Autoantibodies against RNA polymerase I (RPI) have been detected in the sera of all human systemic erythematosus (SLE) patients tested. That these antibodies have an important role in the pathogenesis of the disease has been indicated by investigations utilizing murine model systems. Thus, like the onset of SLE, the appearance of anti-RPI antibodies in the sera is delayed in MRL/++ as compared to MRL/1pr mice. Further, anti- RPI antibodies are selectivity concentrated in the kidneys of lupus mice during the course of disease and the degree of this concentration correlates with the severity of nephritis. RPI is a complex enzyme, composed of nine different polypeptide subunits. The enzyme can be phosphorylated and this modification is important, not only in the control of enzyme activity, but also for immunoreactivity of the enzyme with lupus autoantibodies. In the proposed investigation, which will utilize the MRL strains of lupus mouse, the specificity of anti-RPI antibodies, with respect to phosphorylated sites and individual subunits, will be monitored during the course of disease with particular emphasis on the early stages. This study will define early events in the immune response against the polymerase which must be understood before attempts can be made to prevent their occurrence. Indirect evidence suggests that the autoimmune response against RPI is antigen-driven. In order to obtain more direct evidence, an attempt will be made to augment this immune response, and thus speed progression of the disease, by injecting MRL mice with purified RPI. The possibility that RPI is altered in some way in MRL mice which results in the induction of autoantibody production will be investigated by comparing the quantity and phosphorylated state of the enzyme extracted from MRL and control mouse tissue. In a preliminary investigation, RPI antigen was demonstrated to be in the urine of MRL but not of normal mice. Further, the quantity of RPI antigen in the urine increased with progression of the disease. This phenomenon will be studied further with respect to characterization of RPI in urine, demonstration that it is complexed with antibodies, and that the quantity of the antigen is an accurate indicator of disease status. Finally, an attempt will be made to directly demonstrate an interaction between the RPI/anti-RPI and the DNA/anti-DNA antibody systems. These studies will thus further document the role of RPI and autoantibodies against it in the etiology and pathogenesis of murine SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024855-04
Application #
3138106
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045