Role of Cholesterol Homeostasis in Lupus Pathogenesis
Abstract
Objective/Rationale A major roadblock to our ability to develop novel treatments for systemic lupus erythematosus (SLE) is the significant diversity, or heterogeneity, that accompanies this disorder. In particular lupus patients can develop various clinical manifestations that range from kidney disease to musculoskeletal problems to heart disease. The interaction between the genes of an individual and the exposure of that individual to environmental factors such as diet is likely to be a major contributor to this diversity. A Western life-style, in particular ingestion of a high-cholesterol high-fat diet, has been linked to the development of autoimmunity. Understanding the mechanisms by which consumption of a diet rich in cholesterol and fat affects the development and severity of lupus could thus provide critical insights into the heterogeneity of this disease. Aims 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, termed Autoimmune/Age-associated B cells (ABC), has recently been shown to play a major role in SLE because of their ability to be major producers 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 family of two molecules. We have found that deleting both of these molecules in mice (leading to a Double Knockout [DKO]) leads to the spontaneous development of lupus in mice that shares many features with the human disease, including the fact that the disease primarily affects female mice. We have recently found that manipulating cholesterol levels in these mice can promote the expansion of ABCs and affect the 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 target specific organs and thus, contribute to the heterogeneity of SLE. Focus Area Understanding lupus disease heterogeneity by understanding lupus disease mechanisms. Applicability of the Research We expect to find that exposure to a Western-style diet will affect the development and manifestations of SLE, providing us with a key mechanism by which a major environmental risk factor such as diet can be linked to the development of lupus. The information obtained from these studies will provide a better understanding of whether ingestion of a Western diet rich in fat and cholesterol can trigger and/or exacerbate SLE and whether this effect can vary depending on host-specific factors. In particular, these studies will give us new understanding of whether factors like a cholesterol-rich diet can alter the type of tissue that may get damaged in lupus patients. Since these studies will be coupled with a detailed understanding of the mechanisms underlying these effects, we expect to uncover molecular pathways that lead to tissue damage in lupus. These studies, in turn, will have the potential to uncover new therapeutic targets, as well as uncover markers displayed by patients that are at increased risk to develop these complications. Such results would enable patients exhibiting these markers to undergo earlier and possibly more intensive therapeutic regimens. Therefore, this knowledge could be rapidly translated into changes in therapeutic approaches. Given that ABCs accumulate to a greater extent in African American patients these studies could also provide insights into the reasons why disease is more severe in these patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010372
Entities
People
- Alessandra Pernis
Organizations
- Hospital for Special Surgery
- United States Army