The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome

d’Hennezel, Eva; Dhuban, Khalid Bin; Torgerson, Troy R.; Piccirillo, Ciriaco A.

doi:10.1136/jmedgenet-2012-100759

Cited by 129 publications

(118 citation statements)

References 94 publications

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“…Treg are crucial for the maintenance of mucosal tolerance, so their decreased function might allow resident T and B cells to initiate and sustain responses against commensals, perhaps in conjunction with defects in Th17 cytokines. A parallel can be found in patients with IPEX, a rare autoimmune disease caused by mutations in FOXP3, in which the Treg defect gives rise to severe colitis (44,45). Treg impairment has also been suggested to contribute to the pathogenesis of IBDs (46).…”

Section: Discussionmentioning

confidence: 94%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

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Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti–IL-17 or –IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti–S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO+ population (ρ = −0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3+ cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn’s disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.

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Section: Discussionmentioning

confidence: 94%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

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“…These studies strongly indicate that a threshold of Treg function is required throughout life to restrain autoreactive T cells and/or inflammatory responses, and this prevents autoimmune disease onset. The early development of autoimmune disease in IPEX patients, who lack FOXP3 and Treg,23 confirms that Treg are also essential in humans 24. Functional defects in Treg in type 1 diabetes and inflammatory bowel disease have been reported,25, 26 but there are conflicting reports in the literature about reduced Treg numbers in autoimmune cohorts.…”

Section: Treg and Diseasementioning

confidence: 89%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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“…In addition, FOXP3Luc could be useful for evaluating IPEX mutations for clinical diagnosis. Indeed, as shown by analysis of different known FOXP3 alleles, the M370I, F371C, F373A, and R397W mutations linked to severe IPEX presentations caused dramatic reductions in the readout of FOXP3Luc, whereas the mild IPEX syndrome-associated A384T and F324L mutations caused mild or negligible reductions (35). Therefore, FOXP3Luc provides a practical and simple tool to predict the clinical significance of genetic mutations in the FOXP3 gene.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of MEK1 Promotes Treg Cell Instability in Vivo

Guo

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: Treg cell stability is ensured by a CNS2-Cbf␤-Runx1-Foxp3 feedback loop. Results: Activation of the COT/Tpl2-MEK-ERK pathway decreases the DNA binding activity of Foxp3 and down-regulates Treg cell function and Foxp3 expression in vivo. Conclusion:The COT/Tpl2-MEK-ERK pathway modulates Treg cell identity. Significance: Therapeutic interventions targeting the COT/Tpl2-MEK-ERK pathway might contribute to treating autoimmune diseases and optimize human Treg cell therapy.

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The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome

Cited by 129 publications

References 94 publications

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Constitutive Activation of MEK1 Promotes Treg Cell Instability in Vivo

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