JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome

Chatila, Talal A.; Blaeser, Frank; Ho, Nga; Lederman, Howard M.; Voulgaropoulos, Constantine; Helms, Cindy; Bowcock, Anne M.

doi:10.1172/jci11679

Cited by 831 publications

(586 citation statements)

References 25 publications

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“…Mutations in the Foxp3 (murine)/ FOXP3 (human) gene were identified as the sole genetic defect underlying the phenotypes of the fatal autoimmune diseases of the scurfy mouse [7] and human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy (IPEX) [8] and X-linked autoimmune and allergic dysregulation syndromes (XLAAD) [9]. These autoimmune diseases arise from a lack of functional Treg and it was subsequently demonstrated that Foxp3 gene transfer converted naïve CD4 + CD25 -T cells into a regulatory population [10][11][12].…”

Section: Foxp3 Represents a Single Definitive Treg Markermentioning

confidence: 99%

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

2006

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Regulatory T cells (Treg) provide protection from autoimmune disease, graft‐versus‐host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft‐versus‐host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets.

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Section: Foxp3 Represents a Single Definitive Treg Markermentioning

confidence: 99%

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

2006

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“…The cause of the associated immunodeficiency is not clear and leukocyte count, lymphocyte subsets and T-cell proliferation tests are usually normal. T lymphocytes in these patients have a cytokine profile markedly skewed toward a Th2 phenotype (high concentration of IL-4, IL-5 and IL-13, low concentration of IFN-gamma) [173,174]. Several mutations in JM2, a gene in the pericentromeric region of the X chromosome (Xp11.23-Xq13.3) have been described in patients with XPID [175,173,176] (Fig.…”

Section: ªMonogenicº Diabetes Syndromesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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“…The nuclei of these cells also contain Foxp3, which is a member of the forkhead or winged helix family of transcription factors. Foxp3 is reported to be a key regulatory gene for the development and function of T reg and the most specific marker of T reg (Chatila et al, 2000;Brunkow et al, 2001;Mchugh et al, 2002;Fontenot et al, 2003;Hori et al, 2003;Khattri et al, 2003;Fontenot and Rudensky, 2005).…”

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Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma

et al. 2008

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CD4/8 status has been previously reported to be a critical factor in the prognosis of oesophageal squamous cell carcinoma (OSCC). In the current study, we investigated the effect of regulatory T cells (T reg ; Foxp3 þ lymphocytes) on the status of CD4 þ and CD8 þ T cells in 122 patients with OSCC. Immunohistochemical analysis of T reg was performed using an antibody against Foxp3. The survival rate for low Foxp3 patients was significantly lower than for high Foxp3 patients (P ¼ 0.0028 by log-rank test), but Foxp3 status did not significantly correlate with prognosis in CD4/8( þ / þ ) patients or CD4/8( þ /À) or (À/ þ ) patients (P ¼ 0.5185 and 0.8479, respectively, by log-rank test). We also found that Foxp3 status correlated with CD4/8 status (P ¼ 0.0002 by w 2 test) and that the variance of CD8/CD4 ratio in patients with low Foxp3 was larger than in patients with high Foxp3 (Po0.0001 by F-test). Thus, the results do not support the idea that T reg suppress anti-tumour immunity in patients with OSCC. Rather, the CD8/CD4 ratio and CD4/8 status appear to be critical factors in anti-tumour immunity. Furthermore, T reg numbers correlate with both the CD8/CD4 ratio and the CD4/8 status, suggesting that T reg number is not a factor to predict patient's survival in OSCC.

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JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome

Cited by 831 publications

References 25 publications

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

Genetic control of autoimmunity in Type I diabetes and associated disorders

Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma

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JM2, encoding a fork head–related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome

Cited by 831 publications

References 25 publications

FOXP3+ regulatory T cells: Current controversies and future perspectives

FOXP3+ regulatory T cells: Current controversies and future perspectives

Genetic control of autoimmunity in Type I diabetes and associated disorders

Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma

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FOXP3⁺ regulatory T cells: Current controversies and future perspectives

FOXP3⁺ regulatory T cells: Current controversies and future perspectives