The Immunogenetics of IPEX Syndrome
The Immunogenetics of IPEX Syndrome
Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a rare disorder in humans caused by germ-line mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4 regulatory T (Treg) cells. This T cell subset has global inhibitory functions that maintain immune homeostasis and mediate self-tolerance. Treg developmental deficiency or dysfunction is a hallmark of IPEX. It leads to severe, multi-organ, autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy and other organ-specific diseases such as anaemia, thrombocytopenia, hepatitis and nephritis. In this review, the genetic, immunological and clinical characteristics of IPEX syndrome are described, and the impact of heritable mutations on the function of Treg cells highlighted.
Thirty years ago, Powell et al first described the clinical syndrome that has come to be known as immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome in a large non-consanguineous family. The syndrome had a clear X linked recessive pattern of inheritance, with exclusive expression in males. It presented most commonly with early onset diarrhoeal disease, type 1 diabetes (T1D), and an accompanying failure to thrive and dermatitis. Without aggressive treatment the disease was fatal in most affected children within the first two years of life. The devastating clinical outcome of IPEX suggested that the genetic determinant(s) responsible for disease impacted major regulatory processes governing immune homeostasis. An analogous disease process was also observed in a spontaneous mutant mouse known as 'Scurfy'. Using the Scurfy mouse model, researchers mapped the causative locus to the gene encoding the forkhead box protein 3 (FOXP3), a member of the forkhead/winged-helix family of DNA-binding transcriptional regulators. In humans, the gene is located on the X chromosome at Xp11.23-Xq13.3, near the WAS gene, which is responsible for Wiskott–Aldrich syndrome. The identification of heritable mutations in the FOXP3 gene as the cause of IPEX and Scurfy provided the clearest demonstration to date, that defects in a single gene could consistently disrupt immune homeostasis and lead to severe autoimmunity. They also suggested that the FOXP3 gene was involved in the dominant regulation of immune responses to self-antigens.
The immune system requires a set of 'self-check' control mechanisms that establish a homeostatic balance between the need to generate protective immune responses to various foreign antigens, tolerate self-antigens and suppress the consequences of immune-mediated pathology. IPEX is the result of defective development of a naturally arising CD4 T cell lineage called regulatory T (Treg) cells whose function serves to maintain self-tolerance. Treg cells develop in the thymus, and represent 1–10% of thymic and peripheral CD4 T cells. They constitutively express high levels of the interleukin 2 receptor α-chain (IL-2Rα chain or CD25) and FOXP3 protein. Treg cells are critical mediators of immune homeostasis. They determine the balance between protective immunity and tolerance, mediate peripheral tolerance to self and non-self antigens, and suppress excessive inflammation that can cause pathology. The critical functions of FOXP3 Treg cells in immune homeostasis have been amply demonstrated in several mouse models where abrogation of the development, homeostasis or function of FOXP3 Treg cells simultaneously triggers multi-organ autoimmunity, and provokes immunity to tumours, transplants, infectious and commensal microbes, and allergens.
Numerous studies now show that stable FOXP3 expression is essential for the programming of Treg cell lineage development and function. In the resting state, FOXP3 is expressed almost exclusively in CD4 Treg cells, where it functions in a cell-autonomous fashion. Consistently, Foxp3-deficient or Treg-depleted mice develop a fatal, multi-organ autoimmune syndrome that is similar to the autoimmunity observed in Scurfy mice, which express a non-functional, truncated form of the Foxp3 protein lacking the Forkhead DNA-binding domain. Adoptive transfer of CD4/CD25/Foxp3 Treg cells into affected animals readily suppresses the autoimmunity. Moreover, forced overexpression of Foxp3/FOXP3 in conventional murine and human T cells, respectively, redirects their differentiation into the Treg lineage. Of note is that other defects affecting the development and/or function of Treg cells can also break self-tolerance and provoke autoimmunity. Among these, disruption of cytokine and co-stimulatory signalling pathways that are essential for Treg cell development and peripheral homeostasis, can abrogate Treg cell function and provoke autoimmunity as well. Such is the case in CD25, IL2 or STAT5 deficiencies in humans, or in CD28 or ICOS deficiencies in mice.
Hence, Treg cells are critical mediators of self-tolerance, and their development and function heavily depend on FOXP3. However, there exists a considerable level of heterogeneity of severity among IPEX cases, likely due to the multifaceted nature of the molecular functions of FOXP3. Here, we propose a comprehensive review of the IPEX syndrome, covering both the clinical and molecular aspects of the disease, and providing an analysis of the molecular domains of FOXP3 as a platform for understanding the observed clinical heterogeneity and prognosis.
Abstract and Introduction
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a rare disorder in humans caused by germ-line mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4 regulatory T (Treg) cells. This T cell subset has global inhibitory functions that maintain immune homeostasis and mediate self-tolerance. Treg developmental deficiency or dysfunction is a hallmark of IPEX. It leads to severe, multi-organ, autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy and other organ-specific diseases such as anaemia, thrombocytopenia, hepatitis and nephritis. In this review, the genetic, immunological and clinical characteristics of IPEX syndrome are described, and the impact of heritable mutations on the function of Treg cells highlighted.
Introduction
Thirty years ago, Powell et al first described the clinical syndrome that has come to be known as immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome in a large non-consanguineous family. The syndrome had a clear X linked recessive pattern of inheritance, with exclusive expression in males. It presented most commonly with early onset diarrhoeal disease, type 1 diabetes (T1D), and an accompanying failure to thrive and dermatitis. Without aggressive treatment the disease was fatal in most affected children within the first two years of life. The devastating clinical outcome of IPEX suggested that the genetic determinant(s) responsible for disease impacted major regulatory processes governing immune homeostasis. An analogous disease process was also observed in a spontaneous mutant mouse known as 'Scurfy'. Using the Scurfy mouse model, researchers mapped the causative locus to the gene encoding the forkhead box protein 3 (FOXP3), a member of the forkhead/winged-helix family of DNA-binding transcriptional regulators. In humans, the gene is located on the X chromosome at Xp11.23-Xq13.3, near the WAS gene, which is responsible for Wiskott–Aldrich syndrome. The identification of heritable mutations in the FOXP3 gene as the cause of IPEX and Scurfy provided the clearest demonstration to date, that defects in a single gene could consistently disrupt immune homeostasis and lead to severe autoimmunity. They also suggested that the FOXP3 gene was involved in the dominant regulation of immune responses to self-antigens.
The immune system requires a set of 'self-check' control mechanisms that establish a homeostatic balance between the need to generate protective immune responses to various foreign antigens, tolerate self-antigens and suppress the consequences of immune-mediated pathology. IPEX is the result of defective development of a naturally arising CD4 T cell lineage called regulatory T (Treg) cells whose function serves to maintain self-tolerance. Treg cells develop in the thymus, and represent 1–10% of thymic and peripheral CD4 T cells. They constitutively express high levels of the interleukin 2 receptor α-chain (IL-2Rα chain or CD25) and FOXP3 protein. Treg cells are critical mediators of immune homeostasis. They determine the balance between protective immunity and tolerance, mediate peripheral tolerance to self and non-self antigens, and suppress excessive inflammation that can cause pathology. The critical functions of FOXP3 Treg cells in immune homeostasis have been amply demonstrated in several mouse models where abrogation of the development, homeostasis or function of FOXP3 Treg cells simultaneously triggers multi-organ autoimmunity, and provokes immunity to tumours, transplants, infectious and commensal microbes, and allergens.
Numerous studies now show that stable FOXP3 expression is essential for the programming of Treg cell lineage development and function. In the resting state, FOXP3 is expressed almost exclusively in CD4 Treg cells, where it functions in a cell-autonomous fashion. Consistently, Foxp3-deficient or Treg-depleted mice develop a fatal, multi-organ autoimmune syndrome that is similar to the autoimmunity observed in Scurfy mice, which express a non-functional, truncated form of the Foxp3 protein lacking the Forkhead DNA-binding domain. Adoptive transfer of CD4/CD25/Foxp3 Treg cells into affected animals readily suppresses the autoimmunity. Moreover, forced overexpression of Foxp3/FOXP3 in conventional murine and human T cells, respectively, redirects their differentiation into the Treg lineage. Of note is that other defects affecting the development and/or function of Treg cells can also break self-tolerance and provoke autoimmunity. Among these, disruption of cytokine and co-stimulatory signalling pathways that are essential for Treg cell development and peripheral homeostasis, can abrogate Treg cell function and provoke autoimmunity as well. Such is the case in CD25, IL2 or STAT5 deficiencies in humans, or in CD28 or ICOS deficiencies in mice.
Hence, Treg cells are critical mediators of self-tolerance, and their development and function heavily depend on FOXP3. However, there exists a considerable level of heterogeneity of severity among IPEX cases, likely due to the multifaceted nature of the molecular functions of FOXP3. Here, we propose a comprehensive review of the IPEX syndrome, covering both the clinical and molecular aspects of the disease, and providing an analysis of the molecular domains of FOXP3 as a platform for understanding the observed clinical heterogeneity and prognosis.
Source...