by Leigh MacMillan
The first Flexner Discovery Lecture of the academic year featured presentations by two Vanderbilt faculty members. As part of the “Cutting-Edge” series, Meena Madhur, MD, PhD, and Scott Smith, MD, PhD, discussed their latest research findings, which shared a focus on roles the immune system plays in certain diseases.
Madhur, assistant professor of Medicine and Molecular Physiology and Biophysics, described a novel link between inflammation, hypertension and aortic dissection, a tear in the inner layer of the aorta that can lead to aortic rupture and death.
In studies with David Harrison, MD, Betty and Jack Bailey Professor of Cardiology and director of the Division of Clinical Pharmacology, Madhur and others have demonstrated that immune cells play a role in hypertension. Despite the importance of inflammatory factors to hypertension, however, no current therapies specifically target the immune system.
Other investigators used a systems biology approach to identify the gene SH2B3, which encodes the protein LNK (“link”), as one of the key driver genes for hypertension. LNK acts as a negative regulator of cytokine signaling and cell proliferation, and changes that disable LNK “remove the brakes” on immune cells, Madhur said.
“If a normal T cell is a Toyota Camry, a LNK knockout T cell is like a Ferrari — it’s revved up and ready to go,” she said.
Madhur and her colleagues demonstrated that mice missing LNK develop high blood pressure and have vascular and kidney inflammation, and they made the unexpected discovery that LNK-deficient mice develop aortic dissection. The mice are a novel model to study early changes in the aorta that lead to weakness and rupture.
“If we can target some of these early inflammatory pathways, we may be able to alter the progression of this disease,” Madhur said.
Smith, assistant professor of Medicine and Pathology, Microbiology and Immunology, discussed the allergy epidemic and immune system activity that generates allergic reactions.
Allergic disease is on the rise in the United States, and children are increasingly affected by food allergy. Food allergy to nuts very frequently causes anaphylaxis, and sometimes death.
The key to understanding allergic reactions is an immune response called “type 2 immunity,” Smith said. In type 2 immunity, IgE antibodies activate the release of molecules such as histamine from other immune system cells. This response — developed to counter parasitic worm infections — makes the host environment inhospitable for the infecting worm.
“Why would we encode an immune response with such profound host-affecting mediators that … can lead to the death of the host,” Smith said. He explained that type 2 immunity was critical when every person on earth had at least one parasitic worm infection.
Now, this “ancient purpose” for type 2 immunity is central to the modern problem of allergic disease, Smith said.
Smith and his group are the first and only investigators who can make and study IgE monoclonal antibodies directed at specific food and environmental allergens and parasitic worms. They are using the IgE monoclonal antibodies to develop new diagnostic and therapeutic agents for allergic disease.
In early studies, therapeutic anti-peanut allergy antibodies protect mice against anaphylaxis and death.
“We think this strategy has a lot of potential,” Smith said.
The lectures were sponsored by the Offices of the Executive Vice President for Research and the Dean of Basic Sciences. For a complete schedule of the Flexner Discovery Lecture series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.
