Sjogren's syndrome (SS) is a common rheumatic autoimmune disease which initially affects the salivary and lacrimal glands but can effect the lungs, kidneys, central nervous system and vasculature. The etiology and pathological mechanisms are unknown for this disease and therapy is available but far from ideal. SS is an autoimmune disease as evidenced by the almost universal presence of autoantibodies in the sera of patients. The great majority of patients have antibodies binding one or more components of the Ro/LA (or SSA/SSB) ribonucleoprotein particle, which is found in every mammalian cell type examined and whose function is not completely known. There are several animal models of SS but none of these models have high levels of anti-Ro or anti-La. Thus, while these models may prove useful for studying some aspects of the disease, insights into the origin and pathogenic potential of autoimmunity targeting the Ro ribonucleoprotein cannot be sought or found. The investigator has developed a new animal model of SS in which mice are immunized with short peptides (12-20 amino acids) derived from the sequence of the 60 kDa Ro molecule. In some strains of mice the immune response expands with both B cell and T cell epitope spreading. Initially the immunogen peptide induces an immune reaction. Then other epitopes of the 60 kDa Ro molecule are targeted, as are epitopes on other molecules that are components of the Ro particle such as 52 kDa Ro and La. In the SJL/J mouse strain pathology develops in the salivary gland that is similar to that found in humans with SS. This application will investigate this new model of disease that closely replicates its human counterpart. The nature of the cellular infiltrate will be studied as to its content of T and B lymphocytes and subsets. The cell type critical for development of disease will be determined by transfer experiments. Preliminary data indicate that the phenotype of helper T cells is critical to epitope spreading in this model. The relationships among immune response type, immune diversification after Ro-peptide immunization and development of pathology will be determined. Immunization will be carried out in mice deficient in various cytokines and with immune deviation strategies in order to determine whether immune deviation will alter development of epitope spreading and disease pathology.

R55AR047341

2001-09-30

2004-02-28