Jane Salmon, MD

Hospital for Special Surgery, New York, NY

2009 Central Nervous System, General Immune System Function, New Treatments
2013 Kidney, Target Identification

LRI Class of 2013

Activation of iRhom2/ADAM17/HB-EGF/EGFR pathway in immune complex nephritis

Jane Salmon, MDThe Study and What It Means to Patients

"We are investigating whether a type of molecular scissors found on the surface on kidney cells contribute to the kidney damage caused by lupus antibodies and whether these molecular scissors (known as ADAMs) could be blocked to prevent lupus kidney damage."

Summary

In lupus, the immune system can produce misdirected antibodies that stick to and attack the tissues of the kidney, causing the release of inflammatory mediators by kidney cells and potentially life-threatening damage to this essential organ. We have recently found that when antibodies stick to the surface of the kidney cells, the cells respond by turning on certain type of molecule scissors (enzymes) that release inflammatory molecules from the cell surface by snipping them free. We are blocking these molecular scissors (known as ADAMs) in mice with lupus to test if they are a potential new drug target that could be blocked to protect against kidney damage in lupus.

Scientific abstract

Immune complex deposition leads to recruitment and activation of cells in the kidney via Fc gamma receptors (Fc gamma R) and C5a receptors (C5aR) and production of inflammatory mediators, including proteases, growth factors such as heparin-binding epidermal growth factor-like growth factor (HB-EGF), and cytokines such as TNF?. Our preliminary data reveal that C5a and immune complexes activate the cell surface metalloproteinase ADAM17 (a disintegrin and metalloproteinase 17). HB-EGF has recently emerged as a crucial mediator of glomerulonephritis (GN), and ADAM17, the principal sheddase of HB-EGF, is critical for its functional activation and binding to its receptor, the epidermal growth factor receptor. Importantly, iRhomboid2 (iRhom2), the newly discovered essential co-factor and regulator of ADAM17, is required for the ADAM17-dependent release of HB-EGF. The mechanism by which HB-EGF shedding is trigged by immune complexes, the role of activation of HB-EGF by ADAM17 and iRhom2 in GN, and the source of HB-EGF are unexplored potential therapeutic targets. We will use in vitro experiments and animal models of GN to define the role of the cell surface metalloproteinase ADAM17 in immune complex-mediated kidney injury and to determine whether blockade of ADAM17 or iRhom2 could be a new target to treat GN.

Results published in the July 12, 2013 issue of the Journal of Immunology.


LRI Class of 2009

Cholinergic modulation of immune complex-mediated inflammatory responses

In this interdisciplinary study, Dr. Salmon and colleagues will take a novel look at the interface between the immune system and the nervous system—and examine the possibility that neural networks influence immune responses and mediators of injury in lupus.

Their novel idea is that the “cholinergic anti-inflammatory pathway” limits the release of certain chemicals (cytokines and oxidants) in key areas and thereby reduces the intensity of damage caused by autoantibodies in lupus, particularly in the kidneys.

Dr. Salmon’s approach provides new hope that with drugs or with electrical stimulation, we can enhance the activity of this natural anti-inflammatory neural circuit, and harness its power to prevent or decrease organ damage in lupus.