title: Investigating the Antigen Specificity of Multiple Sclerosis Central Nervous System-Derived Immunoglobulins.
abstract: The central nervous system (CNS) of patients with multiple sclerosis (MS) is the site where disease pathology is evident. Damaged CNS tissue is commonly associated with immune cell infiltration. This infiltrate often includes B cells that are found in multiple locations throughout the CNS, including the cerebrospinal fluid (CSF), parenchyma, and the meninges, frequently forming tertiary lymphoid structures in the latter. Several groups, including our own, have shown that B cells from distinct locations within the MS CNS are clonally related and display the characteristics of an antigen-driven response. However, the antigen(s) driving this response have yet to be conclusively defined. To explore the antigen specificity of the MS B cell response, we produced recombinant human immunoglobulin (rIgG) from a series of expanded B cell clones that we isolated from the CNS tissue of six MS brains. The specificity of these MS-derived rIgG and control rIgG derived from non-MS tissues was then examined using multiple methodologies that included testing individual candidate antigens, screening with high-throughput antigen arrays and evaluating binding to CNS-derived cell lines. We report that while several MS-derived rIgG recognized particular antigens, including neurofilament light and a protocadherin isoform, none were unique to MS, as non-MS-derived rIgG used as controls invariably displayed similar binding specificities. We conclude that while MS CNS resident B cells display the characteristics of an antigen-driven B cell response, the antigen(s) driving this response remain at large.
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA ; Walter and Eliza Hall Institute of Medical Research , Parkville, VIC , Australia ; Department of Medical Biology, University of Melbourne , Parkville, VIC , Australia.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Willis
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Stathopoulos
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Chastre
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA.
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Compton
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA ; Department of Immunobiology, Yale School of Medicine , New Haven, CT , USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.affiliation: Department of Neurology, Yale School of Medicine , New Haven, CT , USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
keywords: B cell; autoantibody; autoantigen; multiple sclerosis