title: Method of identifying natural antibodies for remyelination.
abstract: BACKGROUND
  Natural autoantibodies are part of the normal human immunoglobulin repertoire. These antibodies react to self-antigens, are usually polyreactive with relatively low affinity, and typically are of the IgM isotype. Natural IgMs in mice that stimulated remyelination in central nervous system (CNS) demyelinating disease all shared the characteristics of binding to the surface of live oligodendrocytes and myelinated tracts in living slices of CNS tissue.
  
  
  METHODS
  A screen for human IgMs with similar character resulted in two human natural antibodies, which when injected peripherally into animal models of demyelination induced remyelination. A recombinant human IgM (rHIgM22) that also promoted remyelination in vivo was constructed.
  
  
  RESULTS
  Very small doses of this IgM are required for the promotion of remyelination (EC50 is 460 ng per 20-g mouse). It is clear that after peripheral delivery, rHIgM22 enters the CNS and accumulates in CNS lesions. rHIgM22 was tracked in living mice using ferritin-labeled antihuman mu chain antibodies visualized by magnetic resonance imaging and traditional immunocytochemistry. Although the exact antigen recognized by rHIgM22 is not known, all mouse IgMs that promote remyelination bind to myelin membrane lipids, suggesting the antigen for rHIgM22 is similar.
  
  
  CONCLUSIONS
  We propose that the IgMs bind to CNS cells and reorganize the membrane, initiating a signal that results in oligodendrocyte proliferation and/or protection with an end result of increased myelin. Recombinant natural human antibodies are potentially important therapeutic molecules that may modulate a wide spectrum of human disease.
authors.affiliation: Department of Neurology, Guggenheim 401, Mayo Clinic, Rochester, MN 55905, USA. warrington.arthur@mayo.edu
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Warrington
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology*; D001812:Blood-Brain Barrier; D018188:Cardiovirus Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology / Q000628:therapy* / Q000821:virology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology* / Q000627:therapeutic use; D008563:Membrane Lipids / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis; D009186:Myelin Sheath / Q000276:immunology / Q000502:physiology*; D009836:Oligodendroglia / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D012038:Regeneration; D013116:Spinal Cord / Q000276:immunology; D017945:Theilovirus
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007075:Immunoglobulin M; D008563:Membrane Lipids; D011993:Recombinant Fusion Proteins
references.citation: J Neuroimmunol. 2004 Jan;146(1-2):153-61
references.pmid: 14698858
references.citation: Brain. 2000 Mar;123 Pt 3:519-31
references.pmid: 10686175
references.citation: Ann Neurol. 1990 Jan;27(1):12-7
references.pmid: 2301922
references.citation: J Neurosci Res. 2007 Apr;85(5):967-76
references.pmid: 17304578
references.citation: Curr Opin Immunol. 1995 Dec;7(6):812-8
references.pmid: 8679125
references.citation: Neurology. 1992 Feb;42(2):348-57
references.pmid: 1736164
references.citation: Prog Brain Res. 1992;91:149-54
references.pmid: 1410399
references.citation: J Neurosci. 1998 Oct 1;18(19):7700-8
references.pmid: 9742140
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6820-5
references.pmid: 10841576
references.citation: Neurology. 2009 Apr 7;72(14):1269-76
references.pmid: 19349608
references.citation: J Neurosci. 1994 Oct;14(10):6230-8
references.pmid: 7931575
references.citation: FASEB J. 2004 Oct;18(13):1577-9
references.pmid: 15319372
references.citation: Mol Cell Neurosci. 2003 Jan;22(1):14-24
references.pmid: 12595235
references.citation: Neurobiol Dis. 2004 Feb;15(1):120-31
references.pmid: 14751777
references.citation: Crit Rev Immunol. 1987;7(4):325-65
references.pmid: 2827957
references.citation: Glia. 2002 Mar 1;37(3):241-9
references.pmid: 11857682
references.citation: FASEB J. 2002 Aug;16(10):1325-7
references.pmid: 12154009
references.citation: J Neurol Sci. 1997 Sep 10;150(2):103-13
references.pmid: 9268236
references.citation: Exp Neurol. 2007 Aug;206(2):248-56
references.pmid: 17582399
references.citation: J Neuropathol Exp Neurol. 1987 Jan;46(1):84-95
references.pmid: 2432195
references.citation: J Autoimmun. 2007 Dec;29(4):213-8
references.pmid: 17888629
references.citation: J Histochem Cytochem. 1996 Sep;44(9):1005-11
references.pmid: 8773566