Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis

Gambineri, Eleonora; Torgerson, Troy R.; Ochs, Hans D.

doi:10.1097/00002281-200307000-00010

Cited by 521 publications

(381 citation statements)

References 43 publications

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“…A defect in the human FOXP3 gene leads to IPEX (immune deficiency, polyendocrinopathy, enteropathy, X-linked) syndrome, a systemic autoimmune disease, suggesting that FOXP3 is important for T-cell tolerance [58,59]. Recent studies from Rudensky's lab suggest that targeted depletion of FOXP3-expressing T reg cells in mice results in severe autoimmune disease [60].…”

Section: Foxp3 In T Reg -Cell Generationmentioning

confidence: 99%

TGFβ1 and Treg cells: alliance for tolerance

Bommireddy

Doetschman

2007

Trends in Molecular Medicine

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Transforming growth factor β1 (TGFβ1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T reg )-cell and effector-cell function and tumorigenesis. Defects in TGFβ1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFβ1 prevents abnormal T-cell activation through the modulation of Ca 2+ -calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T reg cells, its effects are mediated, at least in part, through SMAD signaling. TGFβ1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T h IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFβ1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

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Section: Foxp3 In T Reg -Cell Generationmentioning

confidence: 99%

TGFβ1 and Treg cells: alliance for tolerance

Bommireddy

Doetschman

2007

Trends in Molecular Medicine

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“…One of the most severe autoimmune diseases in humans is a severe X-linked autoimmune syndrome (denoted IPEX) determined by mutations of Foxp3 (Table 2). [29][30][31] Autoimmune diabetes in NOD mice Most of our knowledge of autoimmunity in T1D comes from the study of animal models, particularly non-obese diabetic (NOD) mice. In these mice, the disease is more severe in females and occurs because insulin-producing b-cells are destroyed following infiltration of islets of Langerhans by macrophages and islet-cell antigenreactive, auto-aggressive T cells.…”

Section: The Autoimmune Basis Of T1dmentioning

confidence: 99%

Plasmid-based gene therapy of diabetes mellitus

Prud’homme

Draghia-Akli²,

Wang

2007

Gene Ther

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Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-b). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

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“…We will focus our discussion on Foxp3 + CD4 + natural T reg cells (which develop in the thymus) because these cells are central for immune homeostasis, as illustrated by the fatal consequence of their absence from mice deficient in IL-2, CD25 or Foxp3 or of their depletion from normal adult mice [7][8][9]17,18 . Notably, like mice, humans with mutations in FOXP3 develop multiorgan autoimmune diseases with fatal consequences 19 .…”

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confidence: 99%

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

2008

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The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.Armed with the potential to destroy invading microorganisms and stop aberrant outgrowth of tumor cells, the immune system has extensive built-in mechanisms for preventing attack of healthy self tissues. The first line of such 'self-tolerance' is the elimination of selfreactive T lymphocytes and B lymphocytes during negative selection in the thymus and bone marrow, respectively. However, there has long been a belief that the immune system must have peripheral mechanisms in place to deal with immune cells that 'escape' central tolerance. For almost 40 years, immunologists have postulated the existence of suppressor T cells that police the immune system to avert unwanted immune responses 1-3 . However, that phenomenology was cast into doubt as various labs presented unique, hard-to-reproduce systems, each with complexities and idiosyncrasies that raised credibility issues. This situation was not unlike the early years of cytokine biology, during which dozens of activities were found in sera and cell supernatants without consistent molecular or biochemical 'signatures'. Fortunately, as biochemistry and the molecular biology revolution rescued the field of cytokine biology by identifying genes and biochemical structures tied to the varied biologic activities, the identification of a constellation of cell surface, transcriptional and biochemical markers that uniquely mark 'regulatory' T cells (T reg cells) has made possible a rebirth of the suppressor T cell field over the past decade.The realization that T reg cells have a unique surface expression profile incorporating CD25, CD62L and specific CD45 isoforms 4-6 , together with the identification of the T reg cellspecific transcription factor Foxp3, catapulted T reg cells from a rare CD4 + T cell subset to

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Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis

Cited by 521 publications

References 43 publications

TGFβ1 and Treg cells: alliance for tolerance

TGFβ1 and Treg cells: alliance for tolerance

Plasmid-based gene therapy of diabetes mellitus

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

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