This research project was designed to gain insight into the pathogenesis of lupus nephritis and proteinuria. We use bacterial lipopolysaccharide (LPS) as a polyclonal activator of B cells in order to achieve acceleration of autoimmune disease and nephritis in three strains of mice (NZB/W, BXSB, and MRL/1). Although these strains of mice have in common features of lupus-like disease comparable to human systemic lupus erythematosus, they differ from each other in that the relative contribution of genetic, immunologic, environmental, and hormonal factors to disease expression vary. Thus, correlation of findings in several strains offers an opportunity to identify common pathogenetic and etiologic aspects of the disease. Our specific objectives are: 1. to study the immunomodulating effect of a polyclonal B cell activator on murine lupus nephritis, 2. to study binding and release of immune complexes from blood cells, and the influence of complement upon such binding and release, 3. to study the role of complement in the solubilization of immune complexes at various stages of lupus nephritis, 4. to study mononuclear phagocyte function through the clearance and uptake of soluble immune complexes at various stages of lupus nephritis, and 5. to study disease expression, serologic and morphologic changes, and alterations in glomerular permeability function at various stages of lupus nephritis in relation to items 1-4. Disease expression is assessed by a variety of immunopathologic, functional, and serologic assays of reactants believed to be of significance in the pathogenesis of lupus nephritis. Alterations in glomerular permeability function are assessed by quantitative and qualitative studies of proteins present in urine, by molecular probes of size- and charge-based barrier function, and by an ultrastructural search of morphologic correlates of increased glomerular permeability. Our efforts to understand dysfunction of the mononuclear phagocyte system and blood cell traffic of immune complexes, and the several pathways of complement interactions with immune complexes and cells should provide several insights into the role of immune complexes in the pathogenesis of inflammation and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038644-05
Application #
3238065
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-09-01
Project End
1991-12-31
Budget Start
1991-09-25
Budget End
1991-12-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Granholm, N A; Cavallo, T (1994) Pathogenesis of early nephritis in lupus prone mice with a genetic accelerating (lpr) factor. Autoimmunity 17:195-202
Granholm, N A; Cavallo, T (1992) Bacterial lipopolysaccharide causes variable deposits of diverse immunoglobulin isotypes in kidneys of lupus-prone mice. Lupus 1:255-61
Cavallo, T; Granholm, N A (1991) Bacterial lipopolysaccharide induces long-lasting IgA deficiency concurrently with features of polyclonal B cell activation in normal and in lupus-prone mice. Clin Exp Immunol 84:134-8
Cavallo, T; Granholm, N A (1990) Bacterial lipopolysaccharide transforms mesangial into proliferative lupus nephritis without interfering with processing of pathogenic immune complexes in NZB/W mice. Am J Pathol 137:971-8
Cavallo, T; Granholm, N A (1990) Accelerated (proliferative) lupus nephritis. Am J Pathol 137:1549-51
Granholm, N A; Cavallo, T (1990) Prolonged circulation of immune complexes due to various altered immune functions contributes to nephritis in MRL/lpr mice. Clin Exp Immunol 82:300-6
Cavallo, T; Granholm, N A (1990) Lipopolysaccharide from gram-negative bacteria enhances polyclonal B cell activation and exacerbates nephritis in MRL/lpr mice. Clin Exp Immunol 82:515-21
Cavallo, T; Granholm, N A (1990) Repeated exposure to bacterial lipopolysaccharide interferes with disposal of pathogenic immune complexes in mice. Clin Exp Immunol 79:253-9
Granholm, N A; Cavallo, T (1990) Mechanism of localization of immune complexes in NZB/W mice with early nephritis. Autoimmunity 8:17-24
Granholm, N A; Cavallo, T (1989) Defective disposal of immune complexes and polyclonal B cell activation persist long after exposure to bacterial lipopolysaccharide in mice. Lab Invest 61:504-8