Toll-like receptor (TLR)7 and TLR9 agonists enhance interferon (IFN) beta-1a's immunoregulatory effects on B cells in patients with relapsing-remitting multiple sclerosis (RRMS).
We report that B cells from patients with RRMS have decreased endogenous IFN-β secretion and deficient IFN receptor (IFNAR)1/2 and TLR7 gene expression in comparison to healthy controls (HCs), which may contribute to disregulation of cytokine secretion by B cells. We propose that TLR7 and TLR9 stimulation with loxorubin (LOX) and CpG, in combination with exogenous IFN-β may effectively reconstitute endogenous IFN-β production deficit and induce the secretion of immunoregulatory cytokines by B cells. Both LOX/IFN-β and CpG/IFN-β in-vitro treatments of B cells from RRMS patients induced higher endogenous IFN-β gene expression in comparison to the exogenous IFN-β alone. CpG/IFN-β combination induced higher secretion of IL-10, TGF-β, and IL-27 in comparison to stimulation with IFN-β. Our study provides a basis for future clinical studies employing IFN-β and TLR7/9 agonists, which may enhance the resolution of the inflammatory response in RRMS.
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
Yazhong
Y
Tao
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
Xin
X
Zhang
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States. Electronic address: markovic@email.unc.edu.
Silva
S
Markovic-Plese
D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D000068717:Glatiramer Acetate / Q000627:therapeutic use; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D060245:Tetraspanin 29 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000172:deficiency; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000187:drug effects
D015704:CD4 Antigens; D016207:Cytokines; C494234:IRF7 protein, human; D007155:Immunologic Factors; D050839:Interferon Regulatory Factor-7; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495348:TLR7 protein, human; D060245:Tetraspanin 29; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D006151:Guanosine; D000068717:Glatiramer Acetate; D016899:Interferon-beta; C068562:loxoribine; D008775:Methylprednisolone
B cells; IFN-β-1a; Multiple sclerosis; TLR7; TLR9