Why are females significantly more susceptible than males to multiple sclerosis and other autoimmune diseases? Within her laboratory at Feinberg, Melissa Brown, PhD, professor of Microbiology-Immunology, aims to answer this question and many others. Brown’s research focuses on uncovering basic immune mechanisms that mediate multiple sclerosis, with the goal of using novel findings to develop new and more specific targeted therapies.
Brown is also associate director of student advising in the Medical Scientist Training Programand a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
What are your research interests?
As an immunologist, I am interested in understanding the basic mechanisms that allow proper functioning of the immune system. Although immune cells are essential for providing protection from infectious microbes, some diseases are actually caused by an overly robust immune response. My research focuses primarily on multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS). In this disease, immune cells are directed to attack a person’s own tissues — the myelin protein structures surrounding nerves that insulate neuronal axons and facilitate nerve impulse conduction. The ensuing inflammatory damage in the brain and spinal cord leads to a number of sometimes devastating sensory, cognitive and motor deficits.
Like many autoimmune diseases, MS is much more prevalent in women. It has been estimated that females develop MS three to four times more frequently than men. Our laboratory investigates the events that promote CNS inflammation in females, but we are also very interested in determining what confers male-specific protection.
What is the ultimate goal of your research?
Scientists have made great strides in MS research in recent years. Treatments that slow disease progression in patients with relapsing-remitting MS — a form of disease characterized by intermittent periods of disability interspersed with temporary recovery — are particularly promising. However, there are some forms of progressive disease for which there are still no good therapies. Like many scientists in autoimmune disease research, our goal is to identify approaches to effective treatments that do not cause global immune suppression, leaving the ability to fight infection completely intact. There is no cure for MS, and we also hope to uncover pathways that will lead to reversing the damage in the brain and spinal cord.
How does your research advance medical science and knowledge?
It has been recognized for some time that there are striking sex-determined discrepancies in susceptibility to disease. Not only do many autoimmune diseases predominate in women, where female to male ratios can approach 11:1, but women also have a reduced incidence of developing some types of tumors and a more vigorous response to infectious microbes. A combination of X chromosome content, microbiota, genetics and hormones contribute to these differences. However, the precise molecular pathways remain largely undefined.
Our most recent work aims to define the mechanisms that promote male resistance to MS. Several previous mouse and human studies have implicated testosterone, a sex hormone present at levels seven to eight times higher in healthy adult men than women, in blocking immune responses and conferring protection from MS. Yet there is still little information available about how this hormone exerts its effects.
Using a mouse model of MS in which females are susceptible and males are resistant, we have identifieda molecular and cellular pathway that explains how testosterone works to suppress harmful immune responses, thus providing an explanation for male-biased disease protection. We show that testosterone activates mast cells to produce the cytokine IL-33. IL-33 then acts on another immune cell, the type 2 innate lymphoid cell (ILC2). ILC2s turn off the harmful immune response and prevent disease development. The lower testosterone levels in females are not sufficient to activate this IL-33 pathway.
While it is not practical to treat most patients with testosterone, this information may allow us to ultimately treat with IL-33 or locally activate the IL-33 pathway in affected females. Most promising is the possibility that IL-33 may have a role in the regeneration of neuronal cell function.
How did you become interested in this area of research?
My foray into MS research was quite personal. My youngest brother was a sophomore in college when he developed optic neuritis, often a first sign of MS, after a bout of mononucleosis. He was treated with steroids to suppress inflammation and the neuritis resolved, but a year later he had another episode. Subsequently he developed other symptoms, including episodic seizures, loss of sensation and memory problems. He wasn't definitively diagnosed until several years later. I was already an investigator in immunology, so I had ready access to published scientific information and of course was eager to learn what was known about MS and what treatments were available to patients.
I was studying the regulation of cytokine production by mast cells, immune cells almost exclusively studied in the context of allergic inflammation at the time. Mast cells are very potent inflammatory cells present in the skin, airways and gastrointestinal tract and are the major source of substances such as histamine and leukotrienes that cause the itching, redness, swelling, mucus production and airway obstruction associated with allergic responses. However, unknown to many, mast cells are also quite numerous in the brain and spinal cord as well as the meninges, structures that are in direct proximity to the brain and spinal cord and enclose the cerebrospinal fluid.
My studies made me realize that mast cells produce many other molecules implicated in the central nervous system inflammation in MS. Although most research had focused on circulating immune T-cells as the orchestrators of brain and spinal cord damage, mast cells have many properties that could significantly increase this inflammation and damage. These ideas were met with a lot of skepticism for many years. However, fast forward and we and others have established critical roles for mast cells not only in MS but in other inflammatory diseases of the central nervous system.
What do you enjoy about teaching and mentoring young scientists in the lab?
Teaching and mentoring are the favorite part of my job. Young scientists bring an enthusiasm and fresh perspective to a project. The majority of the seminal observations our laboratory has published are the direct result of undergraduate and graduate student investigations. There is nothing better than experiencing the joy of a new discovery through their eyes and watching them mature into independent and critical-thinking scientists.
How is your research funded?
My research is funded by the National Institutes of Health and the National Multiple Sclerosis Society.