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Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611
Multiple sclerosis is an immune-mediated demyelinating
disease of unknown etiology that presents with either a
chronic-progressive or relapsing-remitting clinical course. Theiler’s
murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD)
and relapsing-remitting experimental autoimmune encephalomyelitis
(R-EAE) in the SJL/J mouse are both relevant murine CD4+ T
cell-mediated demyelinating models that recapitulate the multiple
sclerosis disease phenotypes. To determine the cellular and molecular
basis for these observed differences in clinical course, we
quantitatively analyzed the temporal expression of pro- and
antiinflammatory cytokine mRNA expression in the central nervous system
(CNS) and the phenotype of the inflammatory mononuclear infiltrates.
TMEV-infected SJL/J mice expressed IFN-
, TNF-
, IL-10, and IL-4
mRNA during the preclinical phase, and their levels continued to
increase throughout the duration of the chronic-progressive disease
course. These data correlated with the continued presence of both
CD4+ T cells and F4/80+ macrophages within the
CNS infiltrates. In contrast, SJL/J mice with
PLP139–151-induced R-EAE displayed a biphasic pattern of
CNS expression for the proinflammatory cytokines, IFN- and TNF-,
with expression peaking at the height of the acute phase and
relapse(s). This pattern correlated with dynamic changes in the
CD4+ T cell and F4/80+ macrophage populations
during relapsing-remitting disease progression. Interestingly, IL-4
message was undetectable until disease remission(s), demonstrating its
potential role in the intrinsic regulation of ongoing disease, whereas
IL-10 was continuously expressed, arguing against a regulatory role in
either disease. These data suggest that the kinetics of cytokine
expression together with the nature of the persistent inflammatory
infiltrates are major contributors to the differences in clinical
course between TMEV-IDD and R-EAE.
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