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Sci Transl Med. 2014 Aug 6;6(248):248ra107. doi: 10.1126/scitranslmed.3008879.

B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.

Author information

1
Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA.
2
Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA. Bioengineering Program, Faculty of Engineering, Bar-Ilan University, Ramat Gan 52900, Israel.
3
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA.
4
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
5
AbVitro Incorporated, Boston, MA 02210, USA.
6
Department of Neurology, Erasmus MC, University Medical Center Rotterdam, and MS Centrum ErasMS, 3000 CA Rotterdam, the Netherlands.
7
Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA.
8
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, and MS Centrum ErasMS, 3000 CA Rotterdam, the Netherlands.
9
Neurology Research, West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
10
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. AbVitro Incorporated, Boston, MA 02210, USA.
11
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.
12
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.
13
Department of Neurology, Yale School of Medicine, New Haven, CT 06511, USA. steven.kleinstein@yale.edu david.hafler@yale.edu kevin.oconnor@yale.edu.

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.

PMID:
25100741
PMCID:
PMC4388137
DOI:
10.1126/scitranslmed.3008879
[Indexed for MEDLINE]
Free PMC Article

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