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Interferon-β inhibits toll-like receptor 9 processing in multiple sclerosis

Konstantin E Balashov1, Latt Latt Aung, Adi Vaknin-Dembinsky

  • 1Department of Neurology, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. kbalashov@yahoo.com

Annals of Neurology
|November 10, 2010
PubMed
Abstract

Insights

Interferon-beta (IFN-β) therapy for multiple sclerosis (MS) may work by blocking plasmacytoid dendritic cell (pDC) activation. This inhibition of Toll-like receptor 9 (TLR9) processing reduces the immune response to viral infections, potentially lowering MS relapse rates.

Area of Science:

  • Immunology
  • Neuroscience
  • Virology

Background:

  • Viral infections are linked to multiple sclerosis (MS) pathogenesis.
  • Plasmacytoid dendritic cells (pDCs) play a role in MS and detect viral DNA via Toll-like receptor 9 (TLR9).
  • TLR9 must be processed to become functional, and its activation promotes T-helper responses implicated in MS.

Purpose of the Study:

  • To investigate the immunomodulatory effects of interferon-beta (IFN-β) on pDCs in MS patients.
  • To determine if IFN-β affects TLR9 processing and subsequent pDC activation.
  • To explore a potential mechanism for how IFN-β reduces MS exacerbations.

Main Methods:

  • pDCs were isolated from healthy individuals and MS patients (relapsing-remitting MS and clinically isolated syndrome).
  • Cytokine secretion from TLR9-activated pDCs was measured using ELISA and multianalyte profiling.
  • TLR9 gene and protein expression levels were analyzed via DNA microarrays and western blot.

Main Results:

  • Untreated MS patients' pDCs produced higher levels of IFN-α (a Th1 cytokine) upon TLR9 activation compared to healthy subjects.
  • IFN-β-treated MS patients' pDCs showed reduced production of IFN-α, IL-6, and TNF-α.
  • pDCs from IFN-β-treated patients had significantly lower levels of processed TLR9 protein, but normal full-length TLR9 protein and gene expression.

Conclusions:

  • Interferon-beta (IFN-β) inhibits pDC activation by blocking Toll-like receptor 9 (TLR9) processing.
  • This mechanism reduces the immune response to viral pathogens, potentially decreasing the frequency of MS relapses.
  • This represents a novel immunomodulatory pathway for IFN-β in managing multiple sclerosis.

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