This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our hypothesis is that the susceptibility for the development of airway hyperresponsiveness and asthma is to a large extent due to an abnormal regulation of immunity by complement. This abnormality resides in one or more of the following sequential stages of complement regulation: complement activation, generation of complement fragments (from C3 and C5), interaction of these fragments with their corresponding receptors on monocytes/macrophages, and production of IL-12 by these cells. Ultimately the dysfunction of this complement sequence results in a reduced amount of IL-12 produced, which is insufficient for the development or maintenance of an appropriate Th1 response. As a result there is an abnormally strong Th2 response and a predisposition to asthma. It is currently thought that studies in humans and mice indicate that complement may play an important part in the pathogenesis of asthma through the participation of fragments from C3 and C5 inregulation of cellular immunity. However, the specific data available from previous human studies is still insufficient to warrant a future specific analysis of this role of complement in susceptibility to asthma (through genetic studies of human populations). The strategy of this study is to investigate whether patients with asthma, in comparison to normal controls, exhibit phenotypic differences in 1) degress of complement activation when their complement is exposed to different substances that specifically initiate each of the various complement activation pathways; 2) the monocyte/macrophage response to C3 and C5 complement fragments with regard to regulation of IL-12 production. Specifically, the goal of this proposal is to establish whether asthmatics have abnormalities in the production of or response to complement fragments that would result in increased suppression of IL-12 production. We will define differences between patients with asthma and normal controls by investigating 1) the functional capacity of the complement system to general C3a, C3bi, and C5a, and 2) the role of complement fragments C3bi and C5a in the regulation of IL-12 production by stimulated monocytes. The role of the GCRC in thi study will be to draw blood from a vein in the subject's arm on two separate occasions. GCRC nurses will be asked to draw an additional unit of blood form the subject's arm on a second occasion 40-6 months after the original study visit. This unit of blood will be used to repeat the experiment for IL-12 inhibition.
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