title: B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.
abstract: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Joel N H
authors.initials: JN
authors.lastname: Stern
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA. Bioengineering Program, Faculty of Engineering, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Gur
authors.initials: G
authors.lastname: Yaari
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Vander Heiden
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: George
authors.initials: G
authors.lastname: Church
authors.affiliation: AbVitro Incorporated, Boston, MA 02210, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Donahue
authors.affiliation: Department of Neurology, Erasmus MC, University Medical Center Rotterdam, and MS Centrum ErasMS, 3000 CA Rotterdam, the Netherlands.
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Huttner
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, and MS Centrum ErasMS, 3000 CA Rotterdam, the Netherlands.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.affiliation: Neurology Research, West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
authors.forename: Rashed M
authors.initials: RM
authors.lastname: Nagra
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Nylander
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pitt
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Ramanan
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Siddiqui
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. AbVitro Incorporated, Boston, MA 02210, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Vigneault
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA. Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA. steven.kleinstein@yale.edu david.hafler@yale.edu kevin.oconnor@yale.edu.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA. Department of Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA. steven.kleinstein@yale.edu david.hafler@yale.edu kevin.oconnor@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA. steven.kleinstein@yale.edu david.hafler@yale.edu kevin.oconnor@yale.edu.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D001921:Brain / Q000473:pathology*; D002451:Cell Compartmentation; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage; D002465:Cell Movement / Q000276:immunology; D002574:Cervical Vertebrae / Q000473:pathology*; D002999:Clone Cells; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology*; D020539:Sequence Analysis, Protein
chemical_list: D000906:Antibodies; D000941:Antigens
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