PULMONARY HUMORAL IMMUNE RESPONSES IN HIV INFECTION

而感染人类免疫缺陷病毒(HIV)是 通常与细胞介导的免疫反应受损有关， 体液免疫或B细胞免疫紊乱也很常见，但 研究较少。体液免疫受损尤为重要 在肺里。细菌性肺炎的发病率，通常得到控制 通过体液免疫，是增加了HIV感染患者。初步 数据显示，受感染的BAL中调理免疫球蛋白水平很低 患者和很少有证据表明局部产生了免疫球蛋白。这一代人 的肺免疫反应可以看作是一个多步骤的过程。 涉及辅助细胞对抗原的摄取并将其运送到区域 发生主要免疫反应的淋巴组织，抗原 向T细胞提呈导致产生“效应器”T细胞 能够为B细胞提供帮助，激活和分化B细胞 T细胞刺激的细胞产生免疫球蛋白， B细胞转运回肺至初始部位 感染，最后在肺泡内扩大免疫反应 环境。在HIV感染中，缺陷可能发生在以下任一步骤 导致产生局部调理抗体的能力受损。 在本提案中，我们将探讨 用HIV感染者的细胞产生体液反应 以及体外感染艾滋病毒的细胞。在本提案中，我们将 (1)测定肺泡巨噬细胞、肺巨噬细胞、 单核细胞、肺树突状细胞和B细胞诱导抗体 如果辅助细胞的HIV感染改变了这种能力， (2)测定正常人和HIV感染者的抗原活化能力 T细胞通过测量T细胞激活标志物来提供B细胞帮助， 细胞因子的分泌和寿命，(3)决定B细胞的能力 通过对正常和HIV感染的抗原激活的T细胞的反应 检测T细胞-B细胞结合物形成，B细胞增殖， 活化标志物的表达、免疫球蛋白分泌和 B细胞过早死亡，(4)确定激活的免疫球蛋白 分泌B细胞表达受体，这将使它们能够运输 回肺，(5)测定抗体特异性B的能力 肺泡内细胞增殖和分泌免疫球蛋白 环境。理解体液损伤背后的机制 HIV感染者肺部的免疫力将起到作用 对我们对肺部发病率的理解有很大的帮助 并对基于免疫的新疗法提出建议 战略。

While infection with the human immunodeficiency virus (HIV) is classically associated with impaired cell mediated immune responses, perturbations in humoral, or B cell, immunity is also common but much less studied. Impairment of humoral immunity is especially important in the lung. The incidence of bacterial pneumonia, typically controlled by humoral immunity, is increased in HIV-infected patients. Preliminary data demonstrates very low levels of opsonizing IgG in BAL of infected patients and little evidence of local production of IgG. The generation of pulmonary immune responses can be viewed as a multi step process involving antigen uptake by accessory cells and transport to regional lymphoid tissue where the primary immune response occurs, antigen presentation to T cells leading to generation of "effector" T cells capable of providing B cell help, activation and differentiation of B cells stimulated by T cells resulting in immunoglobulin production, trafficking of B cells back to the lung to the site of initial infection, and finally expansion of the immune response in the alveolar environment. In HIV infection defects can occur at any of these steps leading to an impaired ability to generate local opsonizing antibody. In this proposal we will explore each of the steps involved in the generation of a humoral response using cells from HIV infected subjects as well as cells infected in vitro with HIV. In this proposal we will (1) determine the ability of alveolar macrophages, lung macrophages, monocytes, lung dendritic cells, and B cells to induce an antibody response and if HIV infection of accessory cells alters this ability, (2) determine the ability of normal and HIV-infected antigen-activated T cells to provide B cell help by measuring T cell activation markers, cytokine secretion, and longevity, (3) determine the ability of B cells to respond to normal and HIV-infected antigen-activated T cells by measuring T cell-B cell conjugate formation, B cell proliferation, expression of activation markers, immunoglobulin secretion, and premature B cell death, (4) determine if activated immunoglobulin secreting B cells express receptors which will allow them to traffic back to the lung, and (5) determine the ability of antibody specific B cells to proliferate and secrete immunoglobulin in an alveolar environment. Understanding mechanisms behind the impairment in humoral immunity in the lungs of HIV-infected individuals will contribute substantially to our understanding of pulmonary morbidity in this disease and offer suggestions on novel immune based therapeutic strategies.