Natural mutations in the Fas and Fas ligand genes have provided insight into the role of these molecules in the immune system. As noted earlier, the autosomal recessive genes lpr (lymphoproliferation) and gld (generalized lymphoproliferative disease) are spontaneously derived mutations in mice that result in the development of progressive lymphadenopathy and splenomegaly. Mice homozygous for the lpr gene express very little Fas due to a mutation that interferes with expression of the full-length Fas protein. The phenotype of gld/gld mice results from a point mutation in the FasL gene that alters the ability of the translated protein to bind to its cognate receptor. Fas. Both mutant mouse strains have a phenotype characterized by hypergammaglobulinemia, autoantibody production, glomerulonephritis, arthritis and vasculitis. Significantly, a functional human equivalent of the lpr/lpr mouse exists. Children with autoimmune lymphoproliferative syndrome (ALPS) have a phenotype that is very similar to the lpr/lpr mouse, including a profound lymphadenopathy characterized by the expansion of CD3+CD4~CD8~ lymphocytes and hypergammaglobulinemia. This syndrome is the result of mutations in the Fas gene that result in premature truncations of Fas translation in a dominant interfering manner and a subsequent defect in Fas-mediated T cell apoptosis.
Just as deficiency in the Fas/FasL apoptotic pathway leads to lymphoproliferation (or more correctly lymphoaccumulation) and autoimmune disease, overexpression of this pathway can result in the unwanted elimination of cells. The finding that the loss of CD4+ T cells in individuals infected with HIV is due to inappropriate apoptosis has prompted many studies on the potential role of Fas in this process. Not only has Fas been shown to be upregulated in T cells from HIV patients but these T cells also show increased susceptibility to Fas-mediated apoptosis. Cross-linking of CD4 on T cells by immune complexes comprised of HIV gpl20 and gpl20-specific antibodies results in susceptibility to Fas-mediated cell death. Moreover, infection of macrophages with HIV or cross-linking of CD4 on macrophages induces expression of FasL and these cells can then induce apoptosis of activated T cells that have increased expression of Fas and become susceptible to Fas-mediated apoptosis. Thus, HIV-infected macrophages may be the prime mediators of apoptosis of bystander T cells in HIV+ patients progressing toward AIDS. Fas may also be involved in the progressive loss of CD4+ T cells in patients with idiopathic CD4+ T lymphocytopenia (ICL). T cells from these patients not only express elevated levels of Fas, but also constitutively express FasL (whereas T cells from normal donors do not) and have an increased rate of spontaneous T cell apoptosis in vitro.
A role for dysregulation of the Fas/FasL pathway has also been suggested in the progression of both hepatitis and Hashimoto's thyroiditis (HT). Although the role of Fas/FasL in these diseases differs mechanistically, together they illustrate how critical regulation of this apoptotic pathway is to prevent tissue pathology. Although FasL is constitutively expressed by thyrocytes, under normal conditions Fas is not. In HT, however, the data suggest that IL-1 upregulates expression of Fas and increases susceptibility to Fas-mediated apoptosis in thyrocytes. The coexpression of Fas and FasL in HT results in apoptotic loss of thyrocytes. On the other hand, hepatocytes constitutively express Fas and therefore infectious agents such as hepatitis B virus and Pro-pionobacterium acnes that induce infiltration of FasL-expressing T cells into the liver can induce apoptosis of hepatocytes. Hepatitis in animal models can be blocked by a soluble form of Fas and thus inhibitors of Fas may have potential in the treatment of diseases where Fas-mediated apoptosis results in disease progression.
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