Although the serologic and histopathologic manifestations of generalized autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are well characterized, little progress has been made over the years towards understanding the etiopathogenesis of such diseases and in establishing specific means for their control. For example, the precise role and mechanisms of autoantibody production, including rheumatoid factor, and the specific genetic, environmental and lymphoid elements that contribute to the above disease processes are relatively unknown. Recently, we described a murine strain (MRL/Mp-lpr-lpr) which, like many other murine strains (NZB, NZB/W, BXSB), spontaneously develops generalized autoimmunity similar serologically and histologically to that seen in human SLE. In addition, uniquely among the various SLE strains, the lpr-lpr substrain develops an arthritic syndrome characterized by joint inflammation, vasculitis and presence in serum of both IgM and IgG rheumatoid factors.
The aim of this project is to utilize this animal model for furthering our knowledge on the etiopathogenesis of rheumatic and autoimmune diseases. Towards the above aim we propose to study a) the phenotypic, immunoglobulin class and subclass, and clonotypic relationship of rheumatoid factors with arthritis development; b) the cellular and humoral factors that influence in vitro and in vivo the production of autoantibodies, particularly rheumatoid factors; c) the genetic factors influencing development of generalized autoimmune diseases by utilizing appropriate crosses and congenic strains of mice and d) the significance of the idiotype network and idiotype mimicry to autoantigens in the induction, pathology, and chronicity of autoimmune diseases; the role of this network will be ascertained follwing production of monoclonal autoantibodies and anti-idiotypic antibodies against them as well as of autoantigen-specific T-cell clones and hybrids. The information obtained from the proposed studies will contribute to our understanding of the fine cellular and molecular mechanisms involved in the pathogenesis of autoimmune and rheumatic diseases and perhaps the establishment of specific procedures for control of such diseases.
