The Class of 2012 will look at why lupus turns the body’s immune system against itself and pioneer strategies for new treatment development. The new awards represent diverse disciplines, from inflammation and medical imaging to evolutionary biology and the emerging field of epigenetics, bringing new talent and new approaches to lupus. Award-winning projects represent the best of the best, with potential to achieve significant results and accelerate drug discovery.
Laying Groundwork for Better B-cell Targeted Therapies
LRI investigators will explore new theories on why B cells start producing autoantibodies against the body’s own cells and tissues and how this could be prevented. They will also ask which type of B cell, of the many types in our immune system, produces harmful autoantibodies and whether this varies from individual to individual — insight that will aid in designing future B cell-targeted therapies and individualized treatment.
Dr. Eline Luning Prak, University of Pennsylvania: “We are using cutting-edge DNA-sequencing technology to identify specific B cells that may cause lupus in individual patients. Different B-cell-targeted lupus therapies such as Benlysta® (belimumab), aim to control the disease by clearing different disease-causing B cells from the immune system. But currently physicians do not know which types of B cells should be eliminated. We hope that our study will take the guesswork out of matching B-cell treatments to patients, improving individualized therapy.”
Dr. Alexander Tarakhovsky, Rockefeller University: “My team’s exploring an entirely novel therapeutic strategy aiming to reverse autoimmunity by targeting proteins that switch on ‘bad’ genes in lupus B cells through a process called epigenetics.”
Dr. Thomas L. Rothstein, The Feinstein Institute for Medical Research: “We’re studying whether B1 cells, a small B cell population whose identity in humans we recently described, produce harmful autoantibodies in lupus. If so, therapies could be developed targeting B1 cells without damaging healthy B cells that protect against infection.”
Dr. William Kovacs, Pennsylvania State University: “We recently found evidence for a link between inherited variations in sensitivity to male sex hormones (androgens) and some aspects of lupus in men. Our LRI study is exploring for the first time how differences in sensitivity to androgens might promote autoimmunity by allowing B cells to more easily switch to production of disease-causing autoantibodies. Since these same hormones are present in much lower amounts in women, we’re also looking at whether such inherited differences in androgen sensitivity might influence the course of lupus in women.”
Understanding Organ Damage
Three investigators will explore how the lupus immune system damages specific organs.
Dr. Meggan Mackay, The Feinstein Institute of Medical Research: “This brain imaging study is the first testing whether autoantibodies against neurotransmitter receptor NMDA impair its activation. With Feinstein neuroimaging experts, we’re using a new radiochemical tracer that binds the NMDA receptor to visualize receptor activity in the brains of lupus patients with this autoantibody. If successful, the technology will be developed as a new biomarker to diagnose neuropsychiatric lupus and monitor therapy response.”
Dr. Mariana Kaplan, University of Michigan: “Our study lays the groundwork for therapies preventing cardiovascular disease in lupus. We’re building on LRI-funded work showing high-density lipoprotein (HDL), “good cholesterol,” is a risk factor for lupus-related cardiovascular disease. We’re investigating in patients whether inflammation damages HDL, disrupting its protective effects on the heart and blood vessels.”
Dr. Sandra Wolin, Yale University: “How does sunlight cause lupus skin flares? Many patients with lupus of the skin produce antibodies against a protein, Ro60, which normally binds RNA inside cells. We are testing whether sun exposure releases Ro60-RNA complexes that interact with the antibodies to cause skin rashes. Our findings could reveal a new pathway and novel drug targets for lupus of the skin.”
Origins of Lupus Autoimmunity
The fundamental causes of lupus remain unknown. Investigators new to lupus bring novel ideas on possible culprits.
Dr. Harmit Malik, Fred Hutchinson Cancer Research Center: “Could a lost evolutionary arms race cause lupus autoimmunity? We’re exploring if autoimmunity results from the evolutionary escape of ancient parasitic genes from defense mechanisms that control them, which could provide a new model for understanding what causes lupus.”
Dr. Matthias Wabl, University of California, San Francisco: “Given lupus patients’ increased risk of non-Hodgkin’s lymphoma, we’re asking whether their fundamental causes might be similar. We’re exploring whether autoreactive B cells can multiply because of retroviruses disrupting critical control genes (as can happen in cancer). If correct, preventing lupus in susceptible individuals may be possible with anti-retroviral drugs, like those for HIV.”
Dr. Yufeng Peng, University of Washington: “Is a breakdown in the body’s housecleaning to blame for the lupus immune system’s self-attack? By revealing how dying cells not cleared effectively may trigger immune cells to attack those cells’ DNA and proteins, we could discover potential targets for interventions.”
Exploring New Treatment Strategies
Two investigators will use animal models to test highly original ideas on curbing the lupus immune system.
Dr. Yousang Gwack, University of California, Los Angeles: Elevation of intracellular calcium concentration is essential to activate immune cells, and inhibiting the calcium increase causes profound immunosuppression. We’ve discovered a potentially therapeutic role of calcium inhibition that could particularly benefit lupus patients. We’re exploring whether treating mice with an inhibitor of a newly discovered subunit of calcium channel, a protein Orai1, induces regulatory T cells to prevent lupus autoimmunity while retaining protective immune responses to infection.
Dr. Janusz Kabarowski, University of Alabama, Birmingham: “We’re investigating whether anti-inflammatory properties of HDL can be harnessed to protect the heart and blood vessels, and stem the immune system’s attack on other organs. If so, therapies increasing HDL levels or improving its protective function could treat lupus nephritis.”