RESUMO
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
Assuntos
Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética , Mutação em Linhagem Germinativa , Interleucina-10 , Linfócitos T Reguladores , Animais , Fatores de Transcrição Forkhead/genética , Camundongos , Interleucina-10/genética , Interleucina-10/imunologia , Terapia Genética/métodos , Linfócitos T Reguladores/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Interleucinas/imunologia , Interleucinas/genética , Diarreia/genética , Diarreia/terapia , Diarreia/imunologia , Enteropatias/imunologia , Enteropatias/genética , Enteropatias/terapia , Dependovirus/genética , Camundongos Endogâmicos C57BL , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/congênito , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congênito , Camundongos Knockout , Ativação Linfocitária/imunologia , Humanos , Interleucina-27/genéticaRESUMO
Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.
Assuntos
Autoimunidade , Benzofuranos , Interleucina-2 , Fator de Transcrição STAT5 , Transdução de Sinais , Linfócitos T Reguladores , Animais , Fator de Transcrição STAT5/metabolismo , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Benzofuranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Interleucina-2/metabolismo , Autoimunidade/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Masculino , Doenças Genéticas Ligadas ao Cromossomo X , Diabetes Mellitus Tipo 1/congênito , Diarreia , Doenças do Sistema Imunitário/congênito , DepsídeosAssuntos
Anticorpos Monoclonais Humanizados , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Fármacos Gastrointestinais/uso terapêutico , Resultado do Tratamento , Diabetes Mellitus Tipo 1/congênito , Diarreia , Doenças do Sistema Imunitário/congênitoRESUMO
A 19-year-old, G1P0, pregnant person was referred at 20w2d gestation for evaluation due to non-immune hydrops fetalis (NIHF), which was confirmed at the time of evaluation. Amniocentesis was performed at 20 w4d, and FISH, karyotype, chromosomal microarray, and exome sequencing (ES) were ordered. Trio ES identified a novel hemizygous c.142 C > T (p.Arg48*; maternally inherited) variant in the FOXP3 gene, resulting in a premature termination codon and establishing the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Intrauterine fetal demise (IUFD) was diagnosed at 21w3d. CVS was performed at 12w1d in a subsequent pregnancy (male fetus) and the known familial variant was identified. NIHF was identified at 18w1d. Ultrasound at 19w2d revealed IUFD. This is the first report of this variant in a diagnosis of IPEX syndrome, presenting with NIHF and male fetal demise. Genotype-phenotype correlations are not available in many cases of IPEX syndrome, as the same genotype can be present with variable severity in different individuals. Given the near identical presentations in this family, we anticipate a more severe phenotype with this variant. We propose a novel variant resulting in an early premature termination codon as an explanation for the severe presentation of IPEX syndrome in two successive fetuses in this family.
Assuntos
Códon sem Sentido , Diabetes Mellitus Tipo 1/congênito , Diarreia , Doenças Genéticas Ligadas ao Cromossomo X , Hidropisia Fetal , Doenças do Sistema Imunitário/congênito , Gravidez , Feminino , Humanos , Masculino , Adulto Jovem , Adulto , Hidropisia Fetal/diagnóstico por imagem , Hidropisia Fetal/genética , Morte Fetal , Fatores de Transcrição Forkhead/genéticaRESUMO
OBJECTIVE: To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Three patients with IPEX syndrome diagnosed at the Children's Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored. RESULTS: All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c.1222G>A (p.V408M), c.767T>C (p.M256T) and c.1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. CONCLUSION: FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário/congênito , Enteropatias , Criança , Humanos , Masculino , Lactente , Diarreia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Enteropatias/genética , Fatores de Transcrição Forkhead/genética , MutaçãoRESUMO
In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Doenças do Sistema Imunitário/congênito , Enteropatias , Poliendocrinopatias Autoimunes , Humanos , Linfócitos T Reguladores , Diarreia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Enteropatias/diagnóstico , Enteropatias/genética , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Mutação , Fatores de Transcrição Forkhead/genética , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/terapiaRESUMO
Glucose 6 phosphate dehydrogenase (G6PD) is expressed in all tissues and is necessary to maintain oxidant stress capacity of cells. G6PD deficiency is the most common enzymopathy in humans and is among the important causes of hemolytic anemia. It has been reported that severe hemolytic anemia due to G6PD deficiency may develop in newly diagnosed diabetes, especially during the correction of hyperglycemia. To date, nine cases have been published. Genetic analysis was not performed for G6PD deficiency in these published patients. We present a case of hemolytic anemia due to G6PD deficiency secondary to newly diagnosed type 1 diabetes mellitus. Genetic testing was performed for the index patient and revealed a previously reported missense pathogenic variant (c.653C>T; p.Ser218Phe) in the G6PD gene.
Assuntos
Anemia Hemolítica , Diabetes Mellitus Tipo 1 , Glucosefosfato Desidrogenase , Humanos , Masculino , Pré-Escolar , Anemia Hemolítica/genética , Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Mutação de Sentido IncorretoRESUMO
Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulatory system caused by forkhead box P3 (FOXP3) mutations. Abnormal numbers or functions of regulatory T (Treg) cells account for the various autoimmune symptoms. We aimed to explore the molecular genetics and phenotypic spectra of patients with atypical IPEX syndrome in China. Methods: We analyzed the molecular, clinical and immune phenotype characteristics of five Chinese patients with FOXP3 mutations. Results: We summarized the molecular and phenotypic features of five patients with FOXP3 mutations, including two novel mutations. Four of the five patients displayed atypical phenotypes, and one developed immune-related peripheral neuropathy. Three of the five patients showed normal frequencies of Treg cells, but the proportions of subsets of Treg cells, CD4+ T cells and B cells were out of balance. Conclusions: Our report broadens the understanding of the clinical features of atypical IPEX syndrome. Our detailed analyses of the immunological characteristics of these patients enhance the understanding of the possible mechanisms underlying the clinical manifestations.
Assuntos
Fatores de Transcrição Forkhead , Poliendocrinopatias Autoimunes , Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/genética , Diarreia/etiologia , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Doenças do Sistema Imunitário/genética , Enteropatias/congênito , Enteropatias/genética , Fenótipo , Poliendocrinopatias Autoimunes/congênito , Poliendocrinopatias Autoimunes/genética , SíndromeRESUMO
Immune dysregulation polyendocrinopathy enteropathy X linked (IPEX) syndrome is an uncurable disease of the immune system, with immune dysregulation that is caused by mutations in FOXP3. Current treatment options, such as pharmacological immune suppression and allogeneic hematopoietic stem cell transplantation, have been beneficial but present limitations, and their life-long consequences are ill-defined. Other similar blood monogenic diseases have been successfully treated using gene transfer in autologous patient cells, thus providing an effective and less invasive therapeutic. Development of gene therapy for patients with IPEX is particularly challenging because successful strategies must restore the complex expression profile of the transcription factor FOXP3, ensuring it is tightly regulated and its cell subset-specific roles are maintained. This review summarizes current efforts toward achieving gene therapy to treat immune dysregulation in IPEX patients.
Assuntos
Diabetes Mellitus Tipo 1 , Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Humanos , Doenças do Sistema Imunitário/congênito , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Mutação , Linfócitos T ReguladoresRESUMO
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genetic disorder that typically presents in the first year of life with severe diarrhea, autoimmune endocrine disorder, and inflammatory dermatitis, most commonly an eczematous dermatitis. IPEX syndrome is caused by variants in the FOXP3 gene leading to dysregulation of T-regulatory (Treg) cells and an aberrant immune response. Here, we present a case of severe IPEX syndrome diagnosed following whole genome sequencing (WGS) in a 2-week-old boy with bloody mucoid diarrhea, failure to thrive, and a diffuse eczematous dermatitis. As multiple variants of interest were identified with WGS, this case highlights the importance of relating the clinical symptoms to the genetic results.
Assuntos
Diabetes Mellitus Tipo 1 , Eczema , Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Enteropatias , Poliendocrinopatias Autoimunes , Diabetes Mellitus Tipo 1/congênito , Diarreia/diagnóstico , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Enteropatias/genética , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genética , SíndromeRESUMO
BACKGROUND: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. OBJECTIVE: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management. METHODS: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. RESULTS: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. CONCLUSIONS: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças do Sistema Imunitário/congênito , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Diarreia/diagnóstico , Diarreia/terapia , Feminino , Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Lactente , Recém-Nascido , Masculino , MutaçãoRESUMO
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an early onset systemic autoimmune genetic disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene. Enteropathy, endocrinopathy and skin manifestations are considered the classic triad of IPEX syndrome. However, patients with IPEX syndrome display a variety of phenotypes including life threatening multi-organ autoimmunity. Here, we present the case of two siblings with IPEX syndrome with the same hemizygous mutation, but with different types of symptomology at onset of the disease.
Assuntos
Diabetes Mellitus Tipo 1 , Doenças Genéticas Ligadas ao Cromossomo X , Enteropatias , Poliendocrinopatias Autoimunes , Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Enteropatias/diagnóstico , Enteropatias/genética , Mutação , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genética , Irmãos , SíndromeAssuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/congênito , Diarreia/sangue , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças do Sistema Imunitário/congênito , Síndrome de Isaacs/sangue , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Adolescente , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/imunologia , Diarreia/terapia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Recém-Nascido , Síndrome de Isaacs/genética , Síndrome de Isaacs/imunologia , Síndrome de Isaacs/terapia , Masculino , MutaçãoAssuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Síndromes Mielodisplásicas/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Diabetes Mellitus Tipo 1/imunologia , Humanos , Doenças do Sistema Imunitário/imunologia , MasculinoRESUMO
This case describes a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with diffuse eczematous dermatitis and severe, intractable pruritus. Despite a bone marrow transplant and immunosuppressive therapy, his skin findings and pruritus persisted. Off-label dupilumab provided significant improvement and almost complete clearance of the dermatitis and pruritus. This is the first known report of dupilumab being used in a patient with IPEX syndrome.
Assuntos
Dermatite Atópica , Eczema , Doenças Genéticas Ligadas ao Cromossomo X , Anticorpos Monoclonais Humanizados , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Diabetes Mellitus Tipo 1/congênito , Diarreia , Eczema/tratamento farmacológico , Eczema/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/congênito , Mutação , Prurido/tratamento farmacológico , Prurido/genéticaRESUMO
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare immune deficiency with a broad clinical presentation. IPEX syndrome causes dysfunctional regulatory T cells, increasing the risk of autoimmune diseases. In this case report, we describe a 7-year-old boy with lymphocytic interstitial pneumonia and bullous pemphigoid who was recently diagnosed with IPEX syndrome.
Assuntos
Doenças Pulmonares Intersticiais , Penfigoide Bolhoso , Criança , Diabetes Mellitus Tipo 1/congênito , Diarreia , Fatores de Transcrição Forkhead , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Doenças do Sistema Imunitário/congênito , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/genética , Masculino , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/genética , Linfócitos T ReguladoresRESUMO
FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/genética , Fatores de Transcrição Forkhead/deficiência , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças do Sistema Imunitário/congênito , Linfócitos T Reguladores/imunologia , Adolescente , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Conjuntos de Dados como Assunto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diarreia/sangue , Diarreia/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Mutação , RNA-Seq , Análise de Célula Única , Linfócitos T Reguladores/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To report on the clinical features and result of genetic testing for a child featuring immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Clinical records, genetic testing, laboratory investigation and treatment of the child were summarized in addition with a comprehensive review of the literature. RESULTS: The 3-year-old boy was administered due to intractable diarrhea, recurrent infections, liver dysfunction and failure to thrive, though no diabetes or skin disorder was observed. Laboratory testing showed elevated liver enzymes and total IgE, decreased albumin and electrolyte imbalance. Gastrointestinal endoscopy revealed erosion and granules in the duodenum, and edema in the terminal ileum and colon. Biopsies showed villous atrophy in the duodenum and terminal ileum. Genetic testing revealed that the patient has carried a missense c.1087A>G (p.I363V) variant in the exon 10 of the FOXP3 gene. He was treated with enteral and parenteral nutrition, anti infection and Sirolimus, and was waiting for hemopoietic stem cell transplantation. CONCLUSION: Although IPEX syndrome usually occur during infancy, it should not be ruled out solely based on the age, and its presentation can be variable. For male children with refractory diarrhea, autoimmune disorder and growth retardation, the diagnosis should be suspected and confirmed by genetic testing.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia , Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário/congênito , Poliendocrinopatias Autoimunes , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos , Humanos , Doenças do Sistema Imunitário/genética , Masculino , Mutação , Poliendocrinopatias Autoimunes/genéticaRESUMO
Treg deficiency causes a lethal, CD4+ T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding Limosilactobacillus reuteri DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with Lacticaseibacillus rhamnosus GG (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, genus_Oscillospira whereas LR reduced phylum_Bacteroidetes, genus_Bacteroides and genus_Parabacteroides, reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of genus_Bacteroides. Both LR and LGG reduced the potentially pathogenic taxon class_γ-proteobacteria. Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: 1) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and 2) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.NEW & NOTEWORTHY In the treatment of Treg-deficiency-induced autoimmunity, Limosilactobacillus reuteri DSM 17938 (LR) showed greater efficacy than Lacticaseibacillus rhamnosus GG (LGG). The study demonstrated that two different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency, but with many similarities in global plasma metabolites in general. However, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.
Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/microbiologia , Microbioma Gastrointestinal/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/microbiologia , Doenças do Sistema Imunitário/congênito , Lacticaseibacillus rhamnosus , Limosilactobacillus reuteri , Linfócitos T Reguladores/imunologia , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Diarreia/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/microbiologia , Camundongos , Camundongos Transgênicos , Probióticos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologiaRESUMO
INTRODUCTION: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is a rare monogenic autoimmune disease, which is caused by mutations in the forkhead box protein 3 gene, can affect various systems. The typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases. However, some atypical phenotypes can easily be misdiagnosed clinically. PATIENT CONCERNS: A 9-year-and-7-month old patient suffered from recurrent wheezing, hematochezia, and eczematous dermatitis at the age of six months, but did not have any manifestations of autoimmune endocrinopathy. The patient was treated with glucocorticoids for more than six years, and he developed bronchiectasis. DIAGNOSIS: Whole exome sequencing revealed a hemizygous pathogenic mutation c.1010G>A, p. (Arg337Gln) in Forkhead box protein 3 gene (NM_014009.3). INTERVENTIONS: The patient was treated with oral mycophenolate mofetil combined with inhaled budesonide formoterol for six months after diagnosis. OUTCOMES: The respiratory symptoms of the patient seemed to be controlled but eczematous dermatitis progressed, which led the patient to give up the treatment. CONCLUSION: Early diagnosis and treatment of IPEX are crucial. Lung injury may be a major problem in the later stages of atypical IPEX, and mycophenolate mofetil seems to control the respiratory symptoms, but could induce significant skin side effects.