2005 Cardiovascular System
2014 General Immune System Function, B cells, T cells, Human Lupus Biology
Mechanisms and Consequences of HDL small RNA Communication in SLE
2014 Immunoregulation MicroRNAs
The study and what it means to patients
My co-investigator, Dr. Kasey Vickers and I, are studying a newly discovered way that T cells and B cells of the immune system communicate using small pieces of genetic material called micro-RNAs (miRNAs) as messengers. We will use cutting edge technology to test if cholesterol transfers miRNAs between immune system cells and if this is altered in lupus causing an imbalance in the immune system. Potentially, the next step would be to develop new drugs that correct miRNA communications to re-balance the immune system and treat the disease.
MicroRNAs (miRNAs) are small pieces of genetic material that are known to act within cells to control which genes are turned on. More recently, it has been discovered that miRNAs also act as messengers to communicate information between cells. It turns out that the miRNAs are transported between cells attached to cholesterol. Because we know that T cells and B cells do not function normally in lupus, we will use sophisticated techniques to take a closer look at the role of miRNAs in communication between these cells and test if this is altered in patients with lupus. If we can demonstrate a damaged miRNA communication process between B cells and T cells in lupus patients that may allow us to identify new drug therapies for this disease.
SLE is a debilitating autoimmune disease with limited treatment options. Features of SLE include chronic T and B cell activation and HDL dysfunction. Studies show that the HDLs from SLE patients lack cardio-protective characteristics and are associated with signaling and protein expression changes, suggesting differential regulatory functions of SLE HDL. We recently reported that HDL transfers functional microRNAs (miRNA) to cells in a scavenger receptor BI (SR-BI)-dependent manner. SR-BI null mice develop a lupus-like autoimmune disorder including T and B cell activation and cell proliferation, pointing to a role for HDL-mediated miRNA transfer in maintaining immune homeostasis. Lending further support to this idea are preliminary data indicating that monocytes, macrophages, and T cells export miRNAs to HDL. Taken together, this suggests that HDL-mediated communication between disparate cell types may be altered in SLE. Therefore, we hypothesize that dysregulation of HDL-mediated miRNA transfer between macrophages, T cells and B cells is an important molecular mechanism underlying SLE disease pathogenesis. Understanding this mechanism will result in alteration of the current paradigm of cell-to-cell communication in autoimmune disorders and allow for identification of novel SLE drug targets.
Why do blood vessels in people with lupus tend to prematurely narrow and harden, a condition called atherosclerosis that sometimes results in fatal heart attacks and devastating strokes?
Using novel mouse models, Dr. Major found that just having lupus is enough to cause accelerated atherosclerosis – you don’t need to have a high fat diet too.
She fed a normal, non-high fat diet to lupus-prone, atherosclerosis-susceptible mice to observe whether the animals quickly develop hardened arteries, all the while examining the effect of slight changes in cholesterol (serum lipoproteins) and the immune system.
In 2008 she won an NIH grant for $1.5 million to further develop this animal model and generate techniques for early detection and prevention of lupus atherosclerosis.
“I am thrilled that I could provide a great return on your investment in me!” Dr. Major said.
Dr. Major also was awarded the Irvine Paige new investigator prize at an American Heart Association meeting, and credits LRI funding for the award.
“Obtaining the LRI grant was a huge spring board for my interest and research in lupus.” - Dr. Major, 2010
Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Stanic AK, Stein CM, Morgan AC, Fazio S, Linton MF, Wakeland EK, Olsen NJ, Major AS. Proc Natl Acad Sci USA. 2006 May 2;103(18):7018-23.
In 2008, Dr. Major won a $1.5 million NIH grant to continue her research in lupus atherosclerosis.
Rev. July 2010