Both control IgG from patients unreactive to the CEM lysate failed to induce any increase in the apoptotic cell population, whereas as expected, the CH11 and the rFas-L control reagents drove >90% of cells to die (Fig
Both control IgG from patients unreactive to the CEM lysate failed to induce any increase in the apoptotic cell population, whereas as expected, the CH11 and the rFas-L control reagents drove >90% of cells to die (Fig. NSC-23766 HCl that antibodies binding that domain NSC-23766 HCl name within the V3 region are effective cross-linkers of Fas and increase apoptosis in peripheral T cells. These results suggest that autologous activation of the Fas pathway, rather than of lymphocytotoxic antibodies, may aggravate lymphopenia in a number of HIV-1+ subjects. Activation-induced apoptosis of antigen-primed CD4+ and CD8+ T lymphocytes has been well documented in peripheral cell cultures from HIV-1+ patients, and has been postulated as a mechanism that is primarily involved in the immunopathogenesis of AIDS (1C4). Chronic immune activation of those cells is indeed thought to significantly enhance their susceptibility to apoptosis NSC-23766 HCl (5C7), whereas the subsequent antigenic stimuli may drive the death program to completion (8, 9). Apoptosis is usually a signal-dependent suicidal process that is regulated in part by Fas or Apo1/CD95 (10C13), namely a 45-kD membrane receptor that transduces the death transmission to its intracellular pathway after ligation with a natural ligand (Fas-L)1 active in trimeric form (14). Fas-mediated apoptosis makes a physiological contribution within the immune system in suppression of autoreactive T cell clones in the thymus (15), as well as in the regulation of its normal response (16) and cytotoxicity (17). Moreover, the mutated expression of genes encoding either Fas or Fas-L may afford resistance to apoptosis in mature T cells from (18) or (19) mice, respectively. Both phenotype strains suffer from a lymphoproliferative disorder that leads to autoimmune syndromes (20) that are highly much like SLE. In this disorder, the abnormal expression of soluble Fas (21) is usually associated with an increased rate of apoptosis in peripheral lymphocytes (22), suggesting the involvement of Fas deregulation in driving the SLE autoreactivity. Further evidence of the role of apoptosis in human autoimmunity has been provided by the demonstration that synovial cells from patients with rheumatoid arthritis are highly subject to death by Fas overexpression (23). Autoimmunity (24C26) and Fas overexpression (27, 28) have also been described during the HIV-1 contamination, even though no linkage between these conditions has been documented so far. We have recently reported that this abnormal overexpression of Fas by T cells in advanced HIV-1 contamination correlates with the high responsiveness of the receptor to its extracellular binding, even when using a monomeric ligand, as provided by mouse IgG1 mAb from your UB-2 clone (29). This obtaining emphasizes the hypothesis that Fas is usually somehow involved in the increased in vitro apoptosis of peripheral cells from HIV-1Cinfected individuals, and that the Fas pathway may play a pathogenic role by aggravating the T cell lymphopenia that is related to the progression of their disease. Aggravation has also been associated to autoimmune phenomena (30C32), and we have illustrated the lymphopenic effect of T cellCreactive autoantibodies in a considerable number of patients, since their serum levels apparently parallel the progression of CD4+ lymphocyte decline (33, 34). As a result of their ability to react with a 43.5-kD marker located on CD4+ clonotypic lymphoblasts of the CEM line, these molecules were found to be powerful inducers of cytolysis in complement-mediated cytotoxicity, when either peripheral T lymphocytes or CEM were used as the cell target (35). NSC-23766 HCl In the present study, we provide evidence that in most patients with variable serum titers of T cell binding antibodies, the molecular target of these reactivities may include Fas. Therefore, activation of the Fas pathway by autoantibodies is at least partly responsible for the increased apoptosis that contributes to T cell depletion because of the receptor’s high sensitivity. Since antibodies to Fas are also reactive to a specific epitope shared by the gp120 V3 loop of HIV-1, however, it is conceivable that antibodies primarily elicited to neutralize the computer virus may cross-react with Fas and activate Ecscr its function through molecular mimicry. The increment of apoptosis by autologous Fas activation rather than lymphocytotoxic antibodies may therefore account for the aggravation of lymphopenia in patients whose HIV1Cneutralizing IgG may include specificity to the viral domain name shared by Fas. Materials and Methods Study Subjects. Peripheral blood samples were obtained from 74 HIV-1+ individuals.
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