CD40-mediated NF-κB activation in B cells is increased in multiple sclerosis and modulated by therapeutics

Ding Chen, Sara J. Ireland, Gina Remington, Enrique Alvarez, Michael K. Racke, Benjamin Greenberg, Elliot Frohman, Nancy L Monson

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsingremitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-β-1α (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease.

Original languageEnglish (US)
Pages (from-to)4257-4265
Number of pages9
JournalJournal of Immunology
Volume197
Issue number11
DOIs
StatePublished - Dec 1 2016

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Multiple Sclerosis
B-Lymphocytes
Mycophenolic Acid
Phosphorylation
Tissue Donors
Therapeutics
Chronic Progressive Multiple Sclerosis
CD40 Ligand
p38 Mitogen-Activated Protein Kinases
Autoimmune Diseases
Homeostasis
Research

ASJC Scopus subject areas

  • Immunology

Cite this

CD40-mediated NF-κB activation in B cells is increased in multiple sclerosis and modulated by therapeutics. / Chen, Ding; Ireland, Sara J.; Remington, Gina; Alvarez, Enrique; Racke, Michael K.; Greenberg, Benjamin; Frohman, Elliot; Monson, Nancy L.

In: Journal of Immunology, Vol. 197, No. 11, 01.12.2016, p. 4257-4265.

Research output: Contribution to journalArticle

Chen, Ding ; Ireland, Sara J. ; Remington, Gina ; Alvarez, Enrique ; Racke, Michael K. ; Greenberg, Benjamin ; Frohman, Elliot ; Monson, Nancy L. / CD40-mediated NF-κB activation in B cells is increased in multiple sclerosis and modulated by therapeutics. In: Journal of Immunology. 2016 ; Vol. 197, No. 11. pp. 4257-4265.
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