Role of B cell interactions in CNS autoimmune demyelination

点击翻译按钮获取中文摘要

PRJOECT ABSTRACT Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) whereby infiltrating autoreactive clones, with additional pro-inflammatory cell types they recruit and support, work to destroy the protective myelin sheaths surrounding neurons. This results in compromised nerve conduction and myriad pathologies including pain, vision loss, cognitive deficits, and eventual paralysis. It is currently incurable. Due to its early life onset (typically in the third or fourth decade) and that it progressively worsens over time, an MS diagnosis tragically sentences patients to a prolonged battle, representing a significant health and financial burden for nearly 1 million Americans. Understanding the complex immune cell interplay governing pathogenesis and regulation of disease is critical for the discovery of novel therapeutics for patients. The MS mouse model experimental autoimmune encephalomyelitis (EAE) has provided great insights into these processes, and has focused on CD4 T cells (CD4s), which can adoptively transfer paralysis to healthy mice. The role of B cells and CD8 T cells (CD8s) have been understudied in comparison. Targeted B cell-depletion success in recent MS clinical trials has renewed intense interest in the role these cells play in demyelinating disease. However, most EAE models do not account for pathogenic B cells, where myelin peptide-induced models (eg. MOG35-55) exhibit EAE in B-less mice. Full-length recombinant human MOG (hMOG) protein induces B cell-dependent EAE but its production is biochemically cumbersome, time-consuming, and expensive, representing a barrier of access to efficient investigation of B cells in EAE. Additionally, MOG is a minor component and buried within the myelin structure and rodent MOG has residue differences with human MOG that render its induced EAE B cell-independent. Myelin proteolipid protein (PLP) in contrast is the most abundant myelin protein and shares 100% amino acid sequence homology between mouse and human. However, like MOG35-55, PLP178-191 induces B cell-independent EAE. We therefore designed a novel peptide encompassing the extracellular domains of PLP and have found that it drives a robust B cell-dependent EAE. Our group has demonstrated that myelin-specific CD8s in human PBMC have regulatory function and are defective at inhibiting CD4s in MS patients. Further, PLP178-191-specific CD8s suppress EAE and even eliminate paralysis in mice. Thus, B cell interactions with pathogenic CD4s and regulatory CD8s (direct or through TFH cells) can be studied in our novel model. This PLP-driven, B cell- dependent murine model of MS will be developed in the proposed work, and will not only advance the field’s technical capability, but serve as a much-needed arena for investigating B cells in EAE.