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.
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| Wilkes, D S; Twigg 3rd, H L (2001) B-lymphocytes in the lung: a topic to be revisited. Sarcoidosis Vasc Diffuse Lung Dis 18:34-49 |
