The research outlined in this application focuses on two basic questions about primary biliary cirrhosis: (1) What initiating or etiologic factor(s) are involved? and (2) How is the host's immune response regulated to permit initiation or perpetuation of liver injury? As a probe to explore etiologic factors, we will take advantage of our recent demonstration that immune complexes circulate in high titer in the serqm of patients with primary biliary cirrhosis. A variety of approaches will be exploited to purify these complexes, characterize them, and compare them with immune complexes found in other acute and chronic liver diseases. Specifically, by using immunofluorescence techniques, we will attempt to identify immunologically the antigen component of the immune complex bound to Raji cells. Identification of a disease-specific antigen may provide etiologic clues and would serve as an immunologic marker for PBC. Moreover, we will study the role of these complexes in complement activation and search for correlations between the presence and quantity of circulating immune complexes and disease activity. To evaluate immunoregulatory activity, we will assess control of both humoral and cellular immune responsiveness. Intrisic defects will be characterized by testing peripheral blood mononuclear cells from patients with primary biliary cirrhosis for proliferative responses in the presence of B-cell and T-cell mitogens. To study extrinsic regulation of immune responsiveness, we will determine whether these patients lack a population of suppressor cells, found in normal individuals, which regulate T-cell proliferation and/or a population of suppressor cells, also found in normals, which regulate B-cell differentiation. Finally, we will determine whether serum factors, purified immune complexes, and disease-specific antigens influence effector lymphocyte function and immunoregulatory mechanisms in primary biliary cirrhosis. Definition of immunoregulatory abnormalities will suggest therapeutic approaches for their correction.