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2.
J Exp Med ; 216(6): 1311-1327, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040185

RESUMO

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

3.
Nat Immunol ; 20(3): 350-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718914

RESUMO

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Proteínas de Transporte de Cátions/imunologia , Zinco/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Pré-Escolar , Citosol/imunologia , Citosol/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Linhagem , Zinco/metabolismo
5.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907690

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

7.
Front Immunol ; 8: 964, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28861081

RESUMO

BACKGROUND: Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes. OBJECTIVE: We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients. METHODS: We describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources. RESULTS: The observed ICOS gene mutations were all deletions leading to undetectable protein expression. The clinical phenotype of ICOS deficiency is much broader than initially anticipated and includes not only CVID-like disease but an increased susceptibility to viral and opportunistic infections, as well as cancer. Impaired B-cell development led to decreased memory B-cells in all patients, and hypogammaglobulinemia in all but one patient. Circulating CXCR5+ CD4+ follicular T-helper-cell numbers were also reduced in all patients. Treatment included immunoglobulin replacement, regular antibiotic prophylaxis, corticosteroids, and steroid-sparing agents. Three patients underwent hematopoietic stem cell transplantation; one of them died due to capillary leak syndrome on day 5 posttransplantation. CONCLUSION: The disease spectrum of ICOS deficiency is expanding from solely B-cell to combined B- and T-cell immunodeficiency, suggesting genetic and environmental modifiers. Genetic diagnosis is the only tool to distinguish ICOS deficiency from other immunological defects. Patients with antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for ICOS mutations.

8.
J Clin Immunol ; 37(1): 42-50, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27807805

RESUMO

PURPOSE: We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions. METHODS: Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs. RESULTS: We found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions. CONCLUSIONS: We show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.


Assuntos
Éxons , Heterozigoto , Receptores de Interleucina-7/genética , Deleção de Sequência , Sequenciamento Completo do Exoma , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Humanos , Mutação INDEL , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-7/metabolismo , Estudos Retrospectivos , Fator de Transcrição STAT5/metabolismo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Fluxo de Trabalho
11.
J Clin Immunol ; 36(2): 117-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26801501

RESUMO

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.


Assuntos
Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Genes Recessivos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Proteínas Serina-Treonina Quinases/deficiência , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/metabolismo , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Linhagem , Fenótipo , Irmãos
12.
Sci Transl Med ; 7(307): 307ra154, 2015 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-26424569

RESUMO

Type I interferon (IFN-α/ß) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/ß in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/ß receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/ß. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/ß responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/ß in human antiviral immunity.


Assuntos
Antivirais/metabolismo , Imunidade , Receptor de Interferon alfa e beta/deficiência , Evolução Fatal , Genes Recessivos , Teste de Complementação Genética , Humanos , Lactente , Interferons/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais
13.
J Clin Immunol ; 35(7): 598-603, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26399252

RESUMO

ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.


Assuntos
Enterite/diagnóstico , Hepatite/diagnóstico , Herpesvirus Humano 6/imunologia , Síndromes de Imunodeficiência/diagnóstico , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Infecções por Roseolovirus/diagnóstico , Linfócitos T Auxiliares-Indutores/imunologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Enterite/etiologia , Éxons/genética , Evolução Fatal , Feminino , Mutação da Fase de Leitura/genética , Hepatite/etiologia , Humanos , Síndromes de Imunodeficiência/complicações , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Masculino , Paquistão , Linhagem , Infecções por Roseolovirus/imunologia , Deleção de Sequência/genética , Irmãos , Linfócitos T Auxiliares-Indutores/virologia
14.
J Allergy Clin Immunol ; 136(2): 402-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25724123

RESUMO

BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. RESULTS: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.


Assuntos
Infecções Bacterianas/complicações , Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndrome de Job/complicações , Fenótipo , Dermatopatias/complicações , Viroses/complicações , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Antígenos Virais/sangue , Antígenos Virais/imunologia , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/genética , Imunoglobulina M/sangue , Imunoglobulina M/genética , Lactente , Síndrome de Job/genética , Síndrome de Job/imunologia , Síndrome de Job/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/mortalidade , Máquina de Vetores de Suporte , Análise de Sobrevida , Viroses/genética , Viroses/imunologia , Viroses/mortalidade
15.
Blood ; 125(4): 591-9, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25359994

RESUMO

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.


Assuntos
Doenças Autoimunes/genética , Doenças Genéticas Inatas/genética , Transtornos Linfoproliferativos/genética , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Lactente , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Mutação , Fosforilação/genética , Fosforilação/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
16.
Pediatrics ; 134(5): e1458-63, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25332498

RESUMO

Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria, and fungi, typically high serum levels of immunoglobulin E, eosinophilia, and a progressive deterioration of T- and B-cell-mediated immunity. DOCK8 mutations are the second most common cause of hyper-immunoglobulin E syndromes (HIES). We report a case of DOCK8 deficiency associated with systemic lupus erythematosus (SLE). Association of SLE with HIES is very rare; to our knowledge, this is the sixth such case reported in the literature. A 10-year-old girl of consanguineous parents was followed in our clinic because of HIES since early childhood. She developed SLE with purpuric and necrotic skin lesions, diffuse arthritis, and glomerulonephritis. These autoimmune features were corroborated by the presence of antinuclear, anti-DNA, and antiphospholipid antibodies. The combination of HIES and autoimmunity makes treatment difficult, because the use of immunosuppressive drugs needed for SLE may worsen existing symptoms caused by the immunodeficiency. Our observation is the first case of association of SLE with HIES in the literature where the primary immune disease is genetically documented and labeled as DOCK8 deficiency.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Criança , Feminino , Seguimentos , Humanos , Síndrome de Job/complicações , Lúpus Eritematoso Sistêmico/complicações
17.
Curr Top Microbiol Immunol ; 380: 1-18, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25004811

RESUMO

Inflammatory bowel disease (IBD) represents a heterogeneous group of gastrointestinal disorders, where commensal gut flora provokes an either (a) insufficient or (b) uncontrolled immune response. This results either in a lack of or in excessive inflammation mainly manifesting as Crohn's disease or ulcerative colitis. IBD commonly presents in adolescence and adulthood and often follows a chronic relapsing course. Genetic and/or environmental factors contribute to the failure of gut immune homeostasis. Genome-wide association studies have identified over 160 susceptibility loci associated with IBD, including polymorphisms in interleukin-10 (IL-10). The anti-inflammatory cytokine IL-10 dampens intestinal inflammation and is therefore a good candidate gene for IBD. Polymorphisms in the IL-10 receptor are also associated with ulcerative colitis presenting in early childhood. Moreover, severe infantile enterocolitis resembling Crohn's disease, caused by loss-of-function mutations in IL-10 and IL-10 receptor, is characterised by a very early onset (usually within the first 3 months of life), unresponsiveness to standard treatment including immunosuppressive therapy, and severe perianal disease with abscesses and fistulas. In these patients, inflammation and polymorphic infiltrates are mainly confined to the colon with very little involvement of the small intestine. Ulceration and granulomas, bloody diarrhoea and failure to thrive also occur. Furthermore, patients may suffer from recurrent fever and respiratory infections. Individuals with IL-10 receptor mutations also experience cutaneous folliculitis and arthritis. Hematopoietic stem cell transplantation is currently the only curative therapy.


Assuntos
Trato Gastrointestinal/imunologia , Interleucina-10/fisiologia , Polimorfismo Genético , Receptores de Interleucina-10/fisiologia , Animais , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/terapia , Interleucina-10/deficiência , Interleucina-10/genética , Receptores de Interleucina-10/deficiência , Receptores de Interleucina-10/genética
18.
J Allergy Clin Immunol ; 133(5): 1410-9, 1419.e1-13, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24698316

RESUMO

BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.


Assuntos
Cromossomos Humanos Par 6/genética , Doenças Genéticas Inatas/genética , Homozigoto , Imunidade/genética , Imunoglobulina E , Síndrome de Job/genética , Mutação de Sentido Incorreto , Fosfoglucomutase/genética , Adulto , Substituição de Aminoácidos , Proliferação de Células , Criança , Cromossomos Humanos Par 6/metabolismo , Feminino , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/imunologia , Ligação Genética , Glicosilação , Humanos , Lactente , Síndrome de Job/enzimologia , Síndrome de Job/imunologia , Masculino , Fosfoglucomutase/imunologia , Fosfoglucomutase/metabolismo , Linfócitos T/enzimologia , Linfócitos T/imunologia , Tunísia
19.
BMC Immunol ; 15: 10, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24581234

RESUMO

BACKGROUND: Inflammatory bowel disease constitutes a heterogeneous group of conditions, whose aetiology is only partly understood. The prevailing hypothesis on its pathogenesis is that IBD is the result of an inadequate immune response to the resident bacterial flora of the intestine. An autoimmune background, however, has been discussed since the 1950s. Lately, it has been shown that failures in interleukin-10 (IL-10) signalling due to IL-10- and IL-10 receptor (IL-10R) mutations result in IBD. Our study aimed at investigating the existence of inhibitory autoantibodies against IL-10 and IL-10R in IBD patients capable of down-modulating IL-10 signalling thereby mimicking IL-10 or IL-10R deficiency. RESULTS: Thirteen IBD patients had IgG autoantibodies against IL-10, IL-10RA and/or IL-10RB, and three patients had IgA autoantibodies against IL-10. However, the absolute OD values of the serum antibodies measured by ELISA were low, there was overall no significant difference between patients and controls, and positive sera had no neutralizing activity. CONCLUSION: No evidence for an involvement of autoantibodies against IL-10 or IL-10R in the pathogenesis of inflammatory bowel disease could be established.


Assuntos
Autoanticorpos/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Receptores de Interleucina-10/imunologia , Transdução de Sinais , Anticorpos Neutralizantes/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Receptores de Interleucina-10/metabolismo
20.
J Allergy Clin Immunol ; 131(3): 825-30, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23158016

RESUMO

BACKGROUND: Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. OBJECTIVES: We sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). METHODS: We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10/IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled. RESULTS: Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R-deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. CONCLUSION: Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.


Assuntos
Colite/terapia , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Interleucina-10/deficiência , Receptores de Interleucina-10/deficiência , Adulto , Criança , Pré-Escolar , Colite/diagnóstico , Colite/etiologia , Colite/genética , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Lactente , Recém-Nascido , Masculino , Mutação
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