An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy

Powell, Berkley R.; Buist, Neil R. M.; Stenzel, Peter

doi:10.1016/s0022-3476(82)80573-8

Cited by 385 publications

(298 citation statements)

References 15 publications

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“…Loss of this tolerogenic mechanism is associated with fulminate, fatal autoimmunity in both experimental animals and human patients (1)(2)(3)(4)(5)(6). In addition to their physiological role, studies have also shown that mouse Treg cells can effectively prevent allograft rejection (7) and graft-vs-host disease (GVHD) when adoptively transferred into recipient hosts (8 -11), unveiling the attractive perspective of using Treg cells as therapeutic tools for treatment of transplant rejection and GVHD in humans.…”

Section: T He Naturally Arising Regulatory Foxp3mentioning

confidence: 99%

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Chen

Delgado

Jensen

et al. 2009

The Journal of Immunology

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Compelling evidence from animal studies has demonstrated that allospecific FoxP3+CD4+ regulatory T (Treg) cells expanded ex vivo can be used as effective therapeutic tools in the treatment of allograft rejection and graft-vs-host disease. Despite the promising results from animal studies, there remain major barriers to developing Treg cell-based immunotherapy in humans. Currently, no effective approach has been established for selective expansion of human allospecific Treg cells ex vivo. Additionally, the very low frequency of Treg cells present in human peripheral blood could pose a formidable challenge to obtaining a sufficient number of Treg cells from a single donor for ex vivo expansion for therapeutic utilization. Extending our recent finding that mouse B cells preferentially induce expansion of alloreactive Treg cells, we report herein that human Treg cells can be expanded ex vivo with allogeneic B cells. The expanded Treg cells express very high levels of FoxP3, maintain anergic phenotype, and are potent suppressors capable of inhibiting the alloproliferation of third-party responder T cells at very low Treg-to-T effector cell ratio in an alloantigen-specific manner. The alloantigen specificity demonstrated by B cell-expanded Treg cells is not determined by the HLA haplotypes of the Treg cells, but it is induced and determined by the haplotype of the B cells used to expand them. Our findings represent a significant advance in the development of Treg cell-based immunotherapy in humans and raise the possibility of using third-party Treg cells for therapeutic applications.

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Section: T He Naturally Arising Regulatory Foxp3mentioning

confidence: 99%

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Chen

Delgado

Jensen

et al. 2009

The Journal of Immunology

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“…A syndrome affecting males only with diabetes mellitus, thyroiditis, diarrhoea, haemolytic anaemia, eczematoid rashes, immunodeficiency and death during infancy was first described in 1982 [172]. This syndrome is known by various names, including X-linked autoimmunity-allergic disregulation syndrome (XLAAD), X-linked polyendocrinopathy, immune dysfunction, and diarrhoea (XPID) or Xlinked autoimmunity-immunodeficiency syndrome (XLAID).…”

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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“…Genetic lesions in the Foxp3 gene (the scurfy mutant mouse or human patients with immune dysfunction/polyendocrinopathy/enteropathy/X-linked syndrome) lack Treg and develop a fatal autoimmune lymphoproliferative disease [1][2][3][4][5][6][7]. A similar, but less severe, phenotype is observed in mice deficient in IL-2 and components of its receptor complex, .…”

Section: Introductionmentioning

confidence: 99%

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

2007

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Immunological tolerance to self antigens is a tightly regulated process. Recent work has demonstrated that the forkhead family member Foxp3 is a critical element in the differentiation and function of mouse CD4 + CD25 + regulatory T cells (Treg). Recent work has suggested an important role for IL-2 in the development and maintenance of Treg. To directly assess the effect of IL-2 signaling on Treg development and function, we analyzed mice that were genetically deficient in components of the IL-2 receptor (IL-2R). Mice lacking CD25 (IL-2Ra) displayed a slight decrease in Treg within the thymus, while peripheral numbers are unchanged. In contrast, we found that mice deficient in CD122 (IL-2Rb) had a profound reduction in both thymic and peripheral Treg, coinciding with more rapid development of a fatal lymphoproliferative disease. Expression of a Foxp3 transgene restored Treg and protected against the onset of autoimmunity. Thus, a signal mediated by IL-2Rb is essential for the development and homeostasis of Foxp3 + Treg in vivo.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37101_s.pdf IntroductionPeripheral tolerance to self antigens is regulated, in part, by a population of CD4 + CD25 + Foxp3 + regulatory T cells (Treg). Genetic lesions in the Foxp3 gene (the scurfy mutant mouse or human patients with immune dysfunction/polyendocrinopathy/enteropathy/X-linked syndrome) lack Treg and develop a fatal autoimmune lymphoproliferative disease [1][2][3][4][5][6][7]. A similar, but less severe, phenotype is observed in mice deficient in IL-2 and components of its receptor complex, . Thus, disrupting the IL-2R signaling pathway results in severe T cell-mediated autoimmunity rather than immune deficiency, indicating a significant role for IL-2R signaling in Treg development and function.Signaling through the IL-2R complex is initiated by ligand-induced heterodimerization of CD122 and CD132, which activates the associated tyrosine kinases JAK1 and JAK3. Since it has previously been shown that a covalently linked JAK3 molecule can functionally replace the cytoplasmic domain of CD132, the role of CD132 in IL-2R signaling appears to be restricted to the recruitment of JAK3 [13]. By contrast, CD122 provides essential docking sites for at least two major downstream signaling mediators, the adaptor protein Shc and the transcription factor STAT5. CD122 is common to both the IL-2R and IL-15R, with each receptor having a unique a chain that defines receptor specificity (IL-2Ra and IL-15Ra, respectively). Unlike CD122, the role of CD25 appears to be confined to increasing binding affinity (KD *10 -9 -10 -11 M) and it is postulated that the short cytoplasmic domain is unlikely to contribute to signaling [13][14][15][16][17][18].Several lines of evidence suggest that IL-2 is essential for the homeostatic proliferation of Treg. For example, bone marrow chimera studies showed that IL-2 production by non-Treg is required for Treg maintenance [19]. In addition, treatment of mice with...

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An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy

Cited by 385 publications

References 15 publications

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Direct Expansion of Human Allospecific FoxP3+CD4+ Regulatory T Cells with Allogeneic B Cells for Therapeutic Application

Genetic control of autoimmunity in Type I diabetes and associated disorders

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

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