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2.
Immunity ; 50(2): 362-377.e6, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709738

RESUMO

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Mutação , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th2/metabolismo
3.
Transfusion ; 58 Suppl 3: 3056-3064, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30536429

RESUMO

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.


Assuntos
Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/terapia , /imunologia , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/imunologia , Fatores de Risco
4.
Clin Transl Gastroenterol ; 9(10): 201, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385752

RESUMO

OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort. METHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3. RESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002). CONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.


Assuntos
Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Enteropatias/genética , Poliendocrinopatias Autoimunes/genética , Autoanticorpos/sangue , Variação Biológica da População , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Fatores de Transcrição Forkhead/imunologia , França , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunossupressão , Lactente , Recém-Nascido , Enteropatias/imunologia , Enteropatias/terapia , Nefropatias/genética , Masculino , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/terapia , Estudos Retrospectivos , Dermatopatias Genéticas/genética , Taxa de Sobrevida , Síndrome
6.
Clin Immunol ; 197: 219-223, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30368009

RESUMO

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.


Assuntos
Agamaglobulinemia/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Agamaglobulinemia/terapia , Anemia Hemolítica Autoimune/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/terapia , Eczema/imunologia , Família , Feminino , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Switching de Imunoglobulina/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Enteropatias/imunologia , Masculino , Pessoa de Meia-Idade , Linhagem , Pneumonia/imunologia , Recidiva , Sinusite/imunologia , Adulto Jovem
7.
Curr Opin Allergy Clin Immunol ; 18(6): 453-458, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299399

RESUMO

PURPOSE OF REVIEW: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements. RECENT FINDINGS: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease. SUMMARY: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.


Assuntos
Agamaglobulinemia , Edição de Genes/métodos , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética/métodos , Síndrome de Wiskott-Aldrich , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Animais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(3): 389-392, 2018 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-29896738

RESUMO

OBJECTIVE: To report on two cases affected with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). METHODS: Two unrelated Chinese infants affected with IPEX were investigated. Case 1 was a 4-month-old boy with neonatal diabetes and severe enteropathy. Case 2 was a 6-day newborn boy with neonatal diabetes and ketoacidosis. DNA samples of the two infants and their parents were sequenced for FOXP3 gene mutations. Suspected mutations were verified among 100 unrelated healthy controls. The function of mutations was predicted with bioinformatics software. RESULTS: Both infants had onset of the disease during neonatal period, and manifested insulin-dependent diabetes mellitus, persistent diarrhea, eczema and malnutrition. In case 1, a novel splice site mutation was identified in intron 9 (c.967+3A>T) of the FOXP3 gene, for which his mother was a carrier. For case 2, a missense mutation (c.1150G>A) was detected in exon 11 of the FOXP3 gene, for which his mother was also a carrier. The IVS9 c.967+3A mutation was not detected among the 100 healthy controls. As predicted with Human Splicing Finder software, the c.967+3A>T mutation may influence the splicing of mRNA and affect the function of protein. CONCLUSION: Both cases had typical clinical manifestation of the IPEX syndrome, among whom a novel splice site mutation (IVS9 c.967+3A>T) and a missense mutation (c.1150G>A) of the FOXP3 gene were identified. The clinical manifestation of the IPEX syndrome may be variable and the mortality is high. FOXP3 gene sequencing is recommended when insulin-dependent diabetes mellitus is diagnosed during the neonatal period.


Assuntos
Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Enteropatias/genética , Sequência de Bases , Diabetes Mellitus Tipo 1/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Lactente , Recém-Nascido , Enteropatias/imunologia , Masculino , Dados de Sequência Molecular , Mutação
9.
J Allergy Clin Immunol ; 142(6): 1909-1921.e9, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29705245

RESUMO

BACKGROUND: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed. OBJECTIVE: We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology. METHODS: We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice). RESULTS: Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a TH2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels. CONCLUSIONS: These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T/imunologia , Timo/imunologia , Adolescente , Adulto , Animais , Diferenciação Celular , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Homeostase , Humanos , Doenças do Sistema Imunitário/imunologia , Lactente , Recém-Nascido , Masculino , Camundongos Transgênicos , Adulto Jovem
10.
J Allergy Clin Immunol ; 142(6): 1818-1830.e6, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29704593

RESUMO

BACKGROUND: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Colágeno Tipo VII/imunologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Distonina/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T Reguladores/imunologia , Animais , Diabetes Mellitus Tipo 1/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Doenças do Sistema Imunitário/imunologia , Imunoglobulina G/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Transcrição STAT6/genética
12.
Nat Commun ; 9(1): 463, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29386580

RESUMO

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap-/- regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap-/- Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap-/- Treg cells. In addition, Xiap-/- Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap-/- mice. Notably, inflammation-induced reprogramming of Xiap-/- Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap-/- Treg cells confers survival to inflammatory infection in Xiap-/- mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Transtornos Linfoproliferativos/imunologia , Receptores de Interleucina-6/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Estabilidade Proteica , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Linfócitos T Reguladores/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
13.
Allergol. immunopatol ; 46(1): 58-66, ene.-feb. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-170788

RESUMO

Background: X-linked agammaglobulinaemia (XLA) is a genetic disorder affecting B cell maturation, which is characterised by a low number of B cells, agammaglobulinaemia and increased susceptibility to a variety of bacterial infections. This study was performed to assess T cell subpopulations in a group of children with XLA in association with chronic respiratory disease (CRD). Methods: Numbers of T cell subpopulations (CD3+, CD4+, CD8+, CD3+DR+, naïve, memory, recent thymic emigrants (RTE), regulatory T cells, follicular T helpers) were measured by eight-colour flow cytometry in 22 XLA patients and 50 controls. BAFF level was measured by ELISA. Results: XLA patients with CRD had a significantly lower percentage of RTE numbers and Tregs, while significantly higher absolute counts of lymphocytes, CD3+, CD8+, CD3+DR+ and CD4+CD45RO+ T cells were detected as compared with healthy controls. In patients with XLA without CRD, the number of follicular T helper cells was altered significantly (percentage and absolute), as compared with healthy controls. Additionally, they had significantly higher counts (percentage and absolute) of CD4+CD45RA+ cells and lower percentage of CD4+CD45RO+ cells in comparison with healthy controls. Conclusions: Our study affords new information concerning CRD and T cell subsets that differentiate or are maintained in the absence of B cells in children with XLA. T cell's homeostasis depends on the presence of chronic respiratory disease that may be caused by the delay in diagnosis (AU)


No disponible


Assuntos
Humanos , Agamaglobulinemia/imunologia , Infecções Respiratórias/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doença Crônica , Linfócitos T Reguladores/imunologia , Fator Tímico Circulante/imunologia , Fator Ativador de Células B/imunologia , Sinusite/imunologia
14.
J Allergy Clin Immunol ; 141(3): 1036-1049.e5, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241729

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário/congênito , Imunossupressão , Mutação , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Diarreia/mortalidade , Diarreia/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/mortalidade , Doenças do Sistema Imunitário/terapia , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
15.
Allergol Immunopathol (Madr) ; 46(1): 58-66, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28477853

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a genetic disorder affecting B cell maturation, which is characterised by a low number of B cells, agammaglobulinaemia and increased susceptibility to a variety of bacterial infections. This study was performed to assess T cell subpopulations in a group of children with XLA in association with chronic respiratory disease (CRD). METHODS: Numbers of T cell subpopulations (CD3+, CD4+, CD8+, CD3+DR+, naïve, memory, recent thymic emigrants (RTE), regulatory T cells, follicular T helpers) were measured by eight-colour flow cytometry in 22 XLA patients and 50 controls. BAFF level was measured by ELISA. RESULTS: XLA patients with CRD had a significantly lower percentage of RTE numbers and Tregs, while significantly higher absolute counts of lymphocytes, CD3+, CD8+, CD3+DR+ and CD4+CD45RO+ T cells were detected as compared with healthy controls. In patients with XLA without CRD, the number of follicular T helper cells was altered significantly (percentage and absolute), as compared with healthy controls. Additionally, they had significantly higher counts (percentage and absolute) of CD4+CD45RA+ cells and lower percentage of CD4+CD45RO+ cells in comparison with healthy controls. CONCLUSIONS: Our study affords new information concerning CRD and T cell subsets that differentiate or are maintained in the absence of B cells in children with XLA. T cell's homeostasis depends on the presence of chronic respiratory disease that may be caused by the delay in diagnosis.


Assuntos
Agamaglobulinemia/imunologia , Fator Ativador de Células B/metabolismo , Bronquite/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Sinusite/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Timócitos/imunologia , Adolescente , Agamaglobulinemia/complicações , Bronquite/complicações , Separação Celular , Criança , Pré-Escolar , Doença Crônica , Feminino , Citometria de Fluxo , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , Memória Imunológica , Imunofenotipagem , Masculino , Sinusite/complicações
16.
J Allergy Clin Immunol ; 141(3): 1060-1073.e3, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28629746

RESUMO

BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin ß receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.


Assuntos
Displasia Ectodérmica/genética , Displasia Ectodérmica/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Genótipo , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Transdução de Sinais , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Quimiocina CCL20/genética , Quimiocina CCL20/imunologia , Displasia Ectodérmica/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/patologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/imunologia , Mutação Puntual , Transdução de Sinais/genética , Transdução de Sinais/imunologia
17.
Ann N Y Acad Sci ; 1417(1): 5-22, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-26918796

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tTreg ) cells. tTreg  cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Diarreia/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/terapia , Feminino , Fatores de Transcrição Forkhead/química , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Imunossupressão , Recém-Nascido , Masculino , Modelos Genéticos , Modelos Imunológicos , Mutação , Fenótipo , Gravidez , Regiões Promotoras Genéticas , Domínios Proteicos , Sequências Reguladoras de Ácido Nucleico , Subpopulações de Linfócitos T/imunologia
18.
Semin Immunol ; 36: 1-12, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29254755

RESUMO

For almost any given human-tropic virus, bacterium, fungus, or parasite, the clinical outcome of primary infection is enormously variable, ranging from asymptomatic to lethal infection. This variability has long been thought to be largely determined by the germline genetics of the human host, and this is increasingly being demonstrated to be the case. The number and diversity of known inborn errors of immunity is continually increasing, and we focus here on autosomal and X-linked recessive traits underlying complete deficiencies of the encoded protein. Schematically, four types of infectious phenotype have been observed in individuals with such deficiencies, each providing information about the redundancy of the corresponding human gene, in terms of host defense in natural conditions. The lack of a protein can confer vulnerability to a broad range of microbes in most, if not all patients, through the disruption of a key immunological component. In such cases, the gene concerned is of low redundancy. However, the lack of a protein may also confer vulnerability to a narrow range of microbes, sometimes a single pathogen, and not necessarily in all patients. In such cases, the gene concerned is highly redundant. Conversely, the deficiency may be apparently neutral, conferring no detectable predisposition to infection in any individual. In such cases, the gene concerned is completely redundant. Finally, the lack of a protein may, paradoxically, be advantageous to the host, conferring resistance to one or more infections. In such cases, the gene is considered to display beneficial redundancy. These findings reflect the current state of evolution of humans and microbes, and should not be considered predictive of redundancy, or of a lack of redundancy, in the distant future. Nevertheless, these observations are of potential interest to present-day biologists testing immunological hypotheses experimentally and physicians managing patients with immunological or infectious conditions.


Assuntos
Doenças Transmissíveis/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Imunidade/genética , Síndromes de Imunodeficiência/genética , Doenças Assintomáticas , Evolução Biológica , Doenças Transmissíveis/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Síndromes de Imunodeficiência/imunologia , Fenótipo , Tropismo Viral
19.
Immunity ; 47(2): 268-283.e9, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28778586

RESUMO

Foxp3 controls the development and function of regulatory T (Treg) cells, but it remains elusive how Foxp3 functions in vivo. Here, we established mouse models harboring three unique missense Foxp3 mutations that were identified in patients with the autoimmune disease IPEX. The I363V and R397W mutations were loss-of-function mutations, causing multi-organ inflammation by globally compromising Treg cell physiology. By contrast, the A384T mutation induced a distinctive tissue-restricted inflammation by specifically impairing the ability of Treg cells to compete with pathogenic T cells in certain non-lymphoid tissues. Mechanistically, repressed BATF expression contributed to these A384T effects. At the molecular level, the A384T mutation altered Foxp3 interactions with its specific target genes including Batf by broadening its DNA-binding specificity. Our findings identify BATF as a critical regulator of tissue Treg cells and suggest that sequence-specific perturbations of Foxp3-DNA interactions can influence specific facets of Treg cell physiology and the immunopathologies they regulate.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças do Sistema Imunitário/congênito , Inflamação/genética , Linfócitos T Reguladores/fisiologia , Alelos , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Movimento Celular , Células Cultivadas , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diarreia/imunologia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação de Sentido Incorreto/genética , Especificidade de Órgãos/genética
20.
Sci Rep ; 7(1): 6836, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754963

RESUMO

X-linked agammaglobulinemia (XLA) is a rare genetic disorder, caused by mutations in BTK (Bruton's Tyrosine Kinase) gene. Deep high-throughput RNA sequencing (RNA-Seq) approach was utilized to explore the possible differences in transcriptome profiles of primary monocytes in XLA patients compared with healthy subjects. Our analysis revealed the differences in expression of 1,827 protein-coding genes, 95 annotated long non-coding RNAs (lncRNAs) and 20 novel lincRNAs between XLA patients and healthy subjects. GO and KEGG pathway analysis of differentially expressed (DE) protein-coding genes showed downregulation of several innate immune-related genes and upregulation of oxidative phosphorylation and apoptosis-related genes in XLA patients compared to the healthy subjects. Moreover, the functional prediction analysis of DE lncRNAs revealed their potential role in regulating the monocytes cell cycle and apoptosis in XLA patients. Our results suggested that BTK mutations may contribute to the dysregulation of innate immune system and increase susceptibility to apoptosis in monocytes of XLA patients. This study provides significant finding on the regulation of BTK gene in monocytes and the potential for development of innovative biomarkers and therapeutic monitoring strategies to increase the quality of life in XLA patients.


Assuntos
Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Imunidade Inata , Transcriptoma , Adulto , Tirosina Quinase da Agamaglobulinemia/deficiência , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Apoptose , Estudos de Casos e Controles , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Masculino , Monócitos/metabolismo , Fosforilação Oxidativa
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