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2.
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
4.
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
5.
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
7.
Clin Immunol ; 191: 52-58, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29567430

RESUMO

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inherited disorder leading to severe organ-specific autoimmunity. IPEX is caused by hemizygous mutations in FOXP3, which codes for a master transcription factor of regulatory T (TReg) cell development and function. We describe a four-year-old boy with typical but slightly delayed-onset of IPEX with autoimmune diabetes mellitus, enteropathy, hepatitis and skin disease. We found the unreported FOXP3 splice site mutation c.816+2T>A that leads to the loss of leucine-zipper coding exon 7. RNA-Seq revealed that FOXP3Δ7 leads to differential expression of FOXP3 regulated genes. After myeloablative conditioning the patient underwent allogeneic HSCT from a matched unrelated donor. HSCT led to the resolution of all IPEX symptoms including insulin requirement despite persisting autoantibody levels. After initial full donor engraftment nearly complete autologous reconstitution was documented, but donor-derived TReg cells persisted with a lineage-specific chimerism of >70% and the patient remained in clinical remission.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Éxons , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transplante de Células-Tronco Hematopoéticas , Doenças do Sistema Imunitário/congênito , Mutação , Linfócitos T Reguladores/imunologia , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Humanos , Doenças do Sistema Imunitário/genética , Ativação Linfocitária , Masculino
9.
Physiol Res ; 67(2): 331-337, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29303605

RESUMO

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/genética , Epilepsia/genética , Fator de Iniciação 2 em Eucariotos/genética , Genitália/anormalidades , Hipoglicemia/congênito , Hipoglicemia/genética , Hipogonadismo/genética , Hipopituitarismo/congênito , Hipopituitarismo/genética , Retardo Mental Ligado ao Cromossomo X/genética , Microcefalia/genética , Obesidade/genética , Glândulas Endócrinas/metabolismo , Mutação da Fase de Leitura , Humanos , Recém-Nascido , Masculino , Fenótipo , Fatores de Transcrição
10.
Pediatr Diabetes ; 19(3): 388-392, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29193502

RESUMO

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus/genética , Diarreia/diagnóstico , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças do Sistema Imunitário/congênito , Sistema de Registros , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Doenças do Sistema Imunitário/diagnóstico , Lactente , Recém-Nascido , Masculino
11.
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
12.
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
13.
J Ultrasound Med ; 37(4): 1033-1037, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28960390

RESUMO

There are multiple etiologies for fetal dilated bowel loops on ultrasonography (US), and we present a unique case of male siblings with a forkhead box P3 (FOXP3) mutation. Both children presented with fetal bowel anomalies on prenatal US. Family histories of cystic fibrosis and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome were reported. Amniocentesis in both pregnancies identified a normal male karyotype and the familial mutation associated with IPEX syndrome. IPEX syndrome is one of a group of conditions known as congenital diarrhea disorders. Other congenital diarrhea disorder cases have presented with similar prenatal US findings. As a result of these associations, we suggest considering IPEX syndrome as a potential cause of fetal bowel anomalies, particularly with a known family history. However, continued research into the phenotypic and genotypic correlations for IPEX syndrome is likely needed to better understand this possible prenatal presentation.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/diagnóstico por imagem , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças do Sistema Imunitário/congênito , Mutação/genética , Ultrassonografia Pré-Natal/métodos , Adulto , Transplante de Medula Óssea , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Diarreia/terapia , Evolução Fatal , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Doenças do Sistema Imunitário/diagnóstico por imagem , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Lactente , Recém-Nascido , Intestinos/diagnóstico por imagem , Masculino , Gravidez , Irmãos
14.
J Pediatr Endocrinol Metab ; 30(12): 1317-1320, 2017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29127768

RESUMO

BACKGROUND: Diabetic ketoacidosis (DKA) in children less than 1 year of age is a rare occurrence. Typical presentation includes a prodrome of weight loss and polyuria with subsequent presentation to medical care when acidosis becomes symptomatic. CASE PRESENTATION: We describe an unusual case of a previously healthy infant with a 3 days' history of constipation, presenting acutely with abdominal pain, lethargy, and dehydration. On initial evaluation, our patient had profound encephalopathy, with marked tachypnea and work of breathing. Arterial blood gas revealed a pH of 6.9, pCO2 of 20 and a bicarbonate level of <5. There was profound leukocytosis (WBC 77 K/µL), hyperuricemia (uric acid 15.9 mg/dL), and evidence of pre-renal azotemia [blood urea nitrogen (BUN) 54, Cr 0.82]. Blood glucose was >700 mg/dL. Despite fluid resuscitation and insulin infusion of 0.1 unit/kg/h, which are the mainstays of therapy for DKA, her severe metabolic acidosis and altered mental status did not improve. Differential diagnosis for her metabolic derangements included inborn errors of metabolism, insulin receptor defects, toxic ingestions, and septic shock secondary to an underlying oncologic or intra-abdominal process. The patient was treated with broad spectrum antibiotics and rasburicase. She continued to have significant shock for the first 30 h of her hospital stay, requiring moderate vasoactive support. Due to her refractory acidosis and persistent hyperglycemia, insulin infusion was increased to 0.15 units/kg/h. A hemoglobin A1C obtained on the second hospital day revealed a level of 7.4 and helped to solidify the diagnosis. CONCLUSIONS: Metabolic acidosis in an infant requires a broad differential. Rasburicase should be considered in hyperuricemia and DKA.


Assuntos
Encefalopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Insulina/administração & dosagem , Encefalopatias/complicações , Encefalopatias/congênito , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/congênito , Cetoacidose Diabética/complicações , Cetoacidose Diabética/congênito , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperuricemia/complicações , Hiperuricemia/congênito , Lactente , Falha de Tratamento
15.
J Clin Immunol ; 37(8): 811-819, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29058101

RESUMO

PURPOSE: The dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal recessive-combined immunodeficiency whose clinical spectra include recurrent infections, autoimmunity, malignancies, elevated serum IgE, eczema, and food allergies. Here, we report on patients with loss of function DOCK8 mutations with profound immune dysregulation suggestive of an immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like disorder. METHODS: Immunophenotyping of lymphocyte subpopulations and analysis of DOCK8 protein expression were evaluated by flow cytometry. T regulatory (Treg) cells were isolated by cell sorting, and their suppressive activity was analyzed by flow cytometry. Gene mutational analysis was performed by whole-exome and Sanger sequencing. RESULTS: Patient 1 (P1) presented at 10 months of age with chronic severe diarrhea and active colitis in the absence of an infectious trigger, severe eczema with elevated serum IgE, and autoimmune hemolytic anemia, suggestive of an IPEX-related disorder. Whole-exome sequencing revealed a homozygous nonsense mutation in DOCK8 at the DOCK-homology region (DHR)-1 (c.1498C>T; p. R500X). Patient P2, a cousin of P1 who carries the same DOCK8 nonsense mutation, presented with eczema and recurrent ear infections in early infancy, and she developed persistent diarrhea by 3 years of age. Patient P3 presented with lymphoproliferation, severe eczema with allergic dysregulation, and chronic diarrhea with colitis. She harbored a homozygous loss of function DOCK8 mutation (c.2402 -1G→A). Treg cell function was severely compromised by both DOCK8 mutations. CONCLUSION: DOCK8 deficiency may present severe immune dysregulation with features that may overlap with those of IPEX and other IPEX-like disorders.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diabetes Mellitus Tipo 1/congênito , Diarreia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Fatores de Troca do Nucleotídeo Guanina/genética , Hipersensibilidade/diagnóstico , Doenças do Sistema Imunitário/congênito , Mutação/genética , Linfócitos T Reguladores/imunologia , Anemia Hemolítica , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Genes Recessivos/genética , Humanos , Doenças do Sistema Imunitário/diagnóstico , Imunoglobulina E/metabolismo , Imunofenotipagem , Lactente
16.
Phytomedicine ; 33: 1-6, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28887914

RESUMO

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. OBJECTIVE: The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. METHODS: C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. RESULTS: Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4+ T cells. CONCLUSIONS: Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases.


Assuntos
Curcumina/farmacologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças do Sistema Imunitário/congênito , Células Th17/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Dieta , Modelos Animais de Doenças , Doenças do Sistema Imunitário/tratamento farmacológico , Interleucina-17/imunologia , Interleucina-4/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th2/imunologia
17.
Prenat Diagn ; 37(10): 1040-1045, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28833278

RESUMO

OBJECTIVE: To identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males. METHODS: Whole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second-trimester IUFD of males (n = 19). When documented, all deaths occurred at ≤20 weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case. RESULTS: Following variant filtering based on a recessive X-linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome which exclusively affects males and may present with a potentially life-threatening complex autoimmune disorder in early childhood. CONCLUSIONS: Here, we demonstrate the utility of whole genome sequencing-based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3-mediated IUFD in males. © 2017 John Wiley & Sons, Ltd.


Assuntos
Morte Fetal/etiologia , Sequenciamento Completo do Genoma , DNA/análise , Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diarreia/genética , Diarreia/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Mutação da Fase de Leitura/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Idade Gestacional , Humanos , Hidropisia Fetal/genética , Doenças do Sistema Imunitário/congênito , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Masculino , Linhagem , Gravidez , Segundo Trimestre da Gravidez
18.
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
19.
Skinmed ; 15(3): 231-234, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28705291

RESUMO

A 23-year-old man presented to our practice with erythroderma and an unusual retiform eruption, along with alopecia universalis and nail dystrophy. He had had no skin findings at birth, but since early infancy had had localized eczematous eruptions of his skin. At 10 years of age, he had developed a generalized eczematous flare requiring hospitalization, and another generalized episode occurred in October 2010. He was prescribed prednisone 60 mg daily, which initially provided an improvement, but tapering of the corticosteroid resulted in another generalized flare.


Assuntos
Alopecia/etiologia , Dermatite Esfoliativa/etiologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/complicações , Diarreia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças do Sistema Imunitário/congênito , Erupções Liquenoides/etiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Masculino , Unhas Malformadas/etiologia , Adulto Jovem
20.
Pediatr Nephrol ; 32(9): 1621-1624, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28488220

RESUMO

BACKGROUND: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency syndrome characterized by the development of multiple autoimmune disorders in affected individuals. Different forms of renal injury have been reported in IPEX syndrome, and membranous nephropathy (MN) is among the most common glomerulopathies found. However, the exact pathogenesis of MN in this setting has not been elucidated, and it is not clear whether it is part of the clinical spectrum of the disease or secondary to medications, infections or other concomitant insults. DIAGNOSIS/TREATMENT: We describe a child diagnosed with IPEX syndrome shortly after birth who presented with nephrotic syndrome at the age of 11 weeks. Renal biopsy revealed a MN with enhanced immunohistochemical staining for phospholipase A2 receptor (PLA2R). CONCLUSION: This is the first report of a PLA2R-positive MN in a patient with IPEX syndrome. We suggest that, in this context, MN results from an autoimmune process against podocytic antigens, namely PLA2R.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Glomerulonefrite Membranosa/imunologia , Doenças do Sistema Imunitário/congênito , Glomérulos Renais/imunologia , Receptores da Fosfolipase A2/imunologia , Biópsia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diarreia/complicações , Diarreia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/patologia , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Lactente , Glomérulos Renais/patologia , Masculino , Receptores da Fosfolipase A2/análise
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