In-Depth Analysis of Compartmentalized Inflammation in Progressive MS: IMPROVE MS
Abstract
Multiple sclerosis (MS) is the most prevalent chronic inflammatory disease of the central nervous system (CNS) affecting over 2.5 million people worldwide. It is thought to be caused by dysregulated immune cells that mistakenly attack the patient s own brain and spinal cord (CNS). The CNS is responsible for basic neurological processes including movement, sensibility, vision, and cognition. The disease course of patients with MS is heterogeneous. About 85% of MS patients develop a relapsing remitting MS. Within 10-20 years, up to 50% of the relapsing remitting patients suffer from increasing neurological deficiencies characterized by paralysis and cognitive impairment (secondary progressive MS). About 15% of MS patients show a constant worsening of symptoms from the onset of the disease (primary progressive MS patients). While enormous progress has been made in treating the relapsing form of MS, progressive MS remains one of the biggest clinical challenges as therapeutic options are still sparse. Progressive MS is characterized by inflammatory processes of the CNS that partly consist of aggregates of B cells. B cells are white blood cells, which are mostly known for their function of producing antibodies to fight infections. In MS, harmful B cells can enter the CNS, where they contribute significantly to disease progression by attacking the myelin sheath, the isolating layer that protects our nerve fibers, and by affecting other immune cells to enhance inflammation. However, some B cells are known to have a beneficial function by suppressing immune responses. Beneficial, regulatory B cells that produce the antibody IgA were found to travel from the gut to the CNS. The gut microbiota, which represents all microorganisms including bacteria that live in a person s digestive tract, is suggested to be a major contributor to disease progression and the activation of B cells. Yet, little is known about the interaction between the gut microbiota and beneficial B cells in progressive MS. IMPROVE MS aims to understand diverse B cell functions and the influence of gut bacteria on beneficial B cell responses in progressive MS with consequences on the development of novel therapeutic strategies and thus patient care. Specifically, the following Focus Areas and aims will be addressed: Factors contributing to or associated with MS Etiology, Prodrome, Onset, and Disease Course: We will analyze the influence of changes in the gut bacterial composition of different MS patients on beneficial, regulatory B cell responses in MS. 1. Our first aim is to characterize harmful and beneficial B cells in the cerebrospinal fluid (a fluid that surrounds the brain and spinal cord), blood, and gut biopsies from patients with progressive MS versus patients with new diagnosed relapsing remitting MS and healthy controls. 2. Our second aim is to identify the gut bacteria in MS patients that can activate beneficial B cell responses in different MS patients. Understanding the role of gut bacteria in MS and their effect on B cells will pave the way for the development of therapeutic approaches that modulate the composition of bacteria in our gut and induce a beneficial, regulatory B cell response in progressive MS patients. 3. Correlates of Disease Activity and Progression in MS: Our third aim is to assess the correlation of the antibody IgA, which is produced by beneficial B cells, with disease activity and progression in an existing large cohort of well-characterized MS patients. We aim to identify a correlation between IgA and disease activity and progression and by this develop a novel, personalized biomarker to predict disease prognosis and assess treatment response. IMPROVE MS will provide new insights about the role of gut bacteria and beneficial B cell responses in progressive MS. It has the potential (i) to fundamentally advance our knowledge of the development of progressive MS by characterizing diverse B cells of d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311007
Entities
People
- Tradite Neziraj
Organizations
- United States Army
- University of Basel