A monoclonal natural autoantibody that promotes remyelination suppresses central nervous system inflammation and increases virus expression after Theiler's virus-induced demyelination.
We have used an established experimental model of multiple sclerosis to investigate the potential beneficial relationship between natural autoimmunity and remyelination after central nervous system (CNS) demyelination. Intracerebral infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV) produces chronic, progressive, inflammatory CNS demyelination. Chronically infected SJL/J mice show minimal spontaneous remyelination, which is in part due to a T cell-mediated immune response inhibiting myelin repair. We previously identified a monoclonal natural autoantibody, designated SCH94.03, that promotes remyelination when passively transferred to chronically infected SJL/J mice. The mechanism whereby SCH94.03 promotes remyelination is unknown, although previous reports suggest that natural autoantibodies can modulate immune system function. In this report we demonstrate that treatment with SCH94.03 reduced by 2- to 3-fold the number of CD4(+) and CD8(+) cells infiltrating the CNS of SJL/J mice chronically infected with TMEV, in the absence of global lymphocyte depletion. Associated with the decreased inflammation was a 2- to 3-fold increase in virus antigen expression without a significant increase in viral RNA or virus titers. Treatment with SCH94.03 also suppressed the humoral immune response to a T cell-dependent antigen in chronically infected mice. Immunohistochemical staining showed that SCH94.03 labeled MHC class II-positive dendritic cells in peripheral lymphoid organs. These results are consistent with the proposed immunomodulatory function of natural autoantibodies and suggest that one mechanism whereby SCH94.03 promotes CNS remyelination in chronically infected SJL/J mice is through inhibition of a pathogenic immune response.
Miller
D J
DJ
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Njenga
M K
MK
Murray
P D
PD
Leibowitz
J
J
Rodriguez
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes; D003520:Cyclophosphamide / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D018655:Lymphocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000276:immunology; D012367:RNA, Viral / Q000096:biosynthesis; D013116:Spinal Cord / Q000276:immunology; D017945:Theilovirus; D014779:Virus Replication
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D012367:RNA, Viral; D003520:Cyclophosphamide