Identification of a novel nonsense mutation in theFOXP3gene in a fetus with hydrops-Expanding the phenotype of IPEX syndrome

Immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX, OMIM 304790) is a rare, recessive disorder resulting in aggressive autoimmunity and early death. Mutations in FOXP3 have been identified in 13 of 14 patients tested. Research in the mouse model, scurfy, suggests that autoimmunity may stem from a lack of working regulatory T cells. We review published reports regarding the genetics, clinical features, immunology, pathology, and treatment of IPEX. We also report three new patients who were treated with long term immunosuppression, followed by bone marrow transplantation in two. IPEX can be differentiated from other genetic immune disorders by its genetics, clinical presentation, characteristic pattern of pathology, and, except for high IgE, absence of substantial laboratory evidence of immunodeficiency. While chronic treatment with immunosuppressive drugs may provide temporary benefit for some patients, it does not cause complete remission. Remission has been observed with bone marrow transplantation despite incomplete engraftment, but the long term outcome is uncertain.

Establishment and maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens and tolerate paternal alloantigens expressed in fetal tissues. Regulatory T (Treg) cells, a subset of suppressor CD4(+) T cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. Although localized mechanisms contribute to fetal evasion from immune attack, in the last few years it has been observed that Treg cells are essential in promoting fetal survival avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system. Several functional studies have shown that unexplained infertility, miscarriage and pre-clampsia are often associated with deficit in Treg cell number and function while normal pregnancy selectively stimulates the accumulation of maternal forkhead-box-P3(+) (FoxP3(+)) CD4(+) Treg cells with fetal specificity. Some papers have been reported that the number of Treg cells persists at elevated levels long after delivery developing an immune regulatory memory against father's antigens, moreover these memory Treg cells rapidly proliferate during subsequent pregnancies, however, on the other hand, there are several evidence suggesting a clear decline of Treg cells number after delivery. Different factors such as cytokines, adipokines, pregnancy hormones and seminal fluid have immunoregulatory activity and influence the success of pregnancy by increasing Treg cell number and activity. The development of strategies capable of modulating immune responses toward fetal antigens through Treg cell manipulation, could have an impact on the induction of tolerance against fetal antigens during immune-mediated recurrent abortion.

We have recently identified and cloned Foxp3, the gene defective in mice with the scurfy mutation. The immune dysregulation documented in these mice and in humans with mutations in the orthologous gene indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or X-linked autoimmunity-allergic dysregulation syndrome also points to a critical role for scurfin in the regulation of T cell homeostasis. FOXP3 encodes a novel member of the forkhead family of transcription factors. Here we demonstrate that this structural domain is required for nuclear localization and DNA binding. Scurfin, transiently expressed in heterologous cells, represses transcription of a reporter containing a multimeric forkhead binding site. Upon overexpression in CD4 T cells, scurfin attenuates activation-induced cytokine production and proliferation. We have identified FKH binding sequences adjacent to critical NFAT regulatory sites in the promoters of several cytokine genes whose expression is sensitive to changes in SFN abundance. Our findings indicate that the ability of scurfin to bind DNA, and presumably repress transcription, plays a paramount role in determining the amplitude of the response of CD4 T cells to activation.