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Interactions between HIV and STIs at a genital tract level
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Abstracts / Journal of Reproductive Immunology 71 (2006) 135–176
damage, cellular immunity and delayed-type hypersensitivity. Classical activation is detrimental for pregnancy, as IFN␥ primes decidua macrophages for NOproduction in response to LPS, inducing early embryo loss in the mouse. However, the pattern of reeactivity of macrophages to various stimuli includes very different responses. IL-4 inhibits macrophages to express proinflammatory cytokines, but this is not mere deactivation as the macrophage mannose receptor (CD206) and MHC II is increased and endocytosis is enhanced, leading to the concept of alternative activation. The stimulating agents, IL4 and IL13, act via a partially identical receptor, eventually leading to suppression of Th1-mediated immune response (via IL-10), stimulation of Th2 and Tc2 responses, humoral immunity, allergic and antiparasitic reactions. The molecular repertoire of alternatively activated (M2) macrophages differs substantially from the classical one in terms of cytokines, chemokines and immune receptors. The terminology, however, is not uniform and so somewhat confusing: Whereas some authors restrict the term “alternative activation” to stimulation by IL-4 or IL-13, others include stimulation by IL-10 and glucocorticoids. Whereas there are some similarities, the latter agents rather lead to actual deactivation of macrophages, inducing downregulation of MHC-II, anti-inflammatory cytokines (IL-10, TGF␣) and production of PGE2 , eventually leading to immunosuppression. The phenotype of decidua macrophages is similar to M2 cells in a few respects: they express stabilin-1 and the macrophage mannose receptor. Further phenotypic and functional data need to be established in order to answer the question of the activation type of decidua macrophages. doi:10.1016/j.jri.2006.08.011 [K11] Interactions between HIV and STIs at a genital tract level R. Kaul University of Toronto and University Health Network, Canada HIV is generally transmitted from the genital secretions of an infected person, across the mucosal epithelium of their uninfected sexual partner. There is considerable evidence that sexually transmitted infections (STIs) independently increase both susceptibility to infection, and the level of HIV shedding. We have examined the impact of several STIs and their prevention on HIV transmission and subsequent host immune control.
HIV-specific cellular immune responses can be found in the blood and cervix of exposed, uninfected sex workers. These responses were transiently impaired by gonorrhea, which was strongly temporally associated with HIV acquisition. However, prevention of bacterial STIs through mass antibiotic treatment had no impact on HIV incidence. Chronic infection by Herpes simplex type 2 (HSV2) was associated with a 6-fold increase in HIV incidence, and with dramatic alterations in the genital mucosal immune milieu of both HIV-infected and uninfected women. In HIV-infected men, levels of HIV in semen correlated with local inflammation and with asymptomatic reactivation of CMV. Genital tract immune factors and the presence of common bacterial and viral co-infections have clear effects on HIV shedding, susceptibility and immune control. A greater understanding of these factors will be critical to the development of HIV vaccines, microbicides and immunotherapeutics. Acknowledgements Canadian Institutes of Health Research; Ontario HIV Treatment Network; Canada Research Chair Programme; Canadian Network for Vaccines and Immunotherapeutics (CANVAC); Rockefeller Foundation; National Institutes of Health; AIDS Research and Reference Reagent Program, NIH. doi:10.1016/j.jri.2006.08.012 [K12] Antiphospholipid antibodies and complement J.E. Salmon Cornell University, USA The antiphospholipid syndrome (APS), characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies, is a leading cause of miscarriage and maternal and fetal morbidity. Using a mouse model of APS induced by passive transfer of human aPL antibodies, we have shown that complement activation plays an essential and causative role in pregnancy loss and fetal growth restriction. Passive transfer of IgG from patients with aPL antibodies results in a 40% frequency of fetal resorption compared to <10% in mice treated with IgG from healthy individuals, and a 50% reduction in the average weight of surviving fetuses. In our initial studies, we found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor Crry-Ig, prevented fetal loss and growth restriction and that mice lacking complement C3 were resistant
Abstracts / Journal of Reproductive Immunology 71 (2006) 135–176
damage, cellular immunity and delayed-type hypersensitivity. Classical activation is detrimental for pregnancy, as IFN␥ primes decidua macrophages for NOproduction in response to LPS, inducing early embryo loss in the mouse. However, the pattern of reeactivity of macrophages to various stimuli includes very different responses. IL-4 inhibits macrophages to express proinflammatory cytokines, but this is not mere deactivation as the macrophage mannose receptor (CD206) and MHC II is increased and endocytosis is enhanced, leading to the concept of alternative activation. The stimulating agents, IL4 and IL13, act via a partially identical receptor, eventually leading to suppression of Th1-mediated immune response (via IL-10), stimulation of Th2 and Tc2 responses, humoral immunity, allergic and antiparasitic reactions. The molecular repertoire of alternatively activated (M2) macrophages differs substantially from the classical one in terms of cytokines, chemokines and immune receptors. The terminology, however, is not uniform and so somewhat confusing: Whereas some authors restrict the term “alternative activation” to stimulation by IL-4 or IL-13, others include stimulation by IL-10 and glucocorticoids. Whereas there are some similarities, the latter agents rather lead to actual deactivation of macrophages, inducing downregulation of MHC-II, anti-inflammatory cytokines (IL-10, TGF␣) and production of PGE2 , eventually leading to immunosuppression. The phenotype of decidua macrophages is similar to M2 cells in a few respects: they express stabilin-1 and the macrophage mannose receptor. Further phenotypic and functional data need to be established in order to answer the question of the activation type of decidua macrophages. doi:10.1016/j.jri.2006.08.011 [K11] Interactions between HIV and STIs at a genital tract level R. Kaul University of Toronto and University Health Network, Canada HIV is generally transmitted from the genital secretions of an infected person, across the mucosal epithelium of their uninfected sexual partner. There is considerable evidence that sexually transmitted infections (STIs) independently increase both susceptibility to infection, and the level of HIV shedding. We have examined the impact of several STIs and their prevention on HIV transmission and subsequent host immune control.
HIV-specific cellular immune responses can be found in the blood and cervix of exposed, uninfected sex workers. These responses were transiently impaired by gonorrhea, which was strongly temporally associated with HIV acquisition. However, prevention of bacterial STIs through mass antibiotic treatment had no impact on HIV incidence. Chronic infection by Herpes simplex type 2 (HSV2) was associated with a 6-fold increase in HIV incidence, and with dramatic alterations in the genital mucosal immune milieu of both HIV-infected and uninfected women. In HIV-infected men, levels of HIV in semen correlated with local inflammation and with asymptomatic reactivation of CMV. Genital tract immune factors and the presence of common bacterial and viral co-infections have clear effects on HIV shedding, susceptibility and immune control. A greater understanding of these factors will be critical to the development of HIV vaccines, microbicides and immunotherapeutics. Acknowledgements Canadian Institutes of Health Research; Ontario HIV Treatment Network; Canada Research Chair Programme; Canadian Network for Vaccines and Immunotherapeutics (CANVAC); Rockefeller Foundation; National Institutes of Health; AIDS Research and Reference Reagent Program, NIH. doi:10.1016/j.jri.2006.08.012 [K12] Antiphospholipid antibodies and complement J.E. Salmon Cornell University, USA The antiphospholipid syndrome (APS), characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies, is a leading cause of miscarriage and maternal and fetal morbidity. Using a mouse model of APS induced by passive transfer of human aPL antibodies, we have shown that complement activation plays an essential and causative role in pregnancy loss and fetal growth restriction. Passive transfer of IgG from patients with aPL antibodies results in a 40% frequency of fetal resorption compared to <10% in mice treated with IgG from healthy individuals, and a 50% reduction in the average weight of surviving fetuses. In our initial studies, we found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor Crry-Ig, prevented fetal loss and growth restriction and that mice lacking complement C3 were resistant