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)

J Neuroimmunol. 2016 Sep 15;298:181-8. doi: 10.1016/j.jneuroim.2016.07.019. Epub 2016 Jul 22.

Abstract

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.

Keywords: B cells; IFN-β-1a; Multiple sclerosis; TLR7; TLR9.

MeSH terms

  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • CD4 Antigens / metabolism
  • Case-Control Studies
  • Cytokines / genetics
  • Cytokines / metabolism
  • Drug Synergism
  • Female
  • Glatiramer Acetate / therapeutic use
  • Guanosine / analogs & derivatives*
  • Guanosine / pharmacology
  • Humans
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Interferon-beta / therapeutic use
  • Male
  • Methylprednisolone / therapeutic use
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Multiple Sclerosis, Relapsing-Remitting / pathology*
  • Myeloid Differentiation Factor 88 / metabolism
  • STAT1 Transcription Factor / metabolism
  • Tetraspanin 29 / metabolism
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 7 / deficiency
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / drug effects

Substances

  • CD4 Antigens
  • Cytokines
  • IRF7 protein, human
  • Immunologic Factors
  • Interferon Regulatory Factor-7
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • TLR7 protein, human
  • Tetraspanin 29
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Guanosine
  • Glatiramer Acetate
  • Interferon-beta
  • loxoribine
  • Methylprednisolone