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1.
J Allergy Clin Immunol ; 143(6): 2215-2226.e7, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30578871

RESUMO

BACKGROUND: Inflammatory activation of CD8+ T cells can, when left unchecked, drive severe immunopathology. Hyperstimulation of CD8+ T cells through a broad set of triggering signals can precipitate hemophagocytic lymphohistiocytosis (HLH), a life-threatening systemic inflammatory disorder. OBJECTIVE: The mechanism linking CD8+ T-cell hyperactivation to pathology is controversial, with excessive production of IFN-γ and, more recently, excessive consumption of IL-2, which are proposed as competing hypotheses. We formally tested the proximal mechanistic events of each pathway in a mouse model of HLH. METHODS: In addition to reporting a complete autosomal recessive IFN-γ receptor 1-deficient patient with multiple aspects of HLH pathology, we used the mouse model of perforin (Prf1)KO mice infected with lymphocytic choriomeningitis virus to genetically eliminate either IFN-γ production or CD25 expression and assess the immunologic, hematologic, and physiologic disease measurement. RESULTS: We found a striking dichotomy between the mechanistic basis of the hematologic and inflammatory components of CD8+ T cell-mediated pathology. The hematologic features of HLH were completely dependent on IFN-γ production, with complete correction after loss of IFN-γ production without any role for CD8+ T cell-mediated IL-2 consumption. By contrast, the mechanistic contribution of the immunologic features was reversed, with no role for IFN-γ production but substantial correction after reduction of IL-2 consumption by hyperactivated CD8+ T cells. These results were complemented by the characterization of an IFN-γ receptor 1-deficient patients with HLH-like disease, in whom multiple aspects of HLH pathology were observed in the absence of IFN-γ signaling. CONCLUSION: These results synthesize the competing mechanistic models of HLH pathology into a dichotomous pathogenesis driven through discrete pathways. A holistic model provides a new paradigm for understanding HLH and, more broadly, the consequences of CD8+ T-cell hyperactivation, thereby paving the way for clinical intervention based on the features of HLH in individual patients.

2.
Nat Immunol ; 19(9): 973-985, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30127434

RESUMO

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.

3.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

4.
J Clin Immunol ; 38(1): 129-143, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29226301

RESUMO

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.

5.
Pan Afr Med J ; 26: 212, 2017.
Artigo em Francês | MEDLINE | ID: mdl-28690727

RESUMO

Hyper IgM syndrome is a well known genetic (primary) immunodeficiency disorder which was first described in 1961. It is caused by B lymphocyte deficiency characterized by normal or elevated serum IgM levels and low or zero levels of IgG, IgA, IgE resulting from isotype-switching deficiency. Clinical manifestations are dominated by recurrent infections, especially involving the digestive tube of the ENT sphere and the lungs. This syndrome is caused by B-cell immunoglobulin class switch deficiency and decreased capacity to induce proliferation of T lymphocytes. The net result of these deficiencies is reflected in increased susceptibility to Pneumocystis jiroveci, Cryptosporidium spp and other intracellular organisms as well as high rate of bacterial and viral infections. This study aimed to illustrate the importance of understanding the pathophysiological mechanisms associated with this increased susceptibility to infections in order to allow a better diagnosis and therapy in patients with Hyper IgM syndrome (HIM).


Assuntos
Linfócitos B/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/fisiopatologia , Infecções Oportunistas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina M/sangue , Lactente , Masculino , Marrocos , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/microbiologia , Linfócitos T/imunologia
6.
Pan Afr Med J ; 26: 93, 2017.
Artigo em Francês | MEDLINE | ID: mdl-28491224

RESUMO

Macrophage activation syndrome (MAS) is an anatomoclinic entity due to inappropriate macrophage activation. It is a rare pathology, characterized by clinical signs that are not very specific and by biological elements. Their association must evoke the diagnosis. It can be classified as primary or secondary, its prognosis is still unclear. We report the case of a 3-year and 4-month-old infant admitted to our department with primary MAS in order to remind clinicians the importance of suspecting primary cause in specific situations.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Pré-Escolar , Feminino , Humanos , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Síndrome de Ativação Macrofágica/fisiopatologia , Prognóstico
7.
J Clin Immunol ; 37(4): 357-362, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28353165

RESUMO

PURPOSE: Poikiloderma with Neutropenia (PN) is inherited genodermatosis which results from a biallelic mutation in the USB1 gene (U Six Biogenesis 1). PN, first described in Navajo Native Americans, is characterized by early onset poikiloderma, pachyonychia, palmo-plantar hyperkeratosis, and permanent neutropenia. This condition results in frequent respiratory tract infections during infancy and childhood. From 2011 to 2013, four cases of PN were diagnosed in Morocco. In this paper, we report the first four cases of PN diagnosed in Morocco, out of three unrelated consanguinous families. METHODS: We investigated the genetic, immunological, and clinical features of four Moroccan patients with PN from three unrelated consanguinous families. RESULTS: Mean age at onset was 3 months and mean age at diagnosis was 7.5 years. The diagnosis of these PN patients was made based on clinical features and confirmed by molecular analysis for three cases. We identified two undescribed homozygous mutations in the USB1 gene: c.609 + 1G>A in two siblings and c.518 T>G(p.(Leu173Arg)) in the other case. CONCLUSION: This report confirms the clinical and genetic identity of Poikiloderma with Neutropenia syndrome.


Assuntos
Infecção/diagnóstico , Mutação/genética , Neutropenia/diagnóstico , Diester Fosfórico Hidrolases/genética , Anormalidades da Pele/diagnóstico , Adolescente , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Lactente , Infecção/genética , Masculino , Marrocos , Neutropenia/genética , Patologia Molecular , Linhagem , Irmãos , Anormalidades da Pele/genética
8.
J Allergy Clin Immunol ; 140(1): 232-241, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28011069

RESUMO

BACKGROUND: Germline heterozygous mutations in human signal transducer and activator of transcription 1 (STAT1) can cause loss of function (LOF), as in patients with Mendelian susceptibility to mycobacterial diseases, or gain of function (GOF), as in patients with chronic mucocutaneous candidiasis. LOF and GOF mutations are equally rare and can affect the same domains of STAT1, especially the coiled-coil domain (CCD) and DNA-binding domain (DBD). Moreover, 6% of patients with chronic mucocutaneous candidiasis with a GOF STAT1 mutation have mycobacterial disease, obscuring the functional significance of the identified STAT1 mutations. Current computational approaches, such as combined annotation-dependent depletion, do not distinguish LOF and GOF variants. OBJECTIVE: We estimated variations in the CCD/DBD of STAT1. METHODS: We mutagenized 342 individual wild-type amino acids in the CCD/DBD (45.6% of full-length STAT1) to alanine and tested the mutants for STAT1 transcriptional activity. RESULTS: Of these 342 mutants, 201 were neutral, 30 were LOF, and 111 were GOF mutations in a luciferase assay. This assay system correctly estimated all previously reported LOF mutations (100%) and slightly fewer GOF mutations (78.1%) in the CCD/DBD of STAT1. We found that GOF alanine mutants occurred at the interface of the antiparallel STAT1 dimer, suggesting that they destabilize this dimer. This assay also precisely predicted the effect of 2 hypomorphic and dominant negative mutations, E157K and G250E, in the CCD of STAT1 that we found in 2 unrelated patients with Mendelian susceptibility to mycobacterial diseases. CONCLUSION: The systematic alanine-scanning assay is a useful tool to estimate the GOF or LOF status and the effect of heterozygous missense mutations in STAT1 identified in patients with severe infectious diseases, including mycobacterial and fungal diseases.


Assuntos
Alanina/genética , Infecções por Mycobacterium/genética , Fator de Transcrição STAT1/genética , Bioensaio , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutagênese , Mutação , Domínios Proteicos
9.
J Exp Med ; 213(11): 2413-2435, 2016 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-27647349

RESUMO

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.


Assuntos
Alelos , Linfócitos B/imunologia , Proteínas dos Microfilamentos/genética , Mutação/genética , Linfócitos T/imunologia , Adolescente , Adulto , Sequência de Bases , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Dimerização , Feminino , Células HEK293 , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos/patologia , Masculino , NF-kappa B/metabolismo , Linhagem , Fenótipo , Receptores de Antígenos de Linfócitos B , Transdução de Sinais , Células Th17/imunologia , Células Th2/imunologia , Adulto Jovem
10.
J Clin Immunol ; 36(3): 187-94, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26931785

RESUMO

PURPOSE: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. METHODS: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. RESULTS: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed. CONCLUSIONS: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.


Assuntos
Agamaglobulinemia/genética , Expressão Gênica , Frequência do Gene , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Infecções Oportunistas/genética , Proteínas Tirosina Quinases/genética , Adulto , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Idade de Início , Argélia , Alelos , Linfócitos B/imunologia , Linfócitos B/patologia , Criança , Pré-Escolar , Estudos de Associação Genética , Aconselhamento Genético , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Heterozigoto , Humanos , Lactente , Masculino , Marrocos , Infecções Oportunistas/complicações , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Proteínas Tirosina Quinases/imunologia , Análise de Sequência de DNA , Tunísia
11.
J Allergy Clin Immunol ; 138(1): 241-248.e3, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936803

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.


Assuntos
Doença Granulomatosa Crônica/complicações , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Vacina BCG/administração & dosagem , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/mortalidade , Criança , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/mortalidade , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/mortalidade , Micoses/diagnóstico , Micoses/epidemiologia , Micoses/etiologia , Micoses/mortalidade , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Tuberculose/diagnóstico , Tuberculose/etiologia
12.
J Clin Immunol ; 35(8): 727-38, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26445875

RESUMO

There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.


Assuntos
Hipersensibilidade/imunologia , Síndromes de Imunodeficiência/imunologia , Infecção/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Autoimunidade , Prova Pericial , Humanos , Imunidade/genética , Síndromes de Imunodeficiência/classificação , Fenótipo
13.
J Exp Med ; 212(10): 1641-62, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26304966

RESUMO

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/ß, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/ß. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.


Assuntos
Síndrome de Job/etiologia , TYK2 Quinase/deficiência , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-10/farmacologia , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Síndrome de Job/complicações , Síndrome de Job/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Mutação , Infecções por Mycobacterium/etiologia , Linfócitos T/metabolismo , Linfócitos T/patologia , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Viroses/etiologia , Adulto Jovem
14.
Immunol Rev ; 264(1): 103-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25703555

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.


Assuntos
Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/etiologia , Mycobacterium tuberculosis/imunologia , Tuberculose/etiologia , Fatores Etários , Criança , Genes Dominantes , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
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
18.
J Clin Immunol ; 34(4): 452-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24596025

RESUMO

PURPOSE: Chronic granulomatous disease (CGD) is characterized by an inability of phagocytes to produce reactive oxygen species (ROS), which are required to kill some microorganisms. CGD patients are known to suffer from recurrent bacterial and/or fungal infections from the first year of life onwards. From 2009 to 2013, 12 cases of CGD were diagnosed in Morocco. We describe here these Moroccan cases of CGD. METHODS: We investigated the genetic, immunological and clinical features of 12 Moroccan patients with CGD from 10 unrelated kindreds. RESULTS: All patients were children suffering from recurrent bacterial and/or fungal infections. All cases displayed impaired NADPH oxidase activity in nitroblue tetrazolium (NBT), dihydrorhodamine (DHR) or 2',7' dichlorofluorescein diacetate (DCFH-DA) assays. Mutation analysis revealed the presence of four different mutations of CYBB in four kindreds, a recurrent mutation of NCF1 in three kindreds, and a new mutation of NCF2 in three patients from a single kindred. A large deletion of CYBB gene has detected in a patient. The causal mutation in the remaining one kindred was not identified. CONCLUSION: The clinical features and infectious agents found in these patients were similar to those in CGD patients from elsewhere. The results of mutation analysis differed between kindreds, revealing a high level of genetic and allelic heterogeneity among Moroccan CGD patients. The small number of patients in our cohort probably reflects a lack of awareness of physicians. Further studies on a large cohort are required to determine the incidence and prevalence of the disease, and to improve the description of the genetic and clinical features of CGD patients in Morocco.


Assuntos
Aspergilose/genética , Infecções Bacterianas/genética , Doença Granulomatosa Crônica/genética , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Adolescente , Alelos , Aspergilose/complicações , Aspergilose/imunologia , Aspergilose/patologia , Infecções Bacterianas/complicações , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genes Recessivos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , NADPH Oxidase 2 , Linhagem
19.
J Clin Immunol ; 33(6): 1078-87, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23657403

RESUMO

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.


Assuntos
Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/diagnóstico , Guias de Prática Clínica como Assunto , Algoritmos , Diagnóstico Diferencial , Testes Diagnósticos de Rotina/normas , Genótipo , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Testes Imunológicos/métodos , Fenótipo
20.
PLoS One ; 8(3): e58286, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23472171

RESUMO

We report identical twins with intellectual disability, progressive spastic paraplegia and short stature, born to a consanguineous family. Intriguingly, both children presented with lymphadenitis caused by the live Bacillus Calmette-Guérin (BCG) vaccine. Two syndromes - hereditary spastic paraplegia (HSP) and mycobacterial disease - thus occurred simultaneously. Whole-exome sequencing (WES) revealed a homozygous nonsense mutation (p.R1105X) of the AP4E1 gene, which was confirmed by Sanger sequencing. The p.R1105X mutation has no effect on AP4E1 mRNA levels, but results in lower levels of AP-4ε protein and of the other components of the AP-4 complex, as shown by western blotting, immunoprecipitation and immunofluorescence. Thus, the C-terminal part of the AP-4ε subunit plays an important role in maintaining the integrity of the AP-4 complex. No abnormalities of the IL-12/IFN-γ axis or oxidative burst pathways were identified. In conclusion, we identified twins with autosomal recessive AP-4 deficiency associated with HSP and mycobacterial disease, suggesting that AP-4 may play important role in the neurological and immunological systems.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Complexo 4 de Proteínas Adaptadoras/fisiologia , Mutação , Infecções por Micobactéria não Tuberculosa/genética , Paraplegia Espástica Hereditária/genética , Consanguinidade , Análise Mutacional de DNA , Doenças em Gêmeos , Exoma , Feminino , Genes Recessivos , Predisposição Genética para Doença , Homozigoto , Humanos , Interferon gama/metabolismo , Masculino , Marrocos , Linhagem , Fenótipo
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