Description): The goal of these studies is to define human homologues of two new members of the immunoglobulin gene superfamily that the investigators have recently identified in mice and to examine their expression during human development. Coordinately expressed by B-lymphocytes, monocytes/macrophages, granulocytes, and mast cells, the mouse genes are named PIR for paired immunoglobulin-like receptor genes. The two PIR protein isoforms, PIR-A and PIR-B, have very similar extracellular domains but quite different transmembrane and cytoplasmic regions. The distinguishing features of PIR-A and PIR-B suggest that they are activating and inhibitory (braking) receptors, respectively. PIR-B is invariant and encoded by a single copy gene, while the PIR-A proteins exhibit remarkable variability in their extracellular domains. Seven randomly selected PIR-A cDNAs were non-identical and there are multiple PIR-A genes in the mouse genome. The PIR gene family is highly conserved, having been found in mammals, birds, and reptiles. The characteristics of PIR-A and PIR-B and their coordinate expressions in a restricted subset of host defense cells lead to the hypothesis that they play an important regulatory role in humoral, inflammatory and allergic reactions. The known features of PIR-A and PIR-B raise the possibility that they provide recognition elements that could be of special importance in host defense of the fetus and neonate before the adult-type cognate immune system is fully developed. The investigators propose to: 1) Clone and sequence the human homologues to murine PIR-A and PIR-B to determine the extent of the PIR diversity. 2) Produce the corresponding recombinant proteins and use these proteins to produce discriminating monoclonal antibodies and antisera. 3) Define the biochemical features of the human PIR-A and PIR-B homologues and identify associated molecules. 4) Employ the antibody and DNA probes to examine the ontogeny and cellular distribution pattern of the human PIR-A and PIR-B homologues. These studies will permit identification of normal developmental or acquired defects in the expression of this complex gene family and provide a base of information that will lead to clarification of the role of PIR in host defense during the perinatal and adult periods.
