Environmental factors that impact neurological autoimmunity

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) whose etiology is poorly understood. Although genetic factors are known to contribute to disease risk, environmental factors are thought to play an even larger role in MS etiology. Recent work in the MS field has started to explore how genetic and environmental risk factors may interact to influence the onset and severity of MS. The goal of my PhD was to examine how three environmental factors, alcohol consumption, viral infection, and heat exposure, may function to modulate MS disease states either on their own or through their interaction with genetic factors. In my work on alcohol and MS, I explored the concentration-dependent effects of alcohol on oligodendrocytes, the myelinating cells of the CNS that are destroyed in MS. After conducting 3’-Tag RNA sequencing, I found that each dose of alcohol elicited unique changes to the transcriptome that spanned a variety of biological functions including inflammation, cell cycle regulation, and protein translation. I continued my work on alcohol by utilizing an animal model of binge alcohol consumption, the high drinking in the dark (HDID) mouse line. We found that HDID animals, which were selectively bred to consume large amounts of alcohol, had exhibited de novo genetic mutations that were highly enriched in immune pathways. I then conducted immunological assays that found disruptions to the innate and adaptive immune system in HDID mouse lines. During the COVID-19 pandemic, my work expanded to include a major new question that faced MS patients and their treating clinicians: how will immunosuppressive therapies commonly used in MS impact MS patients’ ability to fight off infection or react to vaccination? We followed MS patients on B cell-depleting therapies longitudinally over one year to assess spike antibody titers, lymphocyte composition, and T cell reactivity to SARS-CoV-2 antigens. We found that despite B cell depletion, MS patients mounted a similar T cell response to SARS-CoV-2 antigens. We also found that failure to establish humoral immunity did not result in severe disease. This work has identified cell signatures that may be utilized by clinicians to advise MS patients on the timing of vaccination against COVID-19. Finally, I explored the heat-induced worsening of MS symptoms, a syndrome known as Uhthoff’s phenomenon, and how it may be better defined clinically and potentially mediated through MS lesion location. Uhthoff’s phenomenon is not a well-characterized syndrome in terms of prevalence or specific symptomology, so we utilized survey measures to determine which specific symptoms are worsened during Uhthoff’s phenomenon. We then conducted MRI analysis of brain and spinal cord imaging to quantify CNS lesion location and quantity. We identified a set of symptoms that are worsened with heat in our MS patient cohort with Uhthoff’s phenomenon. We also found that MS patients with Uhthoff’s phenomenon were more likely to have a higher number of supratentorial lesions. My findings across these three projects have led to novel and impactful results that have furthered our understanding of how environmental factors may contribute to MS etiology and severity. My experiments on oligodendrocytes, HDID mice, and Uhthoff’s phenomenon have inspired further studies that are currently underway in our lab that may lead to a further understanding of how alcohol, viruses, and heat exposure impact MS.