2006 Central Nervous System, Human Lupus Biology
2014 Skin, Environmental Triggers, Dendritic cells
Cutaneous and Systemic Lupus induced by UVB
The study and what it means to patients
We are investigating the impact of sunlight in lupus. We will use mice with a human-like response to skin damage that will allow us, for the first time, to gain a better understanding of the cells and molecules involved when sunlight causes disease flares in lupus. Our work will provide opportunities to test therapies to treat skin lupus and prevent disease flares.
Skin rash is one of the most common symptoms of lupus, and it’s well known that the ultraviolet (UV) light in sunlight triggers flares of both cutaneous lupus (lupus of the skin) and systemic lupus (lupus of the internal organs). However, how sunlight actually triggers these autoimmune reactions is not well understood.
To study how UV light triggers cutaneous flares, we will breed mice with immune cells more closely resembling human cells that can respond to human antibodies. This will allow us to test the role of auto-antibodies (which target the body’s own tissues) that bind to molecules and proteins released from damaged skin cells. We will explore the role of specific immune cells in the skin’s response to UV light and the importance of these cells in producing molecules associated with inflammation, such as interferon and tumor necrosis factor. We will also investigate the ways in which specialized sensors known as Toll-like receptors on immune cells recognize genetic material released from sunlight-damaged skin cells, leading to the characteristic inflammation in lupus.
Studies of lupus mice have contributed little to our understanding of the basic pathogenesis of skin disease or ultraviolet (UV) light-induced precipitation of systemic flares. We propose that this is due both to lesser exposure of mice to UVB as well as fundamental differences in plasmacytoid dendritic cells (pDCs) between mice and humans. We have made good progress in creating a new mouse model of UVB-mediated skin disease that is associated with pDC infiltration as well as a type 1 interferon (IFN) signature. We propose to 1) determine what are the stimuli, sensors and role of pDC in skin following UVB exposure; 2) create a humanized mouse model of cutaneous LE and determine which autoantibodies are most potent in initiating IFN production 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 we predict will sensitize mice to UVB exposure. Successful completion of this work will not only provide information on the mechanisms of UVB-induced lupus, but will also provide researchers with useful mouse models for testing therapies.
The cause of most cases of lupus affecting the brain is unknown, but there is good evidence to suggest that certain types of antibodies may play a role.
Dr. Elkon is testing the novel idea that a multi-step antibody process is involved in causing neuropsychiatric lupus, with a sequence of antibodies first damaging brain tissue and other antibodies then capturing antigens and crossing into brain cells, prompting the release of proteins called cytokines—and thereby altering brain function.
Potent induction of interferon-a and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. Santer DM, Yoshio T, Minota S, Möeller T, Elkon KB. J Immunol, 182(2):1192-201.