Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
1.
J Clin Immunol ; 39(7): 702-712, 2019 Oct.
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.

2.
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
3.
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.
Science ; 342(6160): 866-71, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24136356

RESUMO

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.


Assuntos
Predisposição Genética para Doença , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Fosfatidilinositol 3-Quinases/genética , Infecções Respiratórias/genética , Infecções Respiratórias/patologia , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Síndromes de Imunodeficiência/imunologia , Linfócitos/imunologia , Mutação , Linhagem , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Infecções Respiratórias/imunologia
6.
J Exp Med ; 209(13): 2323-30, 2012 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-23230001

RESUMO

DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.


Assuntos
DNA Polimerase II/genética , Ossos Faciais/anormalidades , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Livedo Reticular/enzimologia , Livedo Reticular/genética , Adolescente , Adulto , Processamento Alternativo , Sequência de Bases , Estatura/genética , Proliferação de Células , Criança , Pré-Escolar , Cromossomos Humanos Par 12/genética , Consanguinidade , Análise Mutacional de DNA , DNA Polimerase II/deficiência , Feminino , França , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Expressão Gênica , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/imunologia , Íntrons , Livedo Reticular/patologia , Masculino , Linhagem , Mutação Puntual , Proteínas de Ligação a Poli-ADP-Ribose , Síndrome , Adulto Jovem
7.
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
8.
PLoS One ; 7(8): e44010, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22952854

RESUMO

Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.


Assuntos
Predisposição Genética para Doença , Fator de Crescimento de Hepatócito/deficiência , Fator de Crescimento de Hepatócito/genética , Padrões de Herança/genética , Papillomaviridae/fisiologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Adolescente , Sequência de Aminoácidos , Antígenos Virais/imunologia , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Criança , Códon sem Sentido/genética , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/imunologia , Epidermodisplasia Verruciforme/microbiologia , Epidermodisplasia Verruciforme/virologia , Exoma/genética , Fator de Crescimento de Hepatócito/química , Homozigoto , Humanos , Imunofenotipagem , Lactente , Masculino , Mitógenos/farmacologia , Dados de Sequência Molecular , Papillomaviridae/efeitos dos fármacos , Proteínas Proto-Oncogênicas/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Adulto Jovem
9.
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
10.
Medicine (Baltimore) ; 91(4): e1-19, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22751495

RESUMO

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.


Assuntos
Hospedeiro Imunocomprometido/genética , Síndrome de Job/epidemiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Eczema/epidemiologia , Eczema/etiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Job/complicações , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transdução de Sinais , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/etiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/etiologia , Análise de Sobrevida , Adulto Jovem
11.
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
12.
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
13.
J Cataract Refract Surg ; 37(11): 1977-83, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21940141

RESUMO

PURPOSE: To report long-term outcomes of cataract surgery with primary posterior chamber intraocular lens (IOL) implantation in children with chronic uveitis. SETTING: Department of Ophthalmology, Pitié-Salpêtrière Hospital, Paris, France. DESIGN: Case series. METHODS: This case series comprised patients younger than 16 years with chronic uveitis who underwent phacoemulsification with primary implantation of a heparin surface-modified poly(methyl methacrylate) posterior chamber IOL in the capsular bag. The intraocular inflammation was fully controlled for at least 3 consecutive months before surgery in all cases. The main outcome measures were final corrected distance visual acuity (CDVA), postoperative inflammation, complications, and level of immunosuppressive treatment. RESULTS: Twenty-two eyes of 16 children (7 girls, 9 boys; median age at surgery 9.5 years old) were included. Underlying uveitic entities were juvenile idiopathic arthritis in 9 patients; idiopathic uveitis in 4; and Behçet disease, sarcoidosis, and varicella zoster-associated uveitis in 1 patient each. The final CDVA was 0.3 logMAR or better in all cases. Postoperative complications included posterior capsule opacification requiring laser capsulotomy in 2 eyes, glaucoma in 4 eyes, and cystoid macular edema/macular dysfunction in 3 eyes. The mean dose of oral prednisone was 29.5 mg/day preoperatively and 8.13 mg/day at the last follow-up. The median follow-up was 6 years (range 5 to 19 years). CONCLUSION: The results indicate that uveitis is not a formal contraindication to primary IOL implantation in the management of pediatric cataract surgery in cases with full control of intraocular inflammation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.


Assuntos
Implante de Lente Intraocular , Facoemulsificação , Uveíte/complicações , Adolescente , Opacificação da Cápsula/etiologia , Opacificação da Cápsula/cirurgia , Criança , Pré-Escolar , Doença Crônica , Materiais Revestidos Biocompatíveis , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Heparina , Humanos , Complicações Intraoperatórias , Terapia a Laser , Lasers de Estado Sólido , Lentes Intraoculares , Masculino , Polimetil Metacrilato , Complicações Pós-Operatórias , Resultado do Tratamento , Uveíte/tratamento farmacológico
14.
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 do Antígeno/genética , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de 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
15.
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 , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo , Fator de Necrose Tumoral alfa/imunologia
16.
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
17.
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
18.
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
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA