The central hypothesis of the University of Michigan SCOR is that rheumatoid arthritis (RA) is a pathophysiologically multi-phasic disease. Early and late stages of this disease involve distinct pathobiologic processes. The events that trigger the disease involve an immune-specific phase, which is followed by an antigen nonspecific, self-perpetuating phase. This SCOR will take multidisciplinary approach to testing this hypothesis as follows: Project 1 will study the role of antigen specific, MHC-restricted gammadelta T cells in the early stages of RA. The hypothesis of this project is that gammadelta T cells are involved in triggering the inflammatory process in the joint. These cells initiate an immune cascade that results in chronic polyclonal activation and recruitment of other T cells and inflammatory cells. Project 2 will address the role of CD6 as an early polyclonal activation pathway of T cells in RA. Project 3 will study two novel peptide chemotactic factors in RA. This project postulates that Neutrophil Activating Factor and Monocyte Chemoattractant Protein are playing a role in recruitment of neutrophils and monocytes, respectively, at various stages of RA. Project 4 will investigate the adhesive interaction between synovial microvasculature and monocytes in late RA. Project 5 will address the stage of polyclonal expansion of T cells. This project will investigate the CD28 pathway in the activation of alphabeta T cells by superantigens, and the role of this pathway in a murine experimental model of RA. Four of the projects (P1-4) have clinical components. The clinical material for those projects will be handled centrally by a Clinical Core. This program represents an integrated research effort of investigators trained in internal medicine, pathology, radiology, molecular biology, cellular biology, and immunology. The strengths of this proposal are the investigators' long-standing interest in RA and immunobiology, a highly interactive research program which is an extension of ongoing collaborative research efforts, access to a large and well defined population of RA patients, and an outstanding research environment. The novelty of the research theme and the strengths of this program ensure that substantial advances toward understanding the pathogenesis of RA are likely to be made.
