Role of Cholesterol Homeostasis in Lupus Pathogenesis

Improper regulation of a specific immune cell called a B cell has been long linked to the development of SLE. A subtype of B cells, termedAutoimmune/Age-associated B cells (ABC), has recently been shown to play a major role in SLE because of their ability to be majorproducers of the proteins, also known as autoantibodies, that can cause damage in lupus. Expansion of ABCs in SLE is greater in African American patients and correlates with disease activity and clinical manifestations. The environmental triggers that promote the accumulation of ABCs in lupus patients are largely unknown. Our laboratory has found that the expansion of ABCs in mice is controlled by a small familyof two molecules. We have found that deleting both of these molecules in mice (leading to a Double Knock-out=DKO) leads to thespontaneous development of lupus in mice that shares many features with the human disease including the fact that the disease primarilyaffects female mice. We have recently found that manipulating cholesterol levels in these mice can promote the expansion of ABCs and affectthe extent of inflammation in different organs in these mice. In this proposal we will investigate the hypothesis that alterations in cholesterol,as could be driven by a Western-diet rich in cholesterol, can affect the accumulation of ABCs and the ability of inflammatory cells to targetspecific organs and thus contribute to the heterogeneity of SLE.