria. Other infections such as salmonellosis and candidiasis are also reported. The purpose of this article is to describe a young boy affected with various infectious diseases caused by Mycobacterium tuberculosis complex, Salmonella sp, Klebsiella pneumonie, Citrobacter sp., and Candida sp, complicated with severe enteropathy and transient hypogammaglobulinemia. METHODS: We reviewed medical records and performed flow cytometry staining for lymphocyte populations, lymphocyte proliferation in response to PHA, and intracellular IFN-γ production in T cell PHA blasts in the patient and a healthy control. Sanger sequencing was used to confirm the genetic variants in the patient and relatives. RESULTS: Genetic analysis revealed a bi-allelic mutation in IL12RB1 (C291Y) resulting in complete IL-12Rß1 deficiency. Functional analysis demonstrated the lack of intracellular production of IFN-γ in CD3+ T lymphocytes from the patient in response to rhIL-12p70. CONCLUSIONS: To our knowledge, this is the third patient with MSMD due to IL-12Rß1 deficiency complicated with enteropathy and hypogammaglobulinemia and the first case of this disease to be described in Colombia.


Assuntos
Agamaglobulinemia/genética , Candidíase/genética , Enterite/genética , Infecções por Bactérias Gram-Negativas/genética , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Agamaglobulinemia/tratamento farmacológico , Vacina BCG , Candidíase/tratamento farmacológico , Farmacorresistência Bacteriana , Enterite/tratamento farmacológico , Predisposição Genética para Doença , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Lactente , Mutação , Mycobacterium tuberculosis
5.
J Hepatol ; 66(4): 798-805, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27965154

RESUMO

BACKGROUND & AIMS: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis. METHODS: Treg were expanded by repeated injection of IL-2/IL-2Ab complex in mouse models of cholangitis (Mdr2-/-, DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg. RESULTS: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced pro-inflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL-12rb2-/-) were able to maintain hepatic Treg functionality. CONCLUSIONS: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases. Data accession number: GSE 87898.


Assuntos
Colangite Esclerosante/imunologia , Interleucina-12/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Colangite Esclerosante/genética , Colangite Esclerosante/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Interleucina-2/metabolismo , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Regulação para Cima
7.
Pediatr Blood Cancer ; 64(6)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27873456

RESUMO

Mutations of the IL12B and IL12RB1 genes underlie the development of IL-12 p40 and IL-12Rß1 deficiencies, respectively, both of which cause predisposition to infection with weakly virulent mycobacteria and Salmonella. Infections with other intramacrophagic organisms have only been rarely observed. We identified two patients with visceral leishmaniasis who had autosomal recessive IL-12 p40 and IL-12Rß1 deficiencies, respectively. This finding demonstrates the importance of IFN-γ immunity in the control of leishmaniasis. We also searched the literature for similar reports in patients with these and other primary immunodeficiencies.


Assuntos
Doenças Genéticas Inatas , Síndromes de Imunodeficiência , Subunidade p40 da Interleucina-12/deficiência , Leishmaniose Visceral , Receptores de Interleucina-12/deficiência , Adolescente , Criança , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Leishmaniose Visceral/genética , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/patologia , Masculino
8.
J Neuroimmunol ; 291: 59-69, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26857496

RESUMO

IL-12Rß2 is a common receptor subunit of heterodimeric receptors for IL-12 and IL-35, two cytokines that are implicated in immunopathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We evaluated the role of IL-12Rß2 in relapsing-remitting EAE (RR-EAE). IL-12Rß2-deficient SJL/J mice developed markedly more severe clinical EAE, and had greater mortality and more severe relapses compared with wild-type controls. IL-12Rß2-deficient EAE mice also had more infiltrating mononuclear cells in the CNS, as well as higher T cell proliferative capacity and decreased IFN-γ production at the periphery. These findings demonstrate a protective role of IL-12Rß2 in RR-EAE.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Receptores de Interleucina-12/deficiência , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Citometria de Fluxo , Adjuvante de Freund , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Proteolipídica de Mielina/toxicidade , Infiltração de Neutrófilos/genética , Fragmentos de Peptídeos/toxicidade , Receptores de Interleucina-12/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
9.
Turk J Pediatr ; 58(3): 331-336, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28266204

RESUMO

Clinical disease caused by weakly pathogenic mycobacterial species, which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity. IFN-γ and IL-17 production are defective due to insufficient response to IL-2 and IL-23 in IL-12Rß1 deficiency; so this also causes tendency to intracellular microorganisms and candidal diseases. Here, we present a patient who suffers IL-12Rß1 deficiency caused by a novel bi-allelic mutation with recurrent salmonellosis, mycobacterial, fungal infections and remained asymptomatic during 13 months of follow-up after hIFN-γ treatment. In addition she had hemolytic anemia and midline defects like cleft lip and palate which have not been reported in a patient with MSMD in the literature prior to this case report. In conclusion, diagnosis of MSMD should be kept in mind in patients with recurrent salmonellosis, mycobacterial and fungal infections especially in countries with a high consanguinity rate.


Assuntos
Autoimunidade/genética , Fissura Palatina/complicações , Doenças Transmissíveis/genética , Receptores de Interleucina-12/genética , Alelos , Pré-Escolar , Doenças Transmissíveis/complicações , Feminino , Humanos , Mutação , Receptores de Interleucina-12/deficiência , Síndrome
10.
Turk J Pediatr ; 58(4): 356-361, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28276206

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by infections with weakly virulent mycobacteria (BCG and environmental mycobacteria), M. tuberculosis, Salmonella, candida and some other intracellular microorganisms. Nine different genetic defects have been defined to cause MSMD and IL-12Rß1 deficiency is the most common form. We present here the clinical and genetic features of 18 patients with IL12Rß1 deficiency diagnosed by surface expression of IL-12Rß1 and Sanger's sequencing. Seventeen patients showed classical presentation (infections with BCG, salmonella and candida) while one patient experienced recurrent leishmaniasis. In all patients the percentage of activated lymphocytes with surface expression of IL12Rß1 was < 1% indicating that it is an effective method for the screening of these patients. Three recurrent mutations were responsible for 85% of our families. Prognosis was good in patients, in whom specific antimicrobial therapy was given before dissemination occurs, as well as prophylactic antimicrobial treatment when needed and IFN-γ therapy for severe infectious episodes.


Assuntos
Mycobacterium tuberculosis/imunologia , Receptores de Interleucina-12/genética , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Receptores de Interleucina-12/deficiência , Adulto Jovem
11.
Fam Cancer ; 14(1): 89-94, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25467645

RESUMO

IL-12Rß1 deficiency, also known as immunodeficiency 30 (IMD30, OMIM 614891), is a rare immunodeficiency syndrome caused by biallelic mutations in IL12RB1. Three second-degree relatives of a patient with this syndrome, all women, developed intestinal-type gastric cancer (GC). In the Netherlands the incidence of non-cardia GC in women is only 7 per 100,000 person years. Both relatives that were available for testing proved to be heterozygous for the familial IL12RB1 mutation, suggesting there might be a causal relation. Testing 29 index patients from families with early onset and/or a familial history of GC for germline mutations in both IL12RB1 and IL12RB2, that encodes the binding partner of IL-12Rß1, did not reveal other germline mutations in these genes. Therefore heterozygous inactivating mutations in IL12RB1 and IL12RB2 are unlikely to be frequently involved in GC predisposition. Additional research in families with IL12RB1 mutations is required to determine whether carriers of IL12RB1 mutations have an increased (gastric) cancer risk.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Receptores de Interleucina-12/genética , Neoplasias Gástricas/genética , Idoso , Alelos , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Humanos , Síndromes de Imunodeficiência/genética , Países Baixos , Linhagem , Receptores de Interleucina-12/deficiência
12.
Paediatr Int Child Health ; 35(1): 69-71, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24863105

RESUMO

Although neonatal vaccination with bacille Calmette-Guérin (BCG) is considered to be safe, complications with disseminated disease are associated with underlying immuno-deficiency disorders. A BCG-vaccinated 4-month-old girl of Sri Lankan parentage developed progressive left axillary lymphadenopathy and severe bronchopneumonia. Lymph node biopsy demonstrated epithelioid granulomata and acid-fast bacilli. An older sibling had had a similar clinical presentation and the outcome had been fatal. Investigation for immuno-deficiency detected complete IL12RB1 deficiency. Full recovery followed a prolonged course of anti-tuberculous chemotherapy. She was put on lifelong isoniazid prophylaxis. In HIV-negative infants with unusual complications related to BCG vaccination, a primary immuno-deficiency disorder should be considered.


Assuntos
Vacina BCG/efeitos adversos , Síndromes de Imunodeficiência/complicações , Mycobacterium bovis/isolamento & purificação , Receptores de Interleucina-12/deficiência , Tuberculose/diagnóstico , Tuberculose/microbiologia , Antituberculosos/uso terapêutico , Vacina BCG/administração & dosagem , Biópsia , Feminino , Histocitoquímica , Humanos , Lactente , Pulmão/patologia , Linfonodos/patologia , Sri Lanka , Resultado do Tratamento
13.
Rev Chilena Infectol ; 31(4): 444-51, 2014 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-25327198

RESUMO

BCG disease has been reported in primary and secondary immunodeficiency and as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Investigation of this syndrome has led to the identifications of a series of genetic, inherited defects in the IL-12/IFN-γ axis. MSMD-causing mutations have been found in seven autosomal and two X-linked genes. In these patients, local or disseminated vaccine BCG infections are common. We report a clinical series including two infants with left axillary adenitis ipsilateral to the site of neonatal BCG immunization; one of them member of a family with two previously reported cases and a single sporadic case. All of them were diagnosed sequentially in Puerto Montt, Chile. The aim of this report is to notify the first Chilean disseminated BCG patients without previous immunodeficiency, in whom it was possible to identify an underlying immunodeficiency, although specific tests for IL-12/IFN-γ axis was no performed in our country. Clinical suspicion and international collaboration permitted to confirm IL12-Rß1 deficiency in 2 of 3 familial cases and a sporadic case.


Assuntos
Vacina BCG/efeitos adversos , Predisposição Genética para Doença , Infecções por Micobactéria não Tuberculosa/genética , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Infecções por Micobactéria não Tuberculosa/diagnóstico , Linhagem , Adulto Jovem
14.
Genes Immun ; 15(6): 413-23, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24898389

RESUMO

The induction of functional memory cytotoxic T lymphocytes (CTLs) is a major goal of vaccination against intracellular pathogens. Interleukin (IL)-12 is critical for the generation of memory CTLs, and inhibition of mammalian target of rapamycin (mTOR) by rapamycin can effectively enhance the memory CTL response. Yet, the role of IL-12 in mTOR's regulation of memory CTL is unknown. Here we hypothesized that the immunostimulatory effects of mTOR on memory CTLs requires IL-12 signaling. Our results revealed that rapamycin increased the generation of memory CTLs in vaccinia virus infection, and this enhancement was dependent upon the IL-12 signal. Furthermore, IL-12 receptor deficiency diminished the secondary expansion of rapamycin-regulated memory and resultant secondary memory CTLs were abolished. Rapamycin enhanced IL-12 signaling by upregulating IL-12 receptor ß2 expression and signal transducer and activator of transcription factor 4 phosphorylation in CTLs during early infection. In addition, rapamycin continually suppressed T-bet expression in both wild-type and IL-12 receptor knockout CTLs. These results indicate an essential role for IL-12 in the regulation of memory CTLs by mTOR and highlight the importance of considering the interplay between cytokines and adjuvants during vaccine design.


Assuntos
Memória Imunológica/imunologia , Interleucina-2/imunologia , Linfócitos T Citotóxicos/imunologia , Serina-Treonina Quinases TOR/imunologia , Vírus Vaccinia/imunologia , Vaccinia/imunologia , Transferência Adotiva , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Imunossupressores/imunologia , Imunossupressores/farmacologia , Interleucina-2/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/imunologia , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sirolimo/imunologia , Sirolimo/farmacologia , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Vaccinia/genética , Vaccinia/virologia , Vírus Vaccinia/fisiologia
15.
Pediatr Dermatol ; 31(2): 236-40, 2014 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23004925

RESUMO

Defects in the interleukin 12 (IL-12)/interferon gamma (IFN-γ) pathway result in Mendelian susceptibility to mycobacterial disease (MSMD). IL-12 receptor beta 1 (IL-12Rß1) deficiency, the most common form of MSMD, is associated with weakly virulent mycobacteria and salmonella. Infections in patients with this deficiency are extraintestinal, or septicemic, recurrent infections with nontyphoid salmonellae. Here we report a case of an IL-12Rß1 deficiency with cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis.


Assuntos
Receptores de Interleucina-12/deficiência , Salmonella enteritidis/isolamento & purificação , Vasculite Leucocitoclástica Cutânea/microbiologia , Antibacterianos/uso terapêutico , Biópsia , Ceftriaxona/uso terapêutico , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Vasculite Leucocitoclástica Cutânea/tratamento farmacológico , Vasculite Leucocitoclástica Cutânea/genética
16.
Clin Genet ; 86(2): 161-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23952477

RESUMO

Autosomal recessive interleukin-12 receptor ß1 (IL-12Rß1) deficiency has been described as the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), characterized by clinical disease due to weakly virulent mycobacteria such as Bacille Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM) in children who are normally resistant to most infectious agents. Here, we report the cases of five patients with mycobacterial infection, including one with systemic lupus erythematosus (SLE). Blood samples from patients and healthy controls were activated in vitro with BCG, BCG+IL-12, and BCG+IFN-γ. The results showed reduced or no production of IFN-γ after IL-12 stimulation in all samples. IL-12Rß1 expression on the cell surface was negligible or absent. Genetic analysis showed five novel mutations.


Assuntos
Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Evolução Fatal , Humanos , Lactente , Interleucina-12/sangue , Masculino , Dados de Sequência Molecular , Linfócitos T/metabolismo
17.
Immunology ; 141(4): 549-63, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24224652

RESUMO

Interleukin-12 (IL-12) p70 and IL-23 are bioactive cytokines and their biological functions are becoming clear. Increased expression of IL-7 in the central nervous system as well as in peripheral immune cells is associated with multiple sclerosis and experimental allergic encephalomyelitis. Here, we describe the induction of IL-7 in primary mouse and human microglia, BV-2 microglial cells, mouse peritoneal macrophages and astrocytes by IL-12p70. Interestingly, IL-12 strongly induced the expression of IL-7 whereas IL-23 and other p40 family members remained weak inducers of IL-7 in these cell types. Consistently, IL-12, but not IL-23 and other p40 family members, induced IL-7 promoter-driven luciferase activity in microglial cells. Among various stimuli tested, IL-12 emerged as the most potent stimulus followed by bacterial lipopolysaccharide and HIV-1 gp120 in inducing the activation of IL-7 promoter in microglial cells. Furthermore, increase in IL-7 mRNA expression by over-expression of IL-12p35 subunit, but not p40 and IL-23 p19 subunit, confirm that p35, but not p40 and p19, is responsible for the induction of IL-7. Finally, by using primary microglia from IL-12 receptor ß1-deficient (IL-12Rß1(-/-)) and IL-12Rß2(-/-) mice, we demonstrate that IL-12 induces the expression of IL-7 in microglia and macrophages via both IL-12Rß2 and IL-12Rß1. These studies delineate a novel biological function of IL-12 that is absent in IL-23 and other p40 family members.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Interleucina-7/metabolismo , Macrófagos Peritoneais/metabolismo , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Células Cultivadas , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Genes Reporter , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Subunidade p35 da Interleucina-12/imunologia , Subunidade p35 da Interleucina-12/metabolismo , Subunidade p40 da Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Lipopolissacarídeos/farmacologia , Luciferases/biossíntese , Luciferases/genética , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Cultura Primária de Células , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Transfecção , Regulação para Cima
19.
Hum Mutat ; 34(10): 1329-39, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23864330

RESUMO

IL-12Rß1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rß1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rß1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rß1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rß1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rß1 and molecular genetics of human IL12RB1.


Assuntos
Bases de Dados Genéticas , Mutação , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Efeito Fundador , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Penetrância , Polimorfismo Genético , Receptores de Interleucina-12/metabolismo
20.
Arch Pediatr ; 20(7): 758-61, 2013 Jul.
Artigo em Francês | MEDLINE | ID: mdl-23726680

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic syndrome that predisposes patients to infections caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guérin (BCG) vaccines and nontuberculous environmental mycobacteria in children free of classical immunodeficiencies. This syndrome consists of impaired antimycobacterial immunity (axis IL12/INF-γ) constituting a new immune deficiency and outlining its major role in mycobacterial immunity. We report a new case of MSMD through the observation of a young girl with a disseminated infection due to Mycobacterium avium. The molecular defect was 2 autosomal recessive mutations of the IL12Rß1 gene (gene encoding for the ß1 chain of the IL12 receptor) leading to the absence of the IL12 receptor on the activated T lymphocytes' surface. IL-12RB1 deficiency is the most common genetic etiology of MSMD. Today, there are 6 MSMD-causing genes, leading to 13 distinct genetic disorders. The clinical phenotype differs between patients. The description of the molecular and immunological basis of this syndrome has allowed us to explain the pathophysiology of antimycobacterial immunity and is essential to understanding and managing these diseases.


Assuntos
Predisposição Genética para Doença , Infecção por Mycobacterium avium-intracellulare/genética , Antibacterianos/uso terapêutico , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Mutação , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética
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