CD40L is critical for protection from demyelinating disease and development of spontaneous remyelination in a mouse model of multiple sclerosis.
Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2b mice. CD40L-mediated interactions were also necessary for development of protective H-2b-restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology.
Drescher
K M
KM
Department of Immunology, Mayo Medical School, Rochester, MN 55905, USA.
Zoecklein
L J
LJ
Pavelko
K D
KD
Rivera-Quinones
C
C
Hollenbaugh
D
D
Rodriguez
M
M
D000818:Animals; D023201:CD40 Ligand; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D002531:Cerebellum / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009186:Myelin Sheath / Q000276:immunology* / Q000473:pathology / Q000648:ultrastructure; D017072:Neostriatum / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000276:immunology*; D017945:Theilovirus / Q000276:immunology
D036022:Capsid Proteins; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; D018696:Neuroprotective Agents; C442556:VP2 protein, Theilovirus; D023201:CD40 Ligand