STAT4- and STAT6-signaling molecules in a murine model of multiple sclerosis.
Epidemiological studies suggest that an environmental factor (possibly a virus) acquired early in life may trigger multiple sclerosis (MS). The virus may remain dormant in the central nervous system but then becomes activated in adulthood. All existing models of MS are characterized by inflammation or demyelination that follows days after virus infection or antigen inoculation. While investigating the role of CD4+ T cell responses following Theiler's virus infection in mice deficient in STAT4 or STAT6, we discovered a model in which virus infection was followed by demyelination after a very prolonged incubation period. STAT4-/- mice were resistant to demyelination for 180 days after infection, but developed severe demyelination after this time point. Inflammatory cells and up-regulation of Class I and Class II MHC antigens characterized these lesions. Virus antigen was partially controlled during the early chronic phase of the infection even though viral RNA levels remained high throughout infection. Demyelination correlated with the appearance of virus antigen expression. Bone marrow reconstitution experiments indicated that the mechanism of the late onset demyelination was the result of the STAT4-/- immune system. Thus, virus infection of STAT4-/- mice results in a model that may allow for dissection of the immune events predisposing to late-onset demyelination in MS.
Rodriguez
Moses
M
Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA. rodriguez.moses@mayo.edu
Zoecklein
Laurie
L
Gamez
Jeffrey D
JD
Pavelko
Kevin D
KD
Papke
Louisa M
LM
Nakane
Shunya
S
Howe
Charles
C
Radhakrishnan
Suresh
S
Hansen
Michael J
MJ
David
Chella S
CS
Warrington
Arthur E
AE
Pease
Larry R
LR
D000818:Animals; D001921:Brain / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018188:Cardiovirus Infections / Q000378:metabolism*; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I / Q000235:genetics; D005802:Genes, MHC Class II / Q000235:genetics; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000821:virology; D009474:Neurons / Q000473:pathology; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000473:pathology; D017945:Theilovirus; D013997:Time Factors
D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse