title: Immunoglobulins stimulate cultured Schwann cell maturation and promote their potential to induce axonal outgrowth.
abstract: BACKGROUND
  Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Intravenous immunoglobulins (IVIG) are widely used to treat autoimmune and inflammatory diseases including immune-mediated neuropathies. Nevertheless, promotion of peripheral nerve regeneration is currently an unmet therapeutical goal. We therefore examined whether immunoglobulins affect glial cell homeostasis, differentiation, and Schwann cell dependent nerve regenerative processes.
  
  
  METHODS
  The responses of different primary Schwann cell culture models to IVIG were investigated: immature or differentiation competent Schwann cells, myelinating neuron/glial cocultures, and dorsal root ganglion explants. Immature or differentiating Schwann cells were used to study cellular proliferation, morphology, and gene/protein expression. Myelination rates were determined using myelinating neuron/glia cocultures, whereas axonal outgrowth was assessed using non-myelinating dorsal root ganglion explants.
  
  
  RESULTS
  We found that IVIG specifically bind to Schwann cells and detected CD64 Fc receptor expression on their surface. In response to IVIG binding, Schwann cells reduced proliferation rates and accelerated growth of cellular protrusions. Furthermore, we observed that IVIG treatment transiently boosts myelin gene expression and myelination-related signaling pathways of immature cells, whereas in differentiating Schwann cells, myelin expression is enhanced on a long-term scale. Importantly, myelin gene upregulation was not detected upon application of IgG1 control antibodies. In addition, we demonstrate for the first time that Schwann cells secrete interleukin-18 upon IVIG stimulation and that this cytokine instructs these cells to promote axonal growth.
  
  
  CONCLUSIONS
  We conclude that IVIG can positively influence the Schwann cell differentiation process and that it enhances their regenerative potential.
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. nevena.tzekova@med.uni-duesseldorf.de.
authors.forename: Nevena
authors.initials: N
authors.lastname: Tzekova
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. andre-heinen@uni-duesseldorf.de.
authors.forename: André
authors.initials: A
authors.lastname: Heinen
authors.affiliation: Department of Immunology, Baxter Innovations GmbH, Vienna, Austria. sebastian.bunk@gmx.net.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bunk
authors.affiliation: Medical Affairs EMEA, Baxter Innovations GmbH, Vienna, Austria. corinna_hermann@baxter.com.
authors.forename: Corinna
authors.initials: C
authors.lastname: Hermann
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. Hans-Peter.Hartung@uni-duesseldorf.de.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Immunology, Baxter Innovations GmbH, Vienna, Austria. birgit_reipert@baxter.com.
authors.forename: Birgit
authors.initials: B
authors.lastname: Reipert
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. kuery@uni-duesseldorf.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Küry
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D007136:Immunoglobulins / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007136:Immunoglobulins; D020382:Interleukin-18; D009185:Myelin Proteins; D017452:Receptors, IgG