Friday, December 27, 2024
12/27/2024
The broad, long term objective of this project is to elucidate the role that the B cell arm of the immune system plays in the pathophysiology of aging from the stand-point of, and hypothesis that, B cells and the antibodies they make play a pathogenic role. The specific focus of the present application is to elucidate the immunoglobulin repertoire of B cells present in human cerebral spinal fluid (CSF) samples in comparison with B cells circulating in the periphery to determine the extent to which there is B cell intermingling between the periphery and the central nervous system (CNS) in old age. This work is designed to test a novel and unexplored mechanism underlying the dyscrasias of aging and associated neurodegeneration. B cells exist in the CNS of healthy people as evidenced by their presence in cerebral spinal fluid (CSF). Where do these B cells come from and how do they end up in the CNS? B cells in the periphery circulate throughout the body but one place they do not enter is the central nervous system (protected by the blood brain barrier). Or do they? We addressed this issue by analyzing antibodies produced by individual B cells, because antibody sequence can act as an address or identifier for each B cell. We found that CNS B cells constitute a population separate and distinct from peripheral B cells in healthy young human volunteers. A recent study of young mice by another group confirmed that CNS B cells are completely separate and distinct from peripheral B cells in these animals…BUT, of greater consequence, the same study reported that in old mice, the antibody repertoires of CNS and peripheral B cells overlapped to a significant extent, indicating translocation/migration of peripheral B cells to the CNS. It is now imperative to determine whether the same occurs in old people, as this could constitute a mechanism whereby autoreactive B cells gain access to the CNS and promote inflammation, which is considered an important factor in cognitive aging and the pathogenesis of neurodegenerative illness. The unknown degree to which peripheral B cells contribute to the population of CNS B cells in old people represents a key gap in knowledge whose resolution is likely to have important implications for concepts regarding normal physiology and disease pathology. We propose to test the hypothesis that B cells in the CSF are related to peripheral B cells in old people. We will evaluate the phenotypic nature of CSF vs peripheral blood B cells by immunofluorescent staining in old and young people. We will evaluate overlap between CSF and peripheral blood B cells by PCR amplification and then sequence analysis of B cell-expressed antibodies from samples obtained from the same individuals at the same time. This work will provide completely new information concerning the hypothesis that B cells move from the periphery to the CNS in old age, and in so doing contribute to age- associated degeneration and disease initiation and/or exacerbation. If true, a new paradigm will form for future studies in basic and clinical neuroimmunology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).