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CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2016 Dec 01; Vol. 197 (11), pp. 4257-4265. Date of Electronic Publication: 2016 Oct 26. - Publication Year :
- 2016
-
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 relapsing-remitting 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-1a (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.<br /> (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Subjects :
- Aged
B-Lymphocytes pathology
Drug Therapy, Combination
Extracellular Signal-Regulated MAP Kinases immunology
Female
Humans
Immunologic Memory drug effects
Male
Middle Aged
Phosphorylation drug effects
Phosphorylation immunology
B-Lymphocytes immunology
CD40 Antigens immunology
Glatiramer Acetate administration & dosage
Interferon beta-1a administration & dosage
Lymphocyte Activation drug effects
MAP Kinase Signaling System drug effects
MAP Kinase Signaling System immunology
Multiple Sclerosis drug therapy
Multiple Sclerosis immunology
Multiple Sclerosis pathology
Mycophenolic Acid administration & dosage
Transcription Factor RelA immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 197
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 27798157
- Full Text :
- https://doi.org/10.4049/jimmunol.1600782