Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family

Seidel, Markus G.; Rami, Birgit; Item, Chike B.; Schober, Edith; Zeitlhofer, Petra; Huber, Wolf Dietrich; Heitger, Andreas; Bodamer, Olaf A.; Haas, Oskar A.

doi:10.1530/eje-12-0197

Cited by 7 publications

(7 citation statements)

References 17 publications

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“…The period from onset of T1D to HSCT can affect the therapeutic efficacy for T1D with IPEX. In our late‐onset IPEX patient with R347H mutation, we speculated that HSCT rescued the pancreatic β‐cells because the insulin‐dependent diabetes occurred immediately before transplantation; this is well in agreement with the previous reports . Although the patient had acute onset of insulin‐dependent DM, insulin requirement was reduced to half following engraftment, and thereafter, the endogenous insulin secretion was significantly improved, ultimately resulting in withdrawal of insulin.…”

Section: Discussionsupporting

confidence: 90%

“…Flow cytometry revealed low expression of CD4 + CD25 high CD127 low Treg cells in the peripheral blood (Figure A). Genetic analysis revealed a hemizygous FOXP3 missense mutation c.1040G > A leading to p.R347H, which was also reported previously (Figure B) . Collectively, the patient was clinically and genetically diagnosed with “late‐onset” IPEX syndrome (Table S1).…”

Section: Case Presentationsupporting

confidence: 74%

“…A large multinational cohort study of IPEX syndrome revealed that 92% of the patients developed IPEX syndrome during infancy and 43% were associated with T1D . Thus, T1D‐associated IPEX is often referred to as neonatal diabetes mellitus . A cohort of 54 patients, who developed IPEX syndrome at a median age of 1 month, underwent HSCT at a median age of 1.4 years.…”

Section: Introductionmentioning

confidence: 99%

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Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

et al. 2019

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Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.

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Section: Discussionsupporting

confidence: 90%

Section: Case Presentationsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

et al. 2019

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“…Skewed XCI occurs when the inactivation of one X chromosome is silenced more than the other one (178, 179). Skewed XCI can also result in loss of imbalance of gene products and immune tolerance and thus is involved in many autoimmune diseases (180–183). …”

Section: Epigenetics In Aitdmentioning

confidence: 99%

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

et al. 2017

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Autoimmune thyroid diseases (AITD) are a group of both B cell- and T cell-mediated organ-specific autoimmune diseases. Graves’ disease and Hashimoto thyroiditis are the two main clinical presentations of AITD. Both genetic and environmental factors have important roles in the development of AITD. Epigenetics have been considered to exert key roles in integrating those genetic and environmental factors, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD. Recent studies on the epigenetics of AITD have provided some novel insights into the pathogenesis of AITD. The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, such as DNA methylation, histone modifications, and non-coding RNAs. This review highlights the key roles of epigenetics in the pathogenesis of AITD and potential clinical utility. However, the epigenetic roles in AITD are still not fully elucidated, and more researches are needed to provide further deeper insights into the roles of epigenetics in AITD and to uncover new therapeutic targets. Although there are many studies assessing the epigenetic modifications in AITD patients, the clinical utility of epigenetics in AITD remains poorly defined. More studies are needed to identify the underlying epigenetic modifications that can contribute to accurate diagnosis of AITD, adequate choice of treatment approach, and precise prediction of treatment outcomes.

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“…Previous studies showed that SXCI occurrence in blood cells was associated with autoimmune diseases [40-43] and linked to the development of certain female cancers [44]. For example, in 1999, Buller et al .…”

Section: Discussionmentioning

confidence: 99%

High frequency of the X-chromosome inactivation in young female patients with high-grade glioma

Zhang

Jin

et al. 2013

Diagn Pathol

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BackgroundGliomas are common tumors and high-grade ones account for 62% of primary malignant brain tumors. Though current evidence have suggested that inherited risks play a role in glioma susceptibility, it was conveyed that glioma was such a complex disease, and the direct genetic contribution to glioma risk factors and its relation to other factors should be discussed more deeply. X-chromosome inactivation (XCI) is the mechanism by which gene dosage equivalence is achieved between female mammals with two X chromosomes and male mammals with a single X chromosome. As skewed XCI has been linked to development of some solid tumors, including ovarian, breast, and pulmonary and esophageal carcinomas, it is challenging to elucidate the relation of skewed XCI to high-grade gliomas development.ObjectiveThe present study aimed to determine the general concordance between XCI pattern in blood cells and brain tissues, and SXCI frequencies in female patients with high-grade glioma compared to healthy controls.Methods1,103 Chinese females without a detectable tumor and 173 female high-grade glioma patients, were detected in the study. Normal brain tissues surrounding the lesions in gliomas were obtained from 49 patients among the 173 ones, with the microdissection using a laser microdissection microscope Genomic DNA was extracted from the peripheral blood cells and the normal brain tissues from the subjects. Exon 1 of androgen receptor (AR) gene was amplified, and its products of different alleles were resolved on denaturing polyacrylamide gels and visualized after silver staining. The corrected ratios (CR) of the products before and after HpaII digestion were calculated.ResultsOccurrence of SXCI was detected in both the patients and controls at similar frequencies. However, the phenomenon, as defined as CR ≥ 3, was more frequent in the patients aging ≤40 (23.6%) compared to the corresponding reference group (5.1%, P <0.0001). When CR ≥ 10 was adopted, the frequencies were 5.5% and 1.6%, respectively. Their difference did not attain statistical significance (P = 0.10). When detected, both blood cells and brain tissue were compared after determination of a high concordance of XCI between blood cells and brain tissue collected from the same individuals (n = 48, r =0.57, P <0.01).ConclusionsThe data from the current study demonstrated that SXCI may be a predisposing factor for development of high-grade glioma in young female patients and further study will verify its suitability as a biomarker to assess susceptibility of young female patients to high-grade glioma.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935066233982578

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Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family

Cited by 7 publications

References 17 publications

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

High frequency of the X-chromosome inactivation in young female patients with high-grade glioma

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