Characterizing Multiple Sclerosis Pathophysiology Using Unbiased Single Cell Transcriptional Phenotyping
Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by multifocal areas of demyelination in the central nervous system (CNS). Although the presence of clonally-expanded, receptor-edited and somatically-mutated memory B cells that express brain-reactive antibodies in the cerebrospinal fluid (CSF) and the dramatic clinical response to B cell depletion therapy suggest that autoreactive B cells play a critical role in MS pathology, the inflammatory lesions include a complex mixture of T cells, B cells and macrophages. It is likely that crosstalk between these cell subsets also contributes to disease. We hypothesize that the abnormal autoimmune phenotype of specific innate and/or adaptive immune cell subsets will be discernable in their transcriptional profiles.
Our proof-of-concept preliminary studies of sorted lymphocytes from blood and CSF of MS patients and healthy controls using single cell RNA sequencing-based transcriptional profile analysis has identified at least two unique immune cell subsets in MS patients. The goal of the current project is to perform an expanded transcriptional phenotyping study with a larger cohort of MS patients and additional participants with other CNS inflammatory diseases to extend these preliminary findings using unbiased single cell transcriptional profiling of CSF and peripheral blood, including both innate and adaptive immune cells, to explore their spatial distribution in brain specimens from MS patients, and to perform additional functional studies to determine if the MS-specific cell subsets exhibit any signaling abnormalities to explain their autoreactive pathophysiology.
This work is funded by the National Institute of Allergy and Infectious Diseases (NIH/DHHS) under grant no. 1R21AI122100.