The interplay between diet, metabolism and autoimmunity in the B6.SLE mouse model of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) patients are at increased risk of developing components of the metabolic syndrome. Furthermore, obesity and high-fat diet (HFD) can lead to SLE nephritis exacerbation in humans and mouse models. Study of the interplay between metabolic dysfunction and autoimmunity may inform the care of SLE patients. Chapter one of this thesis provides background on the fields of systemic lupus erythematosus and the metabolic syndrome, and highlights the shared pathogenic mechanisms that may instigate these diseases. Chapter two describes efforts to characterize the development of glucose homeostasis in the lupus-prone B6.SLE strain of mice. We show that B6.SLE mice have significantly worsened glucose tolerance and adipose tissue insulin resistance than B6 controls. This B6.SLE glucose intolerance occurs in the presence of a diabetogenic B cell environment which is characterized by the presence of an increased number of IgG-producing B cells and IgG depositions in the white adipose tissue as well as higher levels of circulating IgG. Most interestingly, this strain of mice develops glucose intolerance and adipose tissue insulin resistance in an adiposity-independent manner, indicating that this strain may be a valid model for insulin resistance in the SLE patient population. These studies provide data that elucidate the pathogenesis of insulin resistance in SLE patients and may provide greater insight into the development of insulin resistance in the obese population. Chapter three shows that high-fat diet feeding does not significantly worsen glomerulonephritis or kidney function in B6.SLE mice. Although this finding is in conflict with earlier studies of SLE models, it is possible that changes in study design could reveal dietary factors that exacerbate or ameliorate disease in the B6.SLE mouse model. Chapter four compares our results to those of other studies in SLE model models and SLE patients and proposes a mechanism for the pathogenesis of glucose intolerance and insulin resistance in the B6.SLE mouse model.