The MHC encodes molecules that initiate immune responses by presenting antigen in the form of peptides to T lymphocytes. Polymorphic MHC-encoded class I molecules (class Ia) have been extensively characterized. However, the mono- or oligomorphic MHC class lb proteins are not well understood. In mammals, one class Ib protein has been selected for presentation of bacterial antigens and another is an Fc receptor that transports IgG from mothers milk across intestinal epithelium. In addition, class Ib molecules may be involved in presentation of peptides from conserved regions of pathogens (or self cells) to provide a """"""""first line of defense"""""""" across epithelial surfaces. Therefore, class lb molecules, formerly reviled as evolutionary waste, are likely to be physiologically significant and appear to serve: 1) as """"""""back-ups"""""""" to class Ia in protection against intracellular pathogens; 2) ~s defense molecules tailored to restrict particular antigens; and 3) non-presenting functions only beginning to be appreciated. We identified a cluster of non-MHC linked class Ib genes in the amphibian Xenopus, at least nine of which are expressed at the RNA level. These genes encode isotypes that are very divergent in the putative peptide-binding and cytoplasmic regions, but conserved in the structural immunoglobulin-like domain. Examination of these genes in an animal that last shared an ancestor with man over 300 million years ago will allow a determination of those class Ib functions essential to a functioning immune system, and will further reveal how plastic class I genes can be in the course of evolution. In addition, the Xenopus system permits an examination of immune responses in an organism with two very different lives (tadpole and adult). MHC gene expression, including class lb production, changes markedly at metamorphosis providing """"""""two models in one"""""""" to analyze MHC function.
The specific aims are: 1) to determine tissue distribution and ontogenic expression of all different class lb isotypes; 2) to prepare class lb- specific antibodies to examine their biochemical structures and cellular distribution; 3) to examine the selection pressures on class Ib genes by studying their polymorphism (whether polymorphism extends to the peptide binding site), their silencing over evolutionary time, and peptides that bind in clefts of particular isotypes; and 4) to determine what governs expression of class lb genes, concentrating on biosynthesis of the proteins under various conditions and on the coexpression of molecules important in class I antigen processing. Our major goals are to employ the Xenopus system as a simple model to reveal functions of some class Ib genes, and to perhaps address when the evolutionary split occurred between the adaptive and non-adaptive immune systems.
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