Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of lacrimal and salivary glands. These patients have markedly increased frequency of lymphadenopathy, circulating paraproteins, and risk of developing non-Hodgkin's lymphoma. Rheumatoid factor (anti-IgG) in the sera of SS patients contains a cross reactive idiotype (CRI) defined by a monoclonal antibody and by synthetic peptides derived from VKappa IIIb light chains. The CRI is shared with RF paraproteins from patients with Waldenstrom's macroglobulinemia. CRI+ B cells in salivary gland (SG) biopsies of SS patients can be detected in high frequency and we have observed two CRI+ lymphomas that arose in the setting of pre-existing SS. In order to examine at the cellular and molecular level the events associated with lymphoid infiltration of the SG and the regulation of autoantibody synthesis, we will: 1. Establish whether the high frequency of CRI expression in SG of SS patients results from expansion of a lymphoid subset utilizing a single variable region gene family. We will examine DNA from B cell hybridomas derived from SG biopsies and compare these variable regions to "germ line" DNA from the same individuals. 2. Determine whether T cell infiltrates in SG biopsies are monoclonal or oligoclonal in origin by analyzing DNA from SG biopsies and from T cell hybridomas derived from these tissue lesions. 3. Assess the role of Epstein Barr virus (EBV) in CRI induction and the regulation of CRI synthesis by specific T cell subsets. We are concentrating on this virus based on our recent finding that EBV is reactivated in the SG of SS patients. The proposed studies will use a molecular biological approach to characterize the B cells, T cells, and putative antigens contributing to a well defined human autoimmune disease.