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During HIV infection, CD4 T cells in lymphoid tissues initiate a highly inflammatory form of cell death that helps cripple the immune system. The activation of a helper T cell and its roles in immunity Phagocytic cell (yellow) engulfing a foreign cell Self-nonself complex Macrophage Microbe B cell T cell receptor Interleukin-2 stimulates cell division 5 3 1 2 Helper T cell 4 6 7 Interleukin-2 activates B cells and other T cells Self protein Antigen from the microbe (nonself molecule) Antigen-presenting cell Binding site for the self protein Interleukin-1 stimulates the helper T cell Binding site for the antigen Humoral immune response (secretion of antibodies by plasma cells) Cytotoxic T cell Cell-mediated immune response (attack on infected cells) How HIV Destroys Immune Cells? For years we’ve just said ‘HIV infects the cells and kills them,’ but it’s clearly more complicated than that. Productively infected by HIV, meaning that the virus has integrated with hostcell genome and can make copies of itself (death occurs through apoptosis mediated by an enzyme called caspase-3). In a 2010 study, Greene and his colleagues showed that 95 percent of CD4 T cells in lymphoid tissue, by contrast, are bystander cells that are “abortively infected”--- the virus penetrates but can’t integrate or replicate (death occurs by pyroptosis, which depends on the activation of caspase-1). Proinflammatory signals released by pyroptosis attract more cells into the infected tissue to die and, in turn, produce more inflammation. 細胞焦亡 細胞凋亡 Pyroptosis is a form of programmed cell death associated with antimicrobial responses during inflammation. In contrast to apoptosis, pyroptosis requires the function of caspase-1. IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV Interferon-gamma–inducible protein 16 (IFI16) Pyroptosis in HIV-infected lymphoid tissues may establish a chronic cycle of CD4 T-cell death and inflammation, which attracts new CD4 T cells and ultimately contributes to disease progression and tissue damage. Inhibitors of caspase 1 such as VX-765 may inhibit pyroptosis in a manner that both preserves CD4 T cells and reduces inflammation. Pyroptosis---a highly inflammatory form of cell death that lures more CD4 T cells to the area, thereby creating a vicious cycle that ultimately wreaks havoc on the immune system. IFI16, which is known to be part of the protein complex that initiates inflammatory immune responses. An existing caspase-1 inhibitor---a drug already shown to be safe in humans;;uppressed CD4 T-cell death and inflammation in cell culture. A technique called DNA affinity chromatography to identify proteins in the CD4 T cells that detect fragments of HIV DNA and alert the enzyme caspase-1. Caspase-1 inhibitors might—and I emphasize might—become a component of a curative cocktail.”