There is only one environmental agent that is consistently linked to cutaneous (CLE) and systemic (SLE) Lupus Erythematosus and that is ultraviolet (UV) light. Despite good mouse models of this disease, lupus mice have contributed little to understanding the basic pathogenesis of skin disease or ultraviolet (UV) light induced-precipitation of systemic flares. The investigators propose that this is due both to lesser exposure of mice to UVB as well as fundamental differences in plasmacytoid dendritic cells (pDC) between mice and humans. In this proposal, the investigators have created a new mouse model of UVB-mediated skin disease that is associated both with pDC infiltration as well as a type 1 interferon (IFN) signature. Using these conditions of UVB exposure, the investigators propose to 1) determine what are the stimuli, sensors and role of pDC following UVB exposure;2) create a humanized mouse model of cutaneous LE and determine which autoantibodies are most potent in initiating IFN and inflammation in the skin;and 3) develop a systemic mouse model of UVB-mediated disease exacerbation using mice that express defined antibodies and Toll Like Receptors that is predicted will sensitize mice to UVB exposure. Successful completion of these Aims will not only inform us of mechanisms responsible for UVB induced lupus but also provide researchers with useful models for trialing therapies.
Disfiguring skin disease is amongst the most common clinical symptoms of lupus, and ultraviolet (UV) light exposure can precipitate major skin and internal flares of disease. To understand how UV light causes skin disease and systemic flares, the investigators have now created a mouse model that has many similarities to human lupus including the involvement of the inflammatory protein interferon. Using this mouse model, the investigators will determine how skin and internal lupus is induced by UV light which, in turn, wil lead to better therapies in the future.
|Elkon, Keith B (2018) Review: Cell Death, Nucleic Acids, and Immunity: Inflammation Beyond the Grave. Arthritis Rheumatol 70:805-816|
|Sontheimer, Clayton; Liggitt, Denny; Elkon, Keith B (2017) Ultraviolet B Irradiation Causes Stimulator of Interferon Genes-Dependent Production of Protective Type I Interferon in Mouse Skin by Recruited Inflammatory Monocytes. Arthritis Rheumatol 69:826-836|