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1.
Nat Immunol ; 13(12): 1178-86, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23104095

RESUMO

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1ß (IL-1ß) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1ß. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1ß responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1ß responses differently in different cell types.


Assuntos
Doença de Depósito de Glicogênio Tipo IV/genética , Doenças Hereditárias Autoinflamatórias/genética , Síndromes de Imunodeficiência/genética , NF-kappa B/metabolismo , Ubiquitina-Proteína Ligases/genética , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Proteínas de Ciclo Celular/genética , Linhagem Celular , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Síndromes de Imunodeficiência/metabolismo , Interleucina-1beta/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Fatores de Transcrição , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
3.
J Clin Immunol ; 39(7): 702-712, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.


Assuntos
Serviços Médicos de Emergência , Hospitalização , Doenças da Imunodeficiência Primária/epidemiologia , Adulto , Criança , Controle de Doenças Transmissíveis , Doenças Transmissíveis/etiologia , Gerenciamento Clínico , França/epidemiologia , Humanos , Incidência , Profilaxia Pré-Exposição , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/terapia , Vigilância em Saúde Pública , Resultado do Tratamento
4.
J Allergy Clin Immunol ; 134(3): 655-662.e8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24985400

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a rare phagocytic disorder that results in not only infections but also potentially severe inflammatory manifestations that can be difficult to diagnose and treat. OBJECTIVE: To describe inflammatory manifestations in a single-center cohort of patients with CGD. METHODS: Medical records of patients treated at Necker-Enfants Malades Hospital (Paris, France) between 1968 and 2009 and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH) were retrospectively reviewed. RESULTS: In a study population of 98 patients, a total of 221 inflammatory episodes were recorded in 68 individuals (69.4%). The incidence rate of inflammatory episodes was 0.15 per person-year (0.18 in patients with X-linked [XL] CGD and 0.08 in patients with autosomal-recessive [AR] CGD). The most commonly affected organs were the gastrointestinal tract (in 88.2% of the patients), lungs (26.4%), the urogenital tract (17.6%), and eyes (8.8%). Inflammation at other sites (the skin, central nervous system, and tympanum) and autoimmune manifestations (lupus, arthritis, etc) were recorded in 19.1% and 10.3% of the patients, respectively. Granuloma was found in 50% of the 44 histological analyses reviewed. The risk of inflammatory episodes was 2-fold higher in patients with XL-CGD than in patients with AR-CGD (relative risk, 2.22; 95% CI, 1.43-3.46). CONCLUSIONS: Patients with XL-CGD have a higher risk of developing inflammatory episodes than do patients with AR-CGD. Although the most commonly affected organ is the gastrointestinal tract, other sites can be involved, making the management of patients with CGD a complex, multidisciplinary task.


Assuntos
Eosinófilos/imunologia , Mucosa Gástrica/imunologia , Gastrite/imunologia , Doença Granulomatosa Crônica/imunologia , Neutrófilos/imunologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Autoanticorpos/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , França , Gastrite/etiologia , Gastrite/prevenção & controle , Predisposição Genética para Doença , Granuloma/imunologia , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Risco , Adulto Jovem
5.
J Allergy Clin Immunol ; 134(6): 1354-1364.e6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25174867

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD. OBJECTIVE: We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency. METHODS: We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed. RESULTS: We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway. CONCLUSIONS: We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD.


Assuntos
Alopecia , Doenças Inflamatórias Intestinais , Linfopenia , Proteínas/genética , Proteínas/imunologia , Adolescente , Adulto , Alopecia/genética , Alopecia/imunologia , Alopecia/patologia , Criança , Pré-Escolar , Colo/patologia , Duodeno/patologia , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Antro Pilórico/patologia , Adulto Jovem , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/imunologia , Proteína rhoA de Ligação ao GTP/imunologia
6.
Proc Natl Acad Sci U S A ; 108(28): 11554-9, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21700883

RESUMO

Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.


Assuntos
Linfócitos B/enzimologia , Linfócitos B/imunologia , Citidina Desaminase/imunologia , Tolerância a Antígenos Próprios/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/genética , Fator Ativador de Células B/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/genética , Síndrome de Job/enzimologia , Síndrome de Job/genética , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Células Precursoras de Linfócitos B/enzimologia , Células Precursoras de Linfócitos B/imunologia , Tolerância a Antígenos Próprios/genética , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
7.
N Engl J Med ; 363(4): 355-64, 2010 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-20660403

RESUMO

BACKGROUND: The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain. METHODS: The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. RESULTS: Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health. CONCLUSIONS: After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)


Assuntos
Terapia Genética , Subunidade gama Comum de Receptores de Interleucina/genética , Imunodeficiência Combinada Severa/terapia , Antígenos CD34 , Linfócitos B/imunologia , Seguimentos , Terapia Genética/efeitos adversos , Humanos , Imunoglobulinas/sangue , Lactente , Subunidade gama Comum de Receptores de Interleucina/deficiência , Células Matadoras Naturais/fisiologia , Contagem de Linfócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia
8.
Blood ; 118(19): 5108-18, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21908431

RESUMO

Inherited deficiency of major histocompatibility complex (MHC) class II molecules impairs antigen presentation to CD4(+) T cells and results in combined immunodeficiency (CID). Autosomal-recessive mutations in the RFXANK gene account for two-thirds of all cases of MHC class II deficiency. We describe here the genetic, clinical, and immunologic features of 35 patients from 30 unrelated kindreds from North Africa sharing the same RFXANK founder mutation, a 26-bp deletion called I5E6-25_I5E6 + 1), and date the founder event responsible for this mutation in this population to approximately 2250 years ago (95% confidence interval [CI]: 1750-3025 years). Ten of the 23 patients who underwent hematopoietic stem cell transplantation (HSCT) were cured, with the recovery of almost normal immune functions. Five of the patients from this cohort who did not undergo HSCT had a poor prognosis and eventually died (at ages of 1-17 years). However, 7 patients who did not undergo HSCT (at ages of 6-32 years) are still alive on Ig treatment and antibiotic prophylaxis. RFXANK deficiency is a severe, often fatal CID for which HSCT is the only curative treatment. However, some patients may survive for relatively long periods if multiple prophylactic measures are implemented.


Assuntos
Efeito Fundador , Genes MHC da Classe II , Mutação , Imunodeficiência Combinada Severa/genética , Fatores de Transcrição/genética , Adolescente , África do Norte , Apresentação de Antígeno/genética , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Gastroenteropatias/etiologia , Expressão Gênica , Genes Recessivos , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Lactente , Recém-Nascido , Hepatopatias/etiologia , Masculino , Infecções Respiratórias/etiologia , Deleção de Sequência , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Fatores de Tempo , Resultado do Tratamento
9.
Blood ; 117(2): 688-96, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-20978268

RESUMO

FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm(3) and 1232/mm(3) CD3(+) cells, 647/mm(3) and 868/mm(3) CD4(+) T cells, 213/mm(3) and 425/mm(3) naive CD4(+) T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3(+) cells, respectively. They have normal CD4 T-cell receptor ß variable repertoires. Both subjects developed antigen-specific proliferative responses and have discontinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.


Assuntos
Fatores de Transcrição Forkhead/deficiência , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/fisiopatologia , Imunodeficiência Combinada Severa/cirurgia , Timo/transplante , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Masculino
10.
J Allergy Clin Immunol ; 129(3): 770-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22153772

RESUMO

BACKGROUND: Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]). OBJECTIVE: This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. METHODS: A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. RESULTS: When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. CONCLUSIONS: IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.


Assuntos
Agamaglobulinemia/imunologia , Anticorpos Antivirais/metabolismo , Infecções por Haemophilus/imunologia , Haemophilus influenzae/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina M/metabolismo , Adolescente , Agamaglobulinemia/complicações , Agamaglobulinemia/epidemiologia , Anticorpos Antivirais/imunologia , Criança , Feminino , Infecções por Haemophilus/complicações , Infecções por Haemophilus/epidemiologia , Haemophilus influenzae/patogenicidade , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/epidemiologia , Imunoglobulina M/imunologia , Incidência , Masculino , Estudos Prospectivos , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Risco
11.
J Infect Dis ; 206(8): 1269-74, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22872736

RESUMO

We report the first prospective study describing the prevalence and clinical consequences of norovirus infection in hospitalized children with primary immunodeficiencies. Fecal samples from 62 children were systematically screened for virus. Norovirus was the most frequent pathogen (11 of 24 positive samples) found in both combined and humoral immunocompromised children. Norovirus shedding was associated with gastrointestinal symptoms and concomitant viremia in 54.5% and 25% of cases, respectively. Norovirus excretion was prolonged: 57.1% of fecal samples were still positive after a median of 9.5-months follow-up. Further large longitudinal studies are needed to evaluate the clinical consequences of norovirus shedding in patients with primary immunodeficiencies.


Assuntos
Infecções por Caliciviridae/epidemiologia , Fezes/virologia , Gastroenterite/epidemiologia , Síndromes de Imunodeficiência/congênito , Norovirus/isolamento & purificação , Eliminação de Partículas Virais , Infecções por Caliciviridae/virologia , Criança , Pré-Escolar , Feminino , Gastroenterite/virologia , Hospitais , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Masculino , Prevalência , Estudos Prospectivos , Viremia/epidemiologia , Viremia/virologia
12.
J Allergy Clin Immunol ; 128(4): 847-53, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21714993

RESUMO

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. OBJECTIVE: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. METHODS: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. RESULTS: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. CONCLUSION: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite , Granuloma , Doença de Hirschsprung , Síndromes de Imunodeficiência , Osteocondrodisplasias/congênito , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Criança , Pré-Escolar , Dermatite/imunologia , Dermatite/patologia , Dermatite/terapia , Feminino , Granuloma/imunologia , Granuloma/patologia , Granuloma/terapia , Cabelo/anormalidades , Cabelo/imunologia , Cabelo/patologia , Transplante de Células-Tronco Hematopoéticas , Doença de Hirschsprung/imunologia , Doença de Hirschsprung/patologia , Doença de Hirschsprung/terapia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/terapia , Masculino , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/patologia , Osteocondrodisplasias/terapia , Doenças da Imunodeficiência Primária , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo , Fator de Necrose Tumoral alfa/imunologia
13.
J Allergy Clin Immunol ; 128(2): 382-9.e1, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21665257

RESUMO

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. OBJECTIVE: We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. METHODS: We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. RESULTS: Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. CONCLUSION: Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.


Assuntos
Ataxia Telangiectasia/genética , Ataxia Telangiectasia/mortalidade , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Ataxia Telangiectasia/epidemiologia , Ataxia Telangiectasia/fisiopatologia , Proteínas Mutadas de Ataxia Telangiectasia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França/epidemiologia , Genótipo , Humanos , Lactente , Recém-Nascido , Leucemia/genética , Linfoma/genética , Masculino , Morbidade , Mutação , Infecções Respiratórias/genética , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
14.
Clin Infect Dis ; 53(12): e159-69, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22080130

RESUMO

BACKGROUND: Invasive fungal infection (IFI) represents a life-threatening condition for patients with chronic granulomatous disease (CGD) and causes one-third of deaths in this population. This study offers a descriptive review of invasive mold infection (mIFI) in children with CGD over an extended period of time. METHODS: In a cohort of patients with CGD registered in the French National database for Primary Immunodeficiency, we performed a retrospective review of proven mIFI episodes (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group 2008 criteria) occurring from 1984 through 2009. RESULTS: Twenty-nine proven mIFIs were identified in 24 patients. Thirteen (54%) of 24 children were receiving itraconazole prophylaxis. Seven episodes were caused by Aspergillus fumigatus, 10 by Aspergillus nidulans, 2 by Aspergillus species, and 6 by other opportunistic molds (4 patients only had positive pathological examination findings). First proven mIFI occurred later in the group that received itraconazole than in the group without (median time to mIFI, 10 vs 4 years; P < .01), with a higher proportion of infections due to A. nidulans and other opportunistic molds (P < .05). Course of IFI was complex, with the median duration of therapy and hospitalization reaching 446 and 153 days, respectively. Combined antifungal therapy was commonly used. Four patients received geno-identical hematopoietic stem cell transplantation as salvage therapy. Global cure rate among the cohort reached 75%, but sequelae were frequent. Prognosis has improved over time (43% mortality during 1985-1990 vs 6% thereafter; P = .06). Mortality tended to be lower in the group that recieved itraconazole prophylaxis but at the cost of a longer duration of therapy among cured patients. CONCLUSIONS: Management of mIFI remains challenging in patients with CGD, but significant improvements have been made over the past decade.


Assuntos
Fungos/classificação , Fungos/isolamento & purificação , Doença Granulomatosa Crônica/complicações , Micoses/epidemiologia , Adolescente , Antifúngicos/administração & dosagem , Aspergillus , Aspergillus fumigatus , Aspergillus nidulans , Criança , Pré-Escolar , Quimioterapia Combinada/métodos , Feminino , França/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Micoses/tratamento farmacológico , Micoses/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
15.
Blood ; 113(17): 4114-24, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19168787

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/psicologia , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
16.
Blood ; 113(13): 3027-30, 2009 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-19176318

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRalphabeta(+) CD4(-)CD8(-) T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.


Assuntos
Doenças Autoimunes/diagnóstico , Proteína Ligante Fas/metabolismo , Interleucina-10/metabolismo , Transtornos Linfoproliferativos/diagnóstico , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/metabolismo , Receptor fas/genética , Adolescente , Adulto , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Antígenos CD4/sangue , Antígenos CD4/metabolismo , Antígenos CD8/sangue , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteína Ligante Fas/sangue , Humanos , Lactente , Recém-Nascido , Interleucina-10/sangue , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/metabolismo , Pessoa de Meia-Idade , Mutação/fisiologia , Síndrome , Linfócitos T/patologia , Adulto Jovem , Receptor fas/fisiologia
17.
N Engl J Med ; 356(26): 2700-3, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17596604

RESUMO

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.


Assuntos
Transplante de Medula Óssea , Erros Inatos do Metabolismo/terapia , Ácido Mevalônico/urina , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Biomarcadores/sangue , Pré-Escolar , Citocinas/sangue , Insuficiência de Crescimento/etiologia , Febre/etiologia , Humanos , Inflamação/etiologia , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/complicações , Mutação de Sentido Incorreto , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Transplante Homólogo
18.
Eur J Immunol ; 39(7): 1966-76, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19548248

RESUMO

Complete lack of function of the tyrosine kinase ZAP70 in humans results in a severe immunodeficiency, characterized by a lack of mature CD8(+) T cells and non-functional CD4(+) T cells. We report herein an immunodeficiency with an inherited hypomorphic mutation of ZAP70 due to a single G-to-A substitution in a non-coding intron. This mutation introduces a new acceptor splice site and allows low levels of normal alternative splicing and of WT ZAP70 expression. This partial deficiency results in a compromised TCR signaling that was totally restored by increased expression of ZAP70, demonstrating that defective activation of the patient T cells was indeed caused by the low level of ZAP70 expression. This partial ZAP70 deficiency was associated with an attenuated clinical and immunological phenotype as compared with complete ZAP70 deficiency. CD4(+) helper T-cell populations including, follicular helper T cells, Th1, Th17 and Treg were detected in the blood. Finally, the patient had no manifestation of autoimmunity suggesting that the T-cell tolerogenic functions were not compromised, in contrast to what has been observed in mice carrying hypomorphic mutations of Zap70. This report extends the phenotype spectrum of ZAP70 deficiency with a residual function of ZAP70.


Assuntos
Síndromes de Imunodeficiência/genética , Mutação Puntual , Proteína-Tirosina Quinase ZAP-70/genética , Sequência de Aminoácidos , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cálcio/metabolismo , Criança , Análise Mutacional de DNA , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Contagem de Linfócitos , Masculino , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Transfecção , Proteína-Tirosina Quinase ZAP-70/metabolismo
20.
BMC Cancer ; 9: 14, 2009 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-19144139

RESUMO

BACKGROUND: We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors. METHODS: Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling. RESULTS: Complete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 +/- 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age<10, leukocyte count <100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 +/- 14% and 33 +/- 15%, respectively). CONCLUSION: Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Medula Óssea/efeitos dos fármacos , Contagem de Leucócitos , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Doença Aguda , Adolescente , Fatores Etários , Antraciclinas , Asparaginase , Benzamidas , Transplante de Medula Óssea , Criança , Pré-Escolar , Cortisona , Feminino , Humanos , Mesilato de Imatinib , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prednisona/administração & dosagem , Recidiva , Resultado do Tratamento , Vincristina , Adulto Jovem
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