Autoimmunity is the antecedent to most glomerulonephritis, the most common cause of end stage renal disease worldwide. Yet rudimentary understanding of etiology compels reliance on non-specific toxic immunosuppressive therapy. We developed Ig transgenic (Tg) mice bearing B cells reactive with nephritogenic antigens (Ag) as tools to dissect mechanisms controlling humoral autoimmunity that destroys kidney. We postulate that: a) B cells reactive with structurally diverse self-Ag relevant to renal injury are regulated by diverse mechanisms; b) There are differences in molecular pathways maintaining B cell tolerance to nephritogenic Ag in autoimmune vs nonautoimmune individuals, and between individuals bearing different constellations of susceptibility genes; and, c) There are fundamental differences in regulation of B cells that promote nephritis in systemic versus organ-restricted disease. This predicts that different regulatory mechanisms are breached in different autoimmune nephritides. We will use Ig Tg models to pursue the following Specific Aims: 1) Determine the role of deletion and anergy in regulating B cells reactive with basement membrane, the only confirmed target in human autoimmune nephritis. Inactivated Rag or endogenous Ig genes will link cell fate to Ag specificity using anti-laminin LamH/LamL and duat specific LamH/VSR """"""""monoclonal"""""""" H+L Ig Tg mice in which collateral regulatory influences are eliminated. 2) Dissect the molecular basis of genetic modification of B cell tolerance. Microarray will be used to monitor and analyze transcriptional profiles in receptor-stimulated tolerant Tg cells from autoimmune MRL and nonsusceptible B6 mice to reveal central regulatory pathways. The LamH Tg, with a well defined tolerance phenotype, will also be established on nephritis-prone (NZBxNZW)F1 and BXSB strains to determine if a single Ag-receptor interaction is differentially tolerogenic in genetically disparate disease-susceptible hosts. 3) Determine and compare the fate of kidney-reactive 238H Ig and anti-alpha3(IV) NC1 collagen Tg B cells associated with nephritis in systemic versus renal-limited autoimmunity, respectively. This will assess contributions of nucleic acid crossreactivity and Ag sequestration, factors known to impact immune deposition, to regulation of nephritogenic B cells. Collectively these studies will identify regulatory pathways to be targeted for tailored pharmacologic intervention in immunologic renal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047424-11
Application #
6759474
Study Section
Pathology A Study Section (PTHA)
Program Officer
Flessner, Michael Francis
Project Start
1998-01-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
11
Fiscal Year
2004
Total Cost
$300,361
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Clark, Amy G; Buckley, Elizabeth S; Foster, Mary H (2018) Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice. Eur J Immunol 48:492-497
Clark, Amy G; Fan, Qihua; Brady, Graham F et al. (2013) Regulation of basement membrane-reactive B cells in BXSB, (NZBxNZW)F1, NZB, and MRL/lpr lupus mice. Autoimmunity 46:188-204
Clark, Amy G; Weston, Melissa L; Foster, Mary H (2013) Lack of galectin-1 or galectin-3 alters B cell deletion and anergy in an autoantibody transgene model. Glycobiology 23:893-903
Clark, Amy G; Mackin, Katherine M; Foster, Mary H (2011) Genetic elimination of ?3(IV) collagen fails to rescue anti-collagen B cells. Immunol Lett 141:134-9
Zhang, Ying; Su, Susan C; Hecox, Douglas B et al. (2008) Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen. J Immunol 181:6092-100
Clark, Amy G; Mackin, Katherine M; Foster, Mary H (2008) Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity. Biomark Insights 3:335-350
Foster, Mary H (2007) T cells and B cells in lupus nephritis. Semin Nephrol 27:47-58
Clark, Amy G; Chen, Sihong; Zhang, Hao et al. (2007) Multifunctional regulators of cell growth are differentially expressed in anergic murine B cells. Mol Immunol 44:1274-85
Foster, Mary H; Zhang, Ying; Clark, Amy G (2006) Deconstructing B cell tolerance to basement membranes. Arch Immunol Ther Exp (Warsz) 54:227-37
Brady, Graham F; Congdon, Kendra L; Clark, Amy G et al. (2004) Kappa editing rescues autoreactive B cells destined for deletion in mice transgenic for a dual specific anti-laminin Ig. J Immunol 172:5313-21

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