In this proposal, a definition of the basis of the dominance-crypticity relationship is attempted as well as a testing of some of its major implications. The fact that each self-molecule has a majority of determinants which are cryptic and rarely exposed to the immune system indicates that there is a corresponding T cell population available for self-reactivity and autoimmunity. The objectives of the proposed experiments are to examine the several implications of the proposition that there is an extensive cryptic self, comprised of determinants that can eventually become engaged if there is upregulation of MHC display and more effective antigen processing. The following experimental systems will be employed to address the listed questions: (I) what is the relationship between self-tolerance and determinant display? Is it true that the organism is tolerant to well-presented determinants and responsiVe to poorly presented ones. Tissues from lysozyme transgenic mice will be studied, as well as antigen presenting lines whose activity can be compared when using exogenous and endogenous sources of antigen. (II) How important is determinant capture in protection from autoimmune disease? In the NOD diabetes model, animals are protected from disease when they are made transgenic for certain extra MHC molecules. We will approach the problem of whether these extrinsic MHG molecules provide highly competitive and dominant binding sites for determinants up- or downstream from the diabetogenic determinant, preventing binding of the latter to the NOD MHC molecule, A(nod). (III) Is the response of a foreign antigen related to a self-antigen dependent on its degree of """"""""foreignness"""""""" or is it dependent on the relative dominance/crypticity of determinants on the two molecules? This issue is very important in considering the initiation of autoimmune disease, and it will be explored fully in the mouse lysozyme system, focusing on the nature of the T cell repertoire raised to the self lysozyme vs. that raised to foreign lysozymes. (IV) How does the immune system regulate the aggressive T cell response to some self-determinants? We will examine the disease experimental allergic encephalomyelitis, and a regulatory circuit based on a dominant idiotypic determinant on T cell receptors from a disease causing T cell clone. This receptor based regulation is very potent and we will characterize the four cells comprising this circuit, with special focus on the CD8+ suppressive regulator and the APC which presents the TcR peptide to the regulatory cells.
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