In addition to Foxp3, IL-2/IL-2R, CTLA-4, there are other molecules, such as CD40 and GITR, that control the development and function of natural Treg. Molecular alteration in their expression or function leads to the development of autoimmune diseases similar to those produced by Treg depletion [38,39].
IPEX as an Example of Human Autoimmune Disease Due to a Genetic Defect of Naturally Arising CD25+CD4+ Treg: Its Implications for Immunologic Self-Tolerance and Autoimmune Disease in Humans
CD25+CD4+ Treg found in rodents are present in humans as well and share similar immunological characteristics . Based on the fact that the development of natural Treg is in part developmentally controlled, it has been suspected that certain autoimmune diseases in humans are due to defects of CD25+CD4+ natural Treg in maintaining self-tolerance. In this regard, IPEX is so far the clearest example that abnormality in naturally arising Treg is a primary cause of human autoimmune disease and for that matter IBD and allergy. Although IPEX is a rare disease, it has important implications for the mechanism of immunologic self-tolerance as well as the etiology and the pathogenetic mechanisms of autoimmune and other immunological diseases.
First, this is the best illustration that the mechanism of dominant self-tolerance is physiologically operating in humans. Because of random inactiva-tion of the X-chromosome (lyonization) in individual Treg, some hemizygous females may have FOXP3-defective Treg and FOXP3-normal ones as a mosaic, but they are completely normal, as are female Scurfy mice, and do not show intermediate disease phenotypes . This indicates that the residual normal Treg dominantly control self-reactive T cells in such hemizygous females.
Second, human autoimmune disease can occur as a result of a solely intrinsic defect of the T-cell immune system. IPEX patients generally develop autoimmune disease within several months after birth and sometimes already at the time of birth . This indicates that autoimmune disease has started to develop in utero in some patients, indicating that autoimmune disease can be triggered without requiring participation of plausible autoimmune-causing environmental agents that might affect the target organs or tissue
Third, defects of a single gene are able to cause autoimmune diseases in multiple organs and tissues by affecting Treg-mediated dominant control of self-reactive T cells. This is illustrated by the clinical findings that IPEX patients frequently develop not only T1D and thyroiditis but also various other autoimmune diseases, including hemolytic anemia, thrombocytopenic purpura, and arthritis .
Furthermore, Foxp3 abnormality can have a more dominant effect in the pathogenesis of various autoimmune diseases than other polymorphic genes known to influence the genetic susceptibility to autoimmune disease. For example, T1D develops in more than 80% of IPEX patients, including even those bearing diabetes-protective HLA haplotypes .
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