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July 2019; 6 (4) ArticleOpen Access

α4-integrin deficiency in B cells does not affect disease in a T-cell–mediated EAE disease model

Rehana Z. Hussain, Petra D. Cravens, William A. Miller-Little, Richard Doelger, Valerie Granados, Emily Herndon, Darin T. Okuda, Todd N. Eagar, Olaf Stüve
First published April 16, 2019, DOI: https://doi.org/10.1212/NXI.0000000000000563
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Abstract

Objective The goal of this study was to investigate the role of CD 19+ B cells within the brain and spinal cord during CNS autoimmunity in a peptide-induced, primarily T-cell–mediated experimental autoimmune encephalomyelitis (EAE) model of MS. We hypothesized that CD19+ B cells outside the CNS drive inflammation in EAE.

Methods We generated CD19.Cre+/− α4-integrinfl/fl mice. EAE was induced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOGp35-55). Multiparameter flow cytometry was used to phenotype leukocyte subsets in primary and secondary lymphoid organs and the CNS. Serum cytokine levels and Ig levels were assessed by bead array. B-cell adoptive transfer was used to determine the compartment-specific pathogenic role of antigen-specific and non–antigen-specific B cells.

Results A genetic ablation of α4-integrin in CD19+/− B cells significantly reduced the number of CD19+ B cells in the CNS but does not affect EAE disease activity in active MOGp35-55-induced disease. The composition of B-cell subsets in the brain, primary lymphoid organs, and secondary lymphoid organs of CD19.Cre+/− α4-integrinfl/fl mice was unchanged during MOGp35-55-induced EAE. Adoptive transfer of purified CD19+ B cells from CD19.Cre+/− α4-integrinfl/fl mice or C57BL/6 wild-type (WT) control mice immunized with recombinant rMOG1-125 or ovalbumin323-339 into MOGp35-55-immunized CD19.Cre+/− α4-integrinfl/fl mice caused worse clinical EAE than was observed in MOGp35-55-immunized C57BL/6 WT control mice that did not receive adoptively transferred CD19+ B cells.

Conclusions Observations made in CD19.Cre+/− α4-integrinfl/fl mice in active MOGp35-55-induced EAE suggest a compartment-specific pathogenic role of CD19+ B cells mostly outside of the CNS that is not necessarily antigen specific.

Glossary

BM=
bone marrow;
DC=
dendritic cell;
EAE=
experimental autoimmune encephalomyelitis;
GC=
germinal center;
IFN=
interferon gamma;
IL=
interleukin;
LN=
lymph node;
MGZ=
marginal zone;
MOG=
myelin oligodendrocyte glycoprotein;
OVA=
ovalbumin;
PB=
plasma blast;
PC=
plasma cell;
WT=
wild type

Footnotes

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.

  • The Article Processing Charge was funded by United States Department of Veterans Affairs I01BX001674.

  • Received November 2, 2018.
  • Accepted in final form February 1, 2019.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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