Autoimmune nephritis is a leading cause of chronic kidney disease and renal failure worldwide and a major source of allograft injury and loss. Yet available therapies are limited to nonspecific toxic regimens. Antigen- and cell-specific therapies hold great promise but development of these novel mechanism-based interventions requires understanding of underlying pathogenesis. The proposed research will determine tolerance mechanisms that regulate nephritogenic lymphocytes with a focus on autoantibodies and B cells. An overarching hypothesis is that commonalities exist in the processes maintaining tolerance in kidney-restricted and systemic autoimmunity.
Aim 1 uses a novel antibody (Ig) transgenic (Tg) model that targets the Goodpasture antigen to test the hypotheses that: i) B cells recognizing pathogenic epitopes on collagen are regulated in vivo;ii) alpha3(IV)NC1 collagen is a tolerogen, and iii) a subset of anti-alpha3(IV)NC1 B cells readily evade or escape tolerance. Immune phenotype will be measured in transgenic and informative mutant backcross strains.
Aim 2 will determine the role of genetic autoimmune susceptibility in altering the fate of nephrotropic B cells.
This aim tests the hypothesis that host modifier genes modulate tolerance at cellular and molecular levels. These studies are possible because the LamH Ig Tg with a well characterized tolerance phenotype has been established on lupus-prone strains MRL, NZB and BXSB, each of which carries a unique constellation of disease susceptibility genes and develops severe nephritis similar to disease in man. Immune phenotype will be measured and compared in these and the related BWF1 Tg strain. The regulatory role of galectins 1 and 3, prominent proteins only recently identified as modifiers of B cell tolerance, will be determined using genetic galectin deficiency. Finally the relevance to human autoimmunity of key regulatory molecules or pathways, determined by oligoarray to maintain B cell anergy in B6 or lupus MRL mice, will be explored through probing existing array databases. It is anticipated that mechanistic insight into regulation of nephritogenic autoimmunity will yield new targets for therapy in immune nephritis.

Public Health Relevance

Autoimmune diseases affect ~6% of the population, and when manifest in the kidney as glomerulonephritis, constitute a leading cause of chronic kidney disease and the single most common cause of end stage renal disease worldwide. Glomerulonephritis also accounts for up to 50% of kidney transplants, over 8% of which are ultimately loss to recurrent disease. Our studies are designed to dissect the tolerance mechanisms that regulate renal autoimmunity, as well as defects that lead to disease. Each of these checkpoints is a potential target for newer more disease specific therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047424-16
Application #
8089506
Study Section
Special Emphasis Panel (ZRG1-RUS-F (51))
Program Officer
Flessner, Michael Francis
Project Start
1998-01-01
Project End
2012-09-24
Budget Start
2011-07-01
Budget End
2012-09-24
Support Year
16
Fiscal Year
2011
Total Cost
$229,343
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; 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
Rudolph, Earl H; Congdon, Kendra L; Sackey, Faustina N A et al. (2002) Humoral autoimmunity to basement membrane antigens is regulated in C57BL/6 and MRL/MpJ mice transgenic for anti-laminin Ig receptors. J Immunol 168:5943-53

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