Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Immunol ; 39(7): 653-667, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376032

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

3.
Pediatr Rheumatol Online J ; 17(1): 7, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764840

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS. METHODS: A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes. RESULTS: An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin ≥500 ng/mL. The rheumatology team was identified as the "gate-keeper," charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected. CONCLUSION: HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Algoritmos , Consenso , Citocinas/sangue , Diagnóstico Diferencial , Medicina Baseada em Evidências/métodos , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/terapia , Guias de Prática Clínica como Assunto , Melhoria de Qualidade
6.
J Allergy Clin Immunol ; 139(5): 1629-1640.e2, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28139313

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor. OBJECTIVE: We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. METHODS: We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells. RESULTS: We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reduced hyperresponsiveness to type I and II interferons, normalized TH1 and follicular T helper cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis, and maintained remission of immune-mediated cytopenias. CONCLUSIONS: Autoimmunity and infection caused by STAT1 GOF mutations are the result of dysregulated T helper cell responses. Janus kinase inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.


Assuntos
Anemia Hemolítica Autoimune/genética , Inibidores de Proteínas Quinases/farmacologia , Púrpura Trombocitopênica Idiopática/genética , Pirazóis/farmacologia , Fator de Transcrição STAT1/genética , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Anemia Hemolítica Autoimune/imunologia , Autoimunidade/efeitos dos fármacos , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/imunologia , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Mutação , Púrpura Trombocitopênica Idiopática/imunologia , Fator de Transcrição STAT1/imunologia , Células Th1/imunologia , Células Th17/imunologia
7.
Proc Natl Acad Sci U S A ; 111(24): 8889-94, 2014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-24889605

RESUMO

Nonhomologous end-joining (NHEJ) is a key pathway for efficient repair of DNA double-strand breaks (DSBs) and V(D)J recombination. NHEJ defects in humans cause immunodeficiency and increased cellular sensitivity to ionizing irradiation (IR) and are variably associated with growth retardation, microcephaly, and neurodevelopmental delay. Repair of DNA DSBs is important for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). To compare the specific contribution of DNA ligase 4 (LIG4), Artemis, and DNA-protein kinase catalytic subunit (PKcs) in this process and to gain insights into phenotypic variability associated with these disorders, we reprogrammed patient-derived fibroblast cell lines with NHEJ defects. Deficiencies of LIG4 and of DNA-PK catalytic activity, but not Artemis deficiency, were associated with markedly reduced reprogramming efficiency, which could be partially rescued by genetic complementation. Moreover, we identified increased genomic instability in LIG4-deficient iPSCs. Cell cycle synchronization revealed a severe defect of DNA repair and a G0/G1 cell cycle arrest, particularly in LIG4- and DNA-PK catalytically deficient iPSCs. Impaired myeloid differentiation was observed in LIG4-, but not Artemis- or DNA-PK-mutated iPSCs. These results indicate a critical importance of the NHEJ pathway for somatic cell reprogramming, with a major role for LIG4 and DNA-PKcs and a minor, if any, for Artemis.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Células-Tronco Pluripotentes Induzidas/citologia , Catálise , Ciclo Celular , Diferenciação Celular , Linhagem Celular , Linhagem da Célula , DNA Ligase Dependente de ATP , DNA Ligases/metabolismo , Proteína Quinase Ativada por DNA/genética , Endonucleases , Fibroblastos/metabolismo , Fibroblastos/patologia , Células-Tronco Hematopoéticas/citologia , Humanos , Mutação , Proteínas Nucleares/metabolismo , Fenótipo
8.
Curr Opin Immunol ; 24(5): 617-24, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22841347

RESUMO

The advent of reprogramming technology has greatly advanced the field of stem cell biology and nurtured our hope to create patient specific renewable stem cell sources. While the number of reports of disease specific induced pluripotent stem cells is continuously rising, the field becomes increasingly more aware that induced pluripotent stem cells are not as similar to embryonic stem cells as initially assumed. Our state of the art understanding of human induced pluripotent stem cells, their capacity, their limitations and their promise as it pertains to the study and treatment of primary immunodeficiencies, is the content of this review.


Assuntos
Diferenciação Celular/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Células-Tronco Pluripotentes/fisiologia , Células-Tronco Pluripotentes/transplante , Medicina Regenerativa/métodos , Animais , Transplante de Células/métodos , Transplante de Células/tendências , Modelos Animais de Doenças , Humanos , Síndromes de Imunodeficiência/fisiopatologia , Células-Tronco Pluripotentes/patologia , Medicina Regenerativa/tendências
9.
Proc Natl Acad Sci U S A ; 107(26): 11976-80, 2010 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-20547868

RESUMO

Bacteroides is an abundant genus of bacteria of the human intestinal microbiota. Bacteroides species synthesize a large number of capsular polysaccharides (PS), a biological property not shared with closely related oral species, suggesting importance for intestinal survival. Bacteroides fragilis, for example, synthesizes eight capsular polysaccharides per strain, each of which phase varies via inversion of the promoters located upstream of seven of the eight polysaccharide biosynthesis operons. In a single cell, many of these polysaccharide loci promoters can be simultaneously oriented on for transcription of the downstream biosynthesis operons. Here, we demonstrate that despite the promoter orientations, concomitant transcription of multiple polysaccharide loci within a cell is inhibited. The proteins encoded by the second gene of each of these eight loci, collectively designated the UpxZ proteins, inhibit the synthesis of heterologous polysaccharides. These unique proteins interfere with the ability of UpxY proteins encoded by other polysaccharide loci to function in transcriptional antitermination of their respective operon. The eight UpxZs have different inhibitory spectra, thus establishing a hierarchical regulatory network for polysaccharide synthesis. Limitation of concurrent polysaccharide synthesis strongly suggests that these bacteria evolved this property as an evasion-type mechanism to avoid killing by polysaccharide-targeting factors in the ecosystem.


Assuntos
Bacteroides fragilis/metabolismo , Intestinos/microbiologia , Metagenoma , Polissacarídeos Bacterianos/biossíntese , Simbiose , Regiões 5' não Traduzidas , Cápsulas Bacterianas/biossíntese , Cápsulas Bacterianas/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bacteroides fragilis/genética , Bacteroides fragilis/isolamento & purificação , Sequência de Bases , Primers do DNA/genética , DNA Bacteriano/genética , Genes Bacterianos , Humanos , Polissacarídeos Bacterianos/genética , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
10.
Mol Microbiol ; 53(5): 1319-30, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15387812

RESUMO

The chromosome of Bacteroides fragilis has been shown to undergo 13 distinct DNA inversions affecting the expression of capsular polysaccharides and mediated by a serine site-specific recombinase designated Mpi. In this study, we demonstrate that members of the tyrosine site-specific recombinase family, conserved in B. fragilis, mediate additional DNA inversions of the B. fragilis genome. These DNA invertases flip promoter regions in their immediate downstream region. The genetic organization of the genes regulated by these invertible promoter regions suggests that they are operons and many of the products are predicted to be outer membrane proteins. Phenotypic analysis of a deletion mutant of one of these DNA invertases, tsr15 (aapI), which resulted in the promoter region for the downstream genes being locked ON, confirmed the synthesis of multiple surface proteins by this operon. In addition, this deletion mutant demonstrated an autoaggregative phenotype and showed significantly greater adherence than wild-type organisms in a biofilm assay, suggesting a possible functional role for these phase-variable outer surface proteins. This study demonstrates that DNA inversion is a universal mechanism used by this commensal microorganism to phase vary expression of its surface molecules and involves at least three conserved DNA invertases from two evolutionarily distinct families.


Assuntos
Proteínas de Bactérias/genética , Bacteroides fragilis/enzimologia , Bacteroides fragilis/genética , Inversão Cromossômica , Proteínas de Membrana/genética , Recombinases/metabolismo , Tirosina/metabolismo , Sequência de Aminoácidos , Animais , Cápsulas Bacterianas/química , Proteínas de Bactérias/metabolismo , Bacteroides fragilis/ultraestrutura , Sequência de Bases , DNA/genética , DNA/metabolismo , Regulação Bacteriana da Expressão Gênica , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Óperon , Fenótipo , Polissacarídeos/genética , Polissacarídeos/metabolismo , Regiões Promotoras Genéticas , Alinhamento de Sequência
11.
Proc Natl Acad Sci U S A ; 100(18): 10446-51, 2003 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-12915735

RESUMO

The mammalian gut represents a complex and diverse ecosystem, consisting of unique interactions between the host and microbial residents. Bacterial surfaces serve as an interface that promotes and responds to this dynamic exchange, a process essential to the biology of both symbionts. The human intestinal microorganism, Bacteroides fragilis, is able to extensively modulate its surface. Analysis of the B. fragilis genomic sequence, together with genetic conservation analyses, cross-species cloning experiments, and mutational studies, revealed that this organism utilizes an endogenous DNA inversion factor to globally modulate the expression of its surface structures. This DNA invertase is necessary for the inversion of at least 13 regions located throughout the genome, including the promoter regions for seven of the capsular polysaccharide biosynthesis loci, an accessory polysaccharide biosynthesis locus, and five other regions containing consensus promoter sequences. Bacterial DNA invertases of the serine site-specific recombinase family are typically encoded by imported elements such as phage and plasmids, and act locally on a single region of the imported element. In contrast, the conservation and unique global regulatory nature of the process in B. fragilis suggest an evolutionarily ancient mechanism for surface adaptation to the changing intestinal milieu during commensalism.


Assuntos
Cápsulas Bacterianas/biossíntese , Proteínas de Bactérias/fisiologia , Bacteroides fragilis/genética , Inversão Cromossômica , DNA Nucleotidiltransferases/fisiologia , Regiões Promotoras Genéticas , Simbiose , Sequência de Bases , Mapeamento Cromossômico , Humanos , Dados de Sequência Molecular , Fenótipo , Recombinases
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA