Our laboratory focuses on defining the mechanisms of the human autoimmune rheumatic diseases, including myositis, scleroderma, SLE, Sjogrens syndrome and Rheumatoid Arthritis. We investigate the human model of these diseases, and utilize samples and tissues from patients with well-defined clinical phenotypes followed longitudinally in the Disease-specific Centers for our work. One of the major challenges to the investigation of the human autoimmune rheumatic diseases is their extraordinary complexity. In spite of this complexity, specific phenotypes are associated with unique autoantibody signatures, implying a potential mechanistic connection between the targeting of specific molecules and particular forms of tissue damage. This phenotype-specific immune response provides important tools to interrogate the basis for this specificity, and hence the events underlying initiation and propagation of rheumatic diseases.We are currently pursuing studies in many areas, including understanding the relevance of autoantigen cleavage and modification on their immunogenicity, quantitation of antigen-specific immune responses in patients with a variety of diseases and the ability to monitor activity and predict outcomes. We have also taken a new approach to defining amplification-specific autoantibodies in rheumatic diseases, and will use these to identify important amplification pathways. We also have projects aimed at understanding the reasons underlying specific targeting of apparently ubiquitously expressed antigens in unique diseases. Several areas are very exciting at present. These include our recent demonstration finding that myositis-specific autoantigens are expressed at low levels in normal healthy muscle, but at elevated levels in muscle obtained from patients with autoimmune myositis. Strikingly, we showed that autoantigen expression is highest in regenerating cells in the diseased muscle. The data suggests that regenerating cells may be the targets of the immune response in autoimmunity, with ongoing tissue damage the proximate cause of increased autoantigen expression, and a basic mechanism underlying the patchy and self-sustaining nature of these diseases. Interdicting such pathways may provide new therapeutic opportunities, and may be relevant to many of the diseases in this spectrum.
Research - Laboratory of Livia Casciola-Rosen, Ph.D. and Antony Rosen, M.D.