This is a research project to study the receptor editing mechanism of immune tolerance. The receptor editing hypothesis proposed that immature, self-reactive B-cells could be controlled by a mechanism, distance from clonal secretion, in which reactive cells are induced to undergo secondary light chain gene rearrangements, which often alters the cells' specificity and rescues them from elimination. In the prior funding period the basic validity of the model was established, albeit in highly contrived experimental models, but many questions remain. How does light chain allelic exclusion occur in the absence of self-antigen and how does autoantigen overcome or reverse this process? To what extent does receptor editing normally occur to immature B-cells? To what extend does receptor editing occur in the peripheral immune system, particularly among cells that are involved in the germinal center reaction. In this proposal, we examine a number of ramifications of the receptor editing model through the following Specific Aims: 1) To determine the scope of receptor edition in normal, lambda+ B-cells by testing the prediction that """"""""edited"""""""" VkappaJkappa exons retained by these cells encoded autoreative receptors. 2) To determine the factors regulating light chain allelic exclusion and receptor editing in vitro. 3) To determine the extent to which receptor editing occurs in peripheral B-cells. The long term goal of this project is to understand the molecular detains and the physiological roles of receptor editing.
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