C-reactive protein (CRP) is an acute phase reactant whose serum concentration rises in a number of diseases associated with inflammation and tissue necrosis. In rheumatoid arthritis (RA), CRP levels correlate with the degree of erosive disease; however, its complete role in the processes of this, and other diseases is not known. We have described an alternative form of CRP which differs physiochemically and antigenically from native-CRP. The alternative form of CRP is consistent with a dissociated and/or altered CRP subunit. We have defined antigenicity associated with the CRP subunit as "neo-CRP" and we have developed reagents and assays for the study of the antigen and of molecules expressing the antigen. In preliminary experiments we have identified neo-CRP in the plasma of 68 of 83, and in the synovial fluid of 3 of 3 RA patients, in concentrations from 70-450 mug/ml; further, levels of native-CRP correlated moderately with neo-CRP (r=0.603, less than 0.05). In selected in vitro effector system assays, molecules expressing neo- but not native-CRP promoted reactions of platelet aggregation and release, enhanced the aggregated IgG respiratory burst of monocytes and neutrophils, and augmented the accessory cell function of adherant cells from the peripheral blood of normal humans as analyzed in a mitogen stimulation assay. Our findings suggest neo-CRP is a naturally occurring, biologically active form of CRP. We propose to elaborate on these findings by doing the following: (1) we will determine the contribution of the rheumatoid joint to the generation of molecules expressing neo- CRP and we will define the specificity of the expression of neo- CRP antigenicity to Rheumatoid Arthritis and to the clinical activity of the disease; (2) we will determine whether neo-CRP in plasma and activity of the disease; (2) we will determine whether neo-CRP in plasma and synovial fluids is identical to neo-CRP made in vitro. We will isolate and characterize naturally occurring neo-CRP and compare its properties to neo-CRP produced in vitro; and (3) we will characterize the mechanisms responsible for the generation and/or degredation of molecules expressing neo-CRP in the rheumatoid joint. We anticipate that neo-CRP antigen will provide a useful marker in understanding the pathophysiology of CRP in RA.