PULMONARY HUMORAL IMMUNE RESPONSES IN HIV INFECTION

虽然感染人类免疫缺陷病毒（艾滋病毒）是 典型地与受损的细胞介导的免疫应答相关， 体液或B细胞免疫的扰动也很常见，但 研究较少。 体液免疫功能受损尤为重要 在肺部。 细菌性肺炎的发病率，通常控制 通过体液免疫，在HIV感染患者中增加。初步 数据表明，在感染者的BAL中调理IgG水平非常低， 病人和很少的证据表明，当地生产的IgG。 生成 肺免疫反应的发生是一个多步骤的过程 涉及辅助细胞对抗原的摄取和转运到局部 发生初次免疫反应的淋巴组织，抗原 呈递给T细胞，导致产生“效应”T细胞 能够提供B细胞帮助、B的活化和分化 T细胞刺激细胞产生免疫球蛋白， 将B细胞运输回肺，到达最初的 感染，并最终扩大肺泡中的免疫应答 环境 在艾滋病毒感染中，缺陷可能发生在这些步骤中的任何一个 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 使用来自HIV感染受试者的细胞产生体液应答 以及体外感染HIV的细胞。 在本提案中，我们将 (1)确定肺泡巨噬细胞，肺巨噬细胞， 单核细胞、肺树突细胞和B细胞以诱导抗体 如果辅助细胞的HIV感染改变了这种能力， (2)确定正常和HIV感染者抗原激活的能力 T细胞通过测量T细胞活化标志物来提供B细胞帮助， 细胞因子分泌和寿命，（3）决定B细胞的能力 对正常和HIV感染的抗原激活的T细胞作出反应， 测量T细胞-B细胞缀合物形成，B细胞增殖， 活化标志物的表达，免疫球蛋白分泌，和 过早的B细胞死亡，（4）确定是否激活免疫球蛋白 分泌型B细胞表达受体， （5）测定抗体特异性B的能力 细胞增殖并分泌免疫球蛋白 环境 理解体液免疫功能受损背后的机制 艾滋病毒感染者肺部的免疫力将有助于 这与我们对肺发病率的理解有很大关系。 疾病，并提供新的免疫为基础的治疗建议 战略布局

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.