SIGA/SIGA/SIGAR MUCOSAL DEFENSE SYS

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DESCRIPTION (Adapted from the applicant's abstract) IgA is found in mucosal secretions in two different forms, monomeric IgA (mIgA) and dimeric secretory IgA (sIgA). Both forms of IgA have traditionally been felt to play a passive role in mucosal defense, blocking adherence and neutralizing toxins. The presence of a receptor for the Fc portion of mIgA (FcamR) on mucosal phagocytes suggest a more active role. It has been assumed that sIgA shared the same Fc receptor as mIgA but this has not been directly demonstrated. The presence of additional chains in sIgA's structure (J chain and secretary component) possibly prevent binding of its Fc domains to traditional Fc receptors. This suggested to us that sIgA may utilize a different phagocytic receptor. The applicant has partially characterized a 6OkD protein from the cell surface of PMN which binds sIgA but not other immunoglobulin isotypes. The applicant proposes that this protein is a unique receptor for sIgA and has termed it sIgAR. The applicant hypothesized that different forms of IgA -have important effects in phagocytic defense of the mucosa which are mediated through these two different receptors, Fca-R and sIgAR. The applicant will investigate the hypotheses through four specific aims. 1). He will characterized and clone the sIgAR. Initially, he will determine if the sIgAR is GPI-linked, glycosylated or associated with other surface proteins. This will assist him in determining the approximate size of the CDNA. A probe will then be constructed from a partial protein sequence which will be used to screen an HL-60 CDNA library. The CDNA will be cloned and sequenced. 2). The expression of the sIgAR on PMN, monocytes, macrophages and eosinophils will be determined. He will also determine how expression is modulated on these blood cells as they move to the mucosa. 3). He will characterize the affinity and cation requirements of the binding of sIgA to sIgAR, and will determine which segments of the protein mediate binding and how the receptor signals. 4). He will determine the interaction of sIgA with PMN, monocytes, macrophages and eosinophils in phagocytosis, superoxide generation and killing assays. Completion of these studies should suggest better ways to prevent and/or intervene in infectious-inflammatory processes in the lung and at other mucosal sites.