Identification of Protein Pathways and Novel Biomarkers in Pre- and Early Clinical MS Individuals with Distinct Patterns of Autoimmunity
Abstract
Multiple sclerosis (MS) is the most common cause of disability in young adults, following traumatic causes. Despite intensive research over the last decades, the events preceding the onset of brain and spinal cord injury remain largely unknown. This damage is caused by different mechanisms, including the activation of different arms of the immune system and aberrant activity of the supporting (i.e., glial) cells in the brain, like the so-called astrocytes and microglial cells. The combined effect of those mechanisms will ultimately lead to the loss of the insulating myelin sheath covering nerve fibers (i.e., axons) in the central nervous system (CNS). Early and precise detection of the different pathways leading to neuronal death provides a unique window of opportunity to understand the MS etiology, initiate the appropriate preventive mechanisms, and protect the nerve cells from irreversible damage. Unfortunately, however, our ability to untangle the complexity of those mechanisms and to measure the effect of each of them separately using standard approaches and clinical cohorts is limited. Therefore, we hypothesize that advanced, sensitive tests using blood samples can lead to a better understanding of what causes MS development, help determine the initial events, and reveal the timing and pace of different mechanisms leading to damage to underlying nerve fibers. In a preliminary work conducted in our lab, such tools allowed for the discovery of a subset of People with MS (PwMS) with unique antibody clusters that can target the brain and spinal cord. In this project, we will use state-of-the-art protein measurement and blood biomarker discovery tools to determine the protein signature that characterizes PwMS before the first clinical symptoms. Through those highly accurate analytical tools, we can compare the abundance of thousands of proteins between presymptomatic samples with evidence of a specific antibody cluster compared to PwMS without any specific immune cluster and healthy controls. Our project will use de-identified, pre-collected samples from unique samples from the Department of Defense Serum Repository (DoDSR) Presymptomatic MS cohort, established in 2019, to assess environmental and genetic risk factors for MS before onset symptoms and diagnosis. MS cases in this cohort (n=250) were selected from the population-based Gulf War Era MS (GWEMS) cohort (n=2,691), which consists of incident MS cases within the U.S. military population with active-duty service between 1990-2007. In collaboration with the Armed Forces Health Surveillance Branch, the DoDSR was used to identify the earliest serum sample (mean 5.0 years) before the first symptom onset of MS and a second sample shortly (mean 1.2 years) after the first symptom onset for 250 MS cases. Another source of samples is the unique ORIGINS cohort at University of California, San Francisco, which includes hundreds of samples from PwMS collected in the earliest clinical stage. All the samples and clinical data will be made available under the study-specific ID according to the Health Insurance Portability and Accountability Act of 1996. No access to the 18 protected health identifiers will be granted to the project personnel, and stringent data protection rules will be imposed. Our work can help reveal the mechanisms leading to neuronal damage and disability accumulation at the earliest stages of the disease, even before the clinical symptoms appear. That can explain the contribution of early events to long-term disability. In addition, detecting early cellular elements contributing to nerve fiber degeneration in the preclinical stage can guide the development of novel targeted preventive strategies, especially for high-risk individuals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310499
Entities
People
- Ahmed Abdelhak
Organizations
- United States Army
- University of California, San Francisco