Stratifying Inflammatory and Degenerative Signatures in Progressive Multiple Sclerosis
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation in the brain due to inflammatory responses targeted at myelin, a protective sheath covering neurons. MS has multiple clinical subtypes, including relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS), that are defined based on the presence or absence of periods of clinical remission. A current lack of specific biomarkers for progressive forms of MS prevents rapid diagnosis and effective monitoring of clinical efficacy. Progressive forms of MS share traits both with autoimmunity, including efficacy of B cell depletion therapy, and neurodegeneration, including hyperactivation of brain-resident cells called microglia. Here, we will for the first time directly compare progressive MS to an autoimmune disease (RRMS) and neurodegenerative disease (Alzheimers disease). We hypothesize that we will be able to identify cell types or states that are associated uniquely with the intersection of inflammation and degeneration seen in progressive MS. We have recently identified a population of monocytes present in the cerebrospinal fluid of healthy individuals and MS patients that have characteristics that are typically associated with microglia. These cells may be uniquely suited to reflect microglial dysfunction in progressive MS, providing a readout of brain-resident cells that are accessible through lumbar punctures. We will pair detailed analysis of this cell type, which is part of the innate immune system, with characterization of the adaptive immune system comprised of T and B cells. Each T and B cell has a unique receptor that reflects its specificity for its target antigen. Upon encountering the antigen that they are specific to, adaptive immune cells divide leading to a population of cells with the same receptor. We will use this to particularly examine expanded populations, which may provide a more targeted scope for biomarker development as these cells may reflect a population that is pathogenically recruited or activated. These traits could then be implemented for diagnosis and clinical monitoring of progressive MS, as well as drive hypotheses about factors contributing to accumulating disability in progressive MS. This study will therefore provide the framework both for future biomarker development and treatments that target both inflammatory and degenerative components of progressive MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910608
Entities
People
- David A. Hafler
Organizations
- United States Army
- Yale University