Abstract
Experimental autoimmune encephalomyelitis (EAE) is - in certain aspects - regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specific immunity is induced in a defined way, the initial processes leading to CNS autoimmunity in humans are so far unknown. Despite essential restrictions, which exist regarding the interpretation of EAE data towards MS, EAE might be a useful model to study certain basic aspects of CNS autoimmunity. Studies in MS have demonstrated that established autoimmune pathology can be critically influenced by environmental factors, in particular viral and bacterial infections. To investigate this interaction, EAE as an instrument to study CNS autoimmunity under defined conditions appears to be a suitable experimental tool. For this reason, we here investigated the influence of the Toll-like-receptor (TLR) ligand CpG oligonucleotide (CpG) on already established CNS autoimmunity in murine proteolipid protein (PLP)-induced EAE in SJL mice. CpG were found to co-stimulate PLPp-specific IFN-γ production in the peripheral immune system and in the CNS. However, CpG induced Interleukin (IL)-17 production in the inflamed CNS both alone and in combination with additional PLPp stimulation. These findings might indicate a mechanism by which systemic infections and the microbial stimuli associated with them may influence already existing CNS autoimmune pathology.
Highlights
Research on the role of T cells in CNS autoimmune disease both in human diseases as well as in their experimental animal models currently centers on the endogenous requirements which are necessary for T cell activation as well as on the exogenous factors which trigger it
Injection of SJL mice with PLPp/CPG/IFA results in a PLPp-specific Th1 response, but not a Th17 response To investigate whether autoantigen specific T lymphocytes are present in the peripheral lymphatic tissue of mice immunized with PLPp/CpG/IFA, measurements of cytokine expression (IFN-g, IL-2, IL-17) in the spleens of animals were conducted by ELISPOT at day 14 after immunisation
The presence of CpG had a considerable superadditive effect on the number of IFN-gproducing cells, p = 0.0012 for PLPp vs. PLPp+CpG), but no effect on IL-2 production (Figure 3). These findings are comparable to cytokine responses of splenocytes isolated out of mice immunized with PLPp/ CpG/IFA at day 14
Summary
Research on the role of T cells in CNS autoimmune disease both in human diseases as well as in their experimental animal models currently centers on the endogenous requirements which are necessary for T cell activation as well as on the exogenous factors which trigger it. The presence of CpG had a considerable superadditive effect on the number of IFN-gproducing cells (mean: 809.43, SD: 367.45), p = 0.0012 for PLPp vs PLPp+CpG), but no effect on IL-2 production (mean: 519.48, SD: 415.49) (Figure 3) These findings are comparable to cytokine responses of splenocytes isolated out of mice immunized with PLPp/ CpG/IFA at day 14. CpG potentiate both autoantigen-specific IFN-g and IL-17 production locally in the CNS during acute EAE To study the impact of microbial components on cytokine responses in the CNS in acute EAE, pooled spinal cord single cell suspensions from mice with acute EAE at day 12 were restimulated with PLPp and CpG and the frequencies of cytokine-producing cells were determined by ELISPOT (Figure 4). The IFN-g/IL-17 ratio substantially differed depending on the type of stimulation (background: 0.19, PLPp: 0.61, PLPp+CpG: 1.18, CpG: 0.03)
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