Our primary objective is to determine the etiology and pathogenesis of secondary amyloidosis in patients with rheumatoid arthritis. Since this life threatening complication of chronic joint disease occurs in a variety of clinical settings, we hypothesize that the critical immunopathological mechanisms are common to many inflammatory disorders. We propose to study these mechanisms in an established experimental model of amyloidosis in mice and to apply the principles derived to the development of a murine model for amyloidosis secondary to inflammatory arthritis. We have recently identified for the first time a single gene which confers resistance to amyloidosis on an inbred line of mice, the A/J strain. We now plan to conduct a complete genetic analysis of susceptibility to azocasein induced amyloidosis in mice. In vitro investigations of T cell, B cell, M cell and macrophage functions will be carried out on pure strains, on F1 hybrids derived from matings of susceptible and resistant strains, and on backcross mice. Use of a spleen biopsy technique will allow separate in vitro and in vivo studies to be carried out on large numbers of individual mice. The genetic approach will be used to determine the effects of each immune function studied on amyloidogenesis. Antigen induced arthritis will be produced in mice by established methods. By studying a number of pure strains and hybrids, mice susceptible to both arthritis and amyloidosis will be identified and used in studies on the pathogenesis of amyloidosis in this model. The final stage of our investigations will direct attention to in vitro assays of immune functions in patients with inflammatory arthritis, in order to identify those patients at greater risk for secondary amyloidosis.