Delivery of an miR155 inhibitor by anti-CD20 single-chain antibody into B cells reduces the acetylcholine receptor-specific autoantibodies and ameliorates experimental autoimmune myasthenia gravis

Clin Exp Immunol. 2014 May;176(2):207-21. doi: 10.1111/cei.12265.

Abstract

MicroRNA-155 (miR155) is required for antibody production after vaccination with attenuated Salmonella. miR155-deficient B cells generated reduced germinal centre responses and failed to produce high-affinity immunoglobulin (Ig)G1 antibodies. In this study, we observed up-regulation of miR155 in the peripheral blood mononuclear cells (PBMCs) of patients with myasthenia gravis (MG), and miR155 was also up-regulated in torpedo acetylcholine receptor (T-AChR)-stimulated B cells. We used an inhibitor of miR155 conjugated to anti-CD20 single-chain antibody to treat both the cultured B cells and the experimental autoimmune MG (EAMG) mice. Our results demonstrated that silencing of miR155 by its inhibitor impaired the B cell-activating factor (BAFF)-R-related signalling pathway and reduced the translocation of nuclear factor (NF)-κB into the nucleus. Additionally, AChR-specific autoantibodies were reduced, which may be related to the altered amounts of marginal zone B cells and memory B cells in the spleens of EAMG mice. Our study suggests that miR155 may be a promising target for the clinical therapy of MG.

Keywords: RNA interference; experimental autoimmune myasthenia gravis; immunomodulation; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Active Transport, Cell Nucleus / immunology
  • Animals
  • Antigens, CD20 / immunology
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Female
  • Gene Expression / immunology
  • Gene Knockdown Techniques
  • Humans
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • Myasthenia Gravis / genetics
  • Myasthenia Gravis / immunology
  • Myasthenia Gravis, Autoimmune, Experimental / genetics
  • Myasthenia Gravis, Autoimmune, Experimental / immunology*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Receptors, Cholinergic / immunology*
  • Receptors, Interleukin-4 / genetics
  • Receptors, Interleukin-4 / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / immunology*
  • Torpedo / immunology
  • Torpedo / metabolism

Substances

  • Antigens, CD20
  • Autoantibodies
  • MIRN155 microRNA, human
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • NF-kappa B
  • Receptors, Cholinergic
  • Receptors, Interleukin-4
  • Single-Chain Antibodies