title: CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics.
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.
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Ding
authors: D
authors: Chen
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Sara J
authors: 0000-0002-7811-197X
authors: SJ
authors: Ireland
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Gina
authors: 0000-0002-8474-495X
authors: G
authors: Remington
authors: Department of Neurology, University of Colorado, Aurora, CO 80045.
authors: Enrique
authors: E
authors: Alvarez
authors: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and.
authors: Michael K
authors: MK
authors: Racke
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Benjamin
authors: 0000-0002-2091-8201
authors: B
authors: Greenberg
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Elliot M
authors: EM
authors: Frohman
authors: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390; nancy.monson@utsouthwestern.edu.|Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors: Nancy L
authors: NL
authors: Monson
mesh_terms: D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology*; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005260:Female; D000068717:Glatiramer Acetate / Q000008:administration & dosage*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D000068556:Interferon beta-1a / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009173:Mycophenolic Acid / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000068717:Glatiramer Acetate; D048049:Extracellular Signal-Regulated MAP Kinases; D009173:Mycophenolic Acid; D000068556:Interferon beta-1a