ALLOTYPE LINKED RESISTANCE TO HERPES STROMAL KERATITIS

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DESCRIPTION (Adapted from Investigator's abstract): Polymorphisms of genes which influence resistance to autoimmune disease have generally been thought to act through their protein products rather than peptides derived from them. The investigator's recent studies show that genetic polymorphisms can also act by changing the structure of self-peptides which tolerize T-cells. The investigators have found that Ig-linked resistance to HSK is mediated through an IgG2ab-derived antigenic peptide rather than the intact Ig molecule. Moreover, resistance to HSK associated with genetic expression of the Ighb allotype can also be conferred by exposure to soluble IgG2ab-derived peptides in adult life. To define the cellular events leading to self-tolerance or viral-induced autoimmunity, the investigators will generate mice carrying a transgenic TCR displayed by the pathogenic murine CD4 clones that they have characterized. These animals, along with appropriate serologic reagents, will be used to provide insight into intrathymic selection and peripheral reactivity of potentially keratogenic T-cell clones in susceptible and resistant strains and to determine mechanisms involving deletion and/or anergy responsible for self-tolerance. In addition, they will fully evaluate the role of HSV-1 in the induction of autoimmune disease, with particular attention to the possibility that HSV-1 may mimic a corneal autoantigen. Finally, they will further clarify the structural basis of this response by defining more precisely the peptides derived from IgG2ab which regulate HSK. Information on the effects of Ig-derived peptides on thymocyte development in TCR transgenic mice should help delineate the mechanisms by which endogenous gene products can influence both thymocyte selection as well as susceptibility to an autoimmune disorder.