Identifying the mechanisms of lupus and how lupus accelerates cardiovascular disease

Lupus -- more specifically systemic lupus erythematosus -- is an inflammatory, autoimmune disease caused when the immune system attacks its own tissues, affecting many organs in the body. One of the major causes of kidney failures, arthritis, cardiovascular disease (CVD), etc., lupus is devastating and difficult to treat. Dr. Amy Major, Associate Professor of Medicine, Pathology, Microbiology and Immunology, studies the mechanisms of autoimmunity and how it accelerates CVD, specifically atherosclerosis, a condition in which fat and lipid deposits sit in the artery wall and cause the artery to harden and eventually rupture. By focusing not only on the mechanisms of lupus but also the complication of lupus-accelerated atherosclerosis, Dr. Major hopes to halt the cause and effect of lupus.

Although truth still remains unknown, Dr. Major and her lab strongly believe that atherosclerosis in lupus patients is vastly different from atherosclerosis in non-lupus patients. Unfortunately, treatment of CVD in lupus patients is not really tailored to their underlying autoimmunity. In fact, many standard therapies for CVD, such as statins, are not as effective in lupus patients. As 1 in 3 lupus patients will die from a cardiovascular event perpetuated by their autoimmune disease and seminal papers have proven that young premenopausal women with lupus have a 50 times greater risk of developing premature atherosclerosis, Dr. Major’s research will change the standard of care for lupus patients and will, hopefully, discover new mechanisms and novel therapies. Currently, Dr. Major collaborates with other researchers at Vanderbilt University and at University of Florida to study the immunological mechanisms of accelerated atherosclerosis in the context of lupus in a unique, viable animal model, to engineer novel treatments for lupus.

Specifically, the team is trying to understand:

  • The relative roles of T and B cells in the atherogenic process: Work performed in Dr. Major’s laboratory has significantly impacted the understanding of how the immune system modulates atherosclerosis as well as how dyslipidemia and the atherosclerotic environment influence normal immune function. It is widely accepted that increased circulating cholesterol and modifications of lipids are the main culprits in the development of atherosclerosis in the general population. However, over the past three decades, increased focus has been on the role of immune cells, such as B cells (cells that produce antibodies) and particular subsets of T cells (cells that actively participate in the immune response), in the atherogenic process. Dr. Major’s laboratory is interested in understanding how abnormal T and B cell biology in autoimmune disease increases a patient’s risk for suffering a heart attack or stroke.
  • How autoimmunity (specifically lupus) exacerbates the atherosclerotic process: Dr. Major has recently established a collaboration with a researcher at the University of Florida who is a leader in the field of lupus to look at the genetic origin of why the animal models they developed acquire accelerated atherosclerosis. Dr. Major hopes to be able to pinpoint a specific gene area that is relevant to the animal model and therefore human, to determine whether or not she can identify specific genes that can cause this increase in lupus patients.
  • How the hyperlipidemic environment associated with atherosclerosis affects immune function (specifically T cells, B cells, and immune complexes): At Vanderbilt, Dr. Major collaborates with investigators at the Vanderbilt Institute for Chemical Biology and in the Biomedical Engineering department. One of her collaborators discovered a small compound may potentially block B cell and T cell interaction, thereby blocking the immune response. Currently, Dr. Major’s team and collaborators are trying to engineer a nanomedicine to target CD4+ T cells -- T cells that are dysfunctional in lupus patients -- to shut down their responses while leaving the other immune cells alone. Because T cells are important for inciting the B cell response and antibody response, this is a very novel approach that targets T cells rather than B cells unlike many other therapies.
  • How molecules such as HDL, typically associated with lipid homeostasis in health, might play a role in lymphocyte activation: Normally, HDL is thought of as good cholesterol, known to be anti-inflammatory in CVD and other inflammatory diseases. In individuals who have lupus, however, HDL doesn’t function correctly and acts pro-inflammatory. Although there have been studies that show that this might be due to some proteins that are associated with HDL, Dr. Major and her team are studying how microRNAs (miRNA)-- small non-coding RNAs with high gene regulatory potential and function in cell-to-cell communication -- associated with HDL may regulate immune function in lupus. Having shown that HDL isolated from lupus patients have a very different miRNA signature than HDL from healthy controls, Dr. Major examines if the HDL does transfer miRNAs between monocytes, macrophages, T cells and B cells, and if this intercellular communication is altered in lupus.

Bio

Dr. Amy S. Major is an Associate Professor in the Departments of Medicine and Pathology, Microbiology and Immunology at Vanderbilt University. She conducted her graduate work in the laboratory of Dr. Christopher F. Cuff in the Department of Microbiology and Immunology at West Virginia University, Morgantown, WV. In Dr. Cuff’s laboratory, Dr. Major studied the regulation of the mucosal immune response to the enteric pathogen, reovirus and received her Ph.D. in May of 1998. She then moved to the laboratories of Drs. MacRae Linton and Sergio Fazio in the Division of Cardiovascular Medicine at Vanderbilt University where she was trained in the molecular and cellular mechanisms of cardiovascular disease and atherosclerosis. Dr. Major joined the faculty at Vanderbilt University as an Assistant Professor in 2004 and was promoted to Associate Professor in 2013. The broad research focus of the Major laboratory is to understand autoimmune mechanisms of cardiovascular disease, specifically lupus-accelerated atherosclerosis. Atherosclerosis is the number one cause of mortality in developed countries and it is known that both lipids and immunity play significant roles. Work from her laboratory has significantly impacted the understanding of how the immune system modulates atherosclerosis as well as how dyslipidemia and the atherosclerotic environment influence normal immune function.

Dr. Major has always loved biology and growing up thought that she wanted to be a physician. The summer between her sophomore and junior year in college, she worked as a research assistant in a laboratory that studied immunology and occupational health. She knew then that she wanted to do biomedical research and be on the frontlines of discovery. She is particularly fascinated by the immune system: how it works in health and disease, and feels strongly about autoimmunity, which is especially devastating because your immune system, something that you should trust to protect you from harm, becomes the aggressor. Autoimmunity also runs in her family -- she has one cousin with multiple sclerosis and another with lupus, while her father is currently suffering from myasthenia gravis.

Dr. Major’s lab is not only interested in uncovering how people develop lupus, but also in understanding how this disease affects the accelerated development of cardiovascular disease which accounts for 30% of all lupus-related deaths. Discovering mechanisms of lupus will reveal new therapeutic targets and new treatments for lupus patients. This is the biggest motivator for Dr. Major, providing patients with answers to questions and ultimately giving them alternatives to old treatments when they feel out of options.

Outside of research, Dr. Major enjoys horseback riding, but is usually busy looking after her two teenagers, one of whom plays on a travel soccer team and the other who is a competitive downhill mountain bike racer. “I am their taxi-driver,” she laughs, thoroughly delighting in her athletic family.

For more information, visit https://medschool.vanderbilt.edu/major-lab/

Awards

Lupus Research Institute Novel Grants Award, 2005 and 2014

Irvine H. Page Young Investigator Research Award (ATVB Council of AHA), 2007

Lupus Foundation of America Project Startup Award, 2003

AHA Postdoctoral Fellowship, 1999

Patents

Application No. PCT/US12/58982: "Compositions and methods for treating and preventing hyperlipidemia, fatty liver, atherosclerosis and other disorders associated with metabolic syndrome"

Hawigier, J.J., Veach, R.A., Zienkiewicz, J., Liu, Y., Collins, R.D., Major, A.S. 10-5-2012.