Exploring the Link between Enteric Glial Cells and Multiple Sclerosis Etiology

About This Grant

Abstract: Multiple Sclerosis (MS) is an extremely debilitating autoimmune disorder characterized by the destruction of myelin that remains incurable. MS impacts more than 1 million American lives, and its prevalence has almost doubled in the last 10 years. Despite the rapid increase in cases, the etiology of MS is poorly understood and is loosely defined as a combination of environmental and genetic risk factors. There is a critical need to further explore the reasons behind MS onset. Gastrointestinal symptoms are prevalent in two-thirds of MS patients, suggesting a potential link between the gut and disease pathology. Notably, a third of MS patients exhibited gastrointestinal symptoms before an MS diagnosis, hinting at a potential role of the gut in disease etiology. Enteric glial cells (EGCs), crucial components of the enteric nervous system governing autonomous digestive tract function, are widely distributed throughout the gastrointestinal (GI) tract. EGCs express myelin proteins observed in the Central Nervous System, and some of these proteins, including Proteolipid protein 1, are known to be targeted in MS patients. EGCs are fully equipped to respond to inflammatory cues and express immune receptors, cytokines, and antigen presentation machinery. Given this, it is compelling to speculate that the initial encounter of self-antigen to activate myelin- specific T cells could be driven by EGC derived myelin antigens in the gut—a highly dynamic environment prone to inflammation and rich in neuroimmune interactions. Our long-term goal is to shed light on the contribution of EGCs to MS initiation. The foundation of this proposal is formed by our data showing that EGCs express myelin transcripts, can perform antigen presentation, are activated in an animal model of MS, and the use of a new model to selectively ablate them. Our central hypothesis is that the destruction of EGCs in an inflammatory setting constitutes a pivotal event in MS onset by priming autoreactive T cells against EGC-derived myelin antigens in the gut-associated lymphoid tissue. We plan to test this hypothesis using experimental autoimmune encephalomyelitis (EAE). This hypothesis will be addressed by pursuing two specific aims: 1) Determine the impact of EGCs ablation on the peripheral immune response, and 2) Determine the impact of EGCs ablation on EAE initiation and progression. Our approach is innovative because it will utilize novel mouse strains to manipulate EGCs and test the role of EGCs in MS onset. The proposed research is significant because it will improve our knowledge about the function of EGCs in pathological conditions. The insights gained from our studies could lead to fundamental advances in preventing MS.