Classification of Disease Associated B Cell Receptors in Multiple Sclerosis

/Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease. It affects over 2 million people worldwide but has historically been challenging to diagnose, categorize, and treat. MS has an autoimmune component that involves the production of B cell receptors (BCRs) and immunoglobulins (Igs) that inappropriately target the tissues in patients. We have recently reanalyzed all publicly available RNA sequencing data from MS patients and extracted over 5 million BCR immunoglobulin heavy chain (IGH) sequences. We then developed a language model capable of identifying BCR sequences associated with MS. In this project, we propose to test the effectiveness of this approach in distinguishing between MS patient peripheral BCR repertoires and those of patients with other neuroinflammatory diseases. We will select a subset of paired BCRs heavy and light chains with a high probability of association with MS and express them recombinantly as antibodies. We will determine if these antibodies bind neurons, myelin, glia, or other central nervous system (CNS) targets using a variety of methods. Based on our strong preliminary data, we expect that we will be able to accurately distinguish MS patients from other neuroinflammatory controls. We do not expect all recombinant antibodies we express will bind CNS targets, but the frequency of CNS target binding is anticipated to be significantly increased when compared to randomly selected control antibodies. This project is highly innovative and offers to make major advances in the field while being supported by strong preliminary data and an interdisciplinary team. Completion of this project may advance our ability to detect MS and other autoimmune diseases in blood samples and speed our ability to identify and study pathogenic antibodies in a variety of conditions. Project Number: 1R21NS142515-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: WENDY MACKLIN | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $427,712 | Activity Code: R21 | Study Section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303956