Immune nephritis afflicts both native and transplanted kidneys and is a leading cause of chronic renaldisease. Nephritis occurs in up to 74% of patients with systemic lupus erythematosus, one of the mostdebilitating of the autoinflammatory diseases. Insights into disease pathogenesis are emerging fromthe complementary study of human and mouse lupus, although rapid progress has been hindered bythe extensive clinical heterogeneity and genetic complexity of this disease. This proposal uses a newmodel system developed over the past five years to track discrete autoimmune cell populations withinthe context of distinct constellations of lupus susceptibility genes. Extensive preliminary studies revealthat each of the four classic lupus strains, NZB, BWF1, BXSB, and MRL/lpr, modified to express theidentical nephritis-associated receptor, displays a unique tolerance phenotype. The goal of thisproposal is to dissect the molecular mechanisms regulating autoimmunity that destroys kidneys. Thiseffort relies on cutting edge but validated technologies and cross-disciplinary collaboration.
SpecificAim 1 will use in vitro and in vivo approaches to identify the cellular and molecular basis of alteredtolerance revealed in NZB, a strain that develops hematologic and renal disease and contributesmajor susceptibility loci to fulminant nephritis.
Specific Aim 2 will use existing subinterval congenicsand genome mapping to localize functional genetic variants that determine the defective tolerancephenotype.
Specific Aim 3 will dissect the cellular, molecular, and genetic basis of altered tolerancein the setting of accelerated lupus nephritis, including determining the basis of the uniquehyperproliferation and marginal zone-like phenotype in BXSB. Collectively, these strains model thegenetic heterogeneity of human lupus, and their study should ultimately provide insight into regulatoryand disease mechanisms applicable to patients.
Up to 74% of patients with systemic lupus erythematosus (SLE) develop immune nephritis, a major cause of acute morbidity and a leading cause of chronic kidney disease. SLE is a debilitating autoimmune disorder typically diagnosed at a young age, such that extensive morbidity and health care costs accrue over a lifetime. Yet pathogenic mechanisms remain largely unknown, existing models are inadequate, and disease-specific interventions do not exist. This proposal uses a new model system to dissect the underlying mechanisms that regulate autoimmunity that destroys kidneys. It is notable that SLE is one of over 100 autoinflammatory diseases that have been identified to date and that are rapidly increasing in incidence in the developed world. This growing public health burden is currently estimated to affect up to 10-20% of the population. Thus the proposed studies, designed to find the root cause of autoimmune diseases, are anticipated to have broad clinical relevance and provide new insights to advance novel therapeutic approaches.
| 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 |
| 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 |
