Abstract
Purpose: :
To determine the effect of innate and adaptive immunity in CNS demyelination in mice ocularly infected with different strains of HSV-1.
Methods: :
Effect of macrophages, DCs, NK cells, B cells, or T cells on CNS demyelination in female BALB/c or C57BL/6 mice following ocular infection with virulent HSV-1 strain McKrae, avirulent HSV-1 strain KOS, or a LAT- and γ-34.5-minus virus was determined at various times post infection by Luxol Fast Blue (LFB). Demyelination in IL-12p35-/-, IL-12p40-/-, IL-23p19-/-, and EBI3-/- was determined in infected mice by LFB. Contributions of T cells to CNS demyelination in the absence of macrophages and protection from CNS demyelination in macrophage-depleted mice injected with IL-12p70 DNA was determined in infected mice by LFB and IHC for HSV-1, GFAP, CD11b, and F4/80.
Results: :
Our results suggest that depletion of macrophages but not DCs, B-cells, NK cells, CD4+ T cells, CD8+ T cells, or both T cells induced CNS demyelination irrespective of virus or mice strain that was used. Similar to macrophage depletion, both IL-12p35-/- and IL-12p40-/- mice showed CNS demyelination following ocular infection, while no demyelination was detected in IL-23p19-/- or IL-35EBI3-/- infected mice. Demyelination was blocked in macrophage depleted mice following injection of IL-12p70 DNA. Similarly, demyelination in IL-12p35-/- or IL-12p40-/- mice was blocked following injection of these mice with IL-12p35 or IL-12p40 DNA or recombinant viruses expressing IL-12p35 or IL-12p40, respectively. Using CD4, CD8, and CD25 depletions and their knockout mice we have shown that demyelination was blocked in the absence of CD4 or CD25. FACS analyses shown elevation of CD4+CD25+FOXP3+ T cells in spleen of macrophage depleted and infected mice. Adoptive transfer of CD4+CD25+ T cells to macrophage-depleted SCID mice induced CNS demyelination in infected recipient mice.
Conclusions: :
In this study for the first time we have shown that macrophages play an important role in maintaining immune balance in the CNS by preventing the CD4 Tregs from becoming auto-reactive via their IL-12p70 function.
Keywords: astrocyte • immunomodulation/immunoregulation • herpes simplex virus