The steady-state intracellular levels of independently-encoded gene products which interact post-translationally to form multichain proteins is usually controlled in a coordinated fashion. Coordinate regulation for the normal expression of various membrane-associated and secreted molecules based on their chain pairing ability is frequently observed among immunologically- relevant proteins; the expression of class I and II histocompatibility antigens, lymphocyte function antigens (LFAs), T cell receptor chains and immunoglobulin (Ig) heavy and light chains are examples. This proposal's initial goals are to investigate two novel situations in B lymphocyte development where post-transcriptional events regulating Ig heavy and light chain expression ultimately determines the molecular phenotype of the B cell. Specifically, the first study deals with the basis for the down-regulation of L chain expression observed in a set of human B cells which synthesize an aberrant form of heavy chain and express only mu chains on the cell surface; this study will aid in our understanding of Ig biosynthesis, assembly and transport and also of how a significant subset of the normal B lymphocyte repertoire in humans is generated. The second project is involved with the biochemistry and physiology of immunoglobulin D mu protein in human B cell lines: its structure, its interaction with other Ig molecules, and how coordinate regulation of D mu protein with heavy and/or light chains determines in which forms of assembled Ig that D mu protein can be potentially expressed. Related with these two aims is a longer-term goal of this proposal toward initiating a study into the role of coordinated Ig expression in the regulation of Ig light chain gene rearrangement. The generation of monoclonal mouse pre-B cell models to be employed in this project will rely heavily on using gene transfer technology in conjunction with host cell lines which can be induced in vitro to undergo productive rearrangement events in their endogenous kappa light chain genes. This application's protracted objective is to contribute towards a molecular explanation of how the mammalian B lymphocyte repertoire develops and is expressed, a research question with direct relevance to any pathologic condition involving immune regulation defects.
| Caldwell, J; McElhone, P; Brokaw, J et al. (1991) Co-expression of full-length and truncated Ig mu-chains in human B lymphocytes results from alternative splicing of a single primary RNA transcript. J Immunol 146:4344-51 |
