Health depends on an exquisitely balanced immune system that defends the body against microbial invaders and helps heal tissue damage while clearing away proteins and cells that are not as they should be.
There are so many ways this balance can be tipped toward disease by an overactive or dysfunctional immune system, including:
At UCLA, our specialists are exploring the immune system because they realize that a dysfunctional immune system affects body-wide systems. The I3T (immunity, inflammation, infection and transplantation) multidisciplinary focus will both expand and focus these collaborative efforts.
Dr. Rhonda Voskuhl, professor in the UCLA Department of Neurology and director of UCLA’s Multiple Sclerosis program, has decided to solve the mystery of why women are much more likely to develop autoimmune diseases than men. The culprit appears to reside in the X chromosome, with research showing that there are effects of the XX genotype (female) that promotes inflammation in autoimmune diseases.
That sex difference has long been noted, but no one knew why. Dr. Voskuhl and her collaborators designed a first-of-its-kind mouse model of sex effects. Here’s how:
MS is a neurological disease in which the immune system targets nerve fibers in the central immune system and it affects about 400,000 people in the U.S. Dr. Voskuhl has already designed and tested a completely different immune-based approach to treating MS.
She investigated the fact that women with MS (and some other autoimmune disorders) tend to have fewer disease symptoms during pregnancy. It was discovered that the fetal placenta produces estriol. Estriol is a form of estrogen that essentially shifts immune system reactivity in order to avoid targeting the fetus, which contains the “foreign” cells of the father. Estriol was also found to improve brain health in animal models of MS.
Armed with this information, Dr. Voskuhl tested 158 non-pregnant women with MS over a two-year period and found that use of estriol reduced disease relapses by 47 percent. Dr. Voskuhl says her findings, published in January 2016 in Lancet Neurology, suggest that estriol could also help women with psoriasis and rheumatoid arthritis.
Many common diseases often coincide with chronic inflammation, but in heart disease, Dr. Jake Lusis, a professor of medicine, cardiology, human genetics, and microbiology, immunology and molecular genetics at UCLA, says inflammation is key.
The connection looks like this:
Dr. Lusis studies the complex genetic traits underlying cardiovascular and metabolic disorders, and he emphasizes that the risk for heart disease depends much more on a person’s genetics than it does on his or her cholesterol load. He says that there is absolutely no question whatsoever that the immune system is deeply involved in heart disease and that genetic variation affecting those immune components contribute to atherosclerosis.
The genes in question are found on the major histocompatibility complex (MHC) on chromosome 6 — an area that contains many of the components that are key to the immune system.
As part of UCLA’s efforts to expand the understanding of the interactions between nature and nurture — genes and the environment — Dr. Lusis has discovered how the gut microbiome can cause inflammation in the heart.
Dr. Lusis, as part of a team of investigators from Cleveland Clinic, traced the toxic molecule, trimethylamine, back to consumption of red meat. They also showed that a naturally occurring, non-toxic molecule can inhibit the production of trimethylamine in gut bacteria.
“As we learn more about the immune system from our I3T work, there will be endless possibilities for modifying the diet and for understanding what happens with gene-immune system interactions that can be targeted,” Dr. Lusis says.