Abstract
Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease affecting the Central Nervous System (CNS), in which Th1 and Th17 cells appear to recognize and react against certain myelin sheath components. Epidemiological evidence has accumulated indicating steady increase in autoimmune disease incidence in developed countries. Reduced infectious disease prevalence in particular has been proposed as the cause. In agreement with this hypothesis, we recently demonstrated significantly better clinical and radiological outcome in helminth-infected MS patients, compared to uninfected ones. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion, including increased TGF-β and IL-10 levels. Interestingly, surface expression of TLR2, on both B cells and dendritic cells (DC) was significantly higher in infected MS patients. Moreover, stimulation of myelin-specific T cell lines with a TLR2 agonist induced inhibition of T cell proliferation, suppression of IFN-γ, IL-12, and IL-17 secretion, as well as increase in IL-10 production, suggesting the functional responses observed correlate with TLR2 expression patterns. Furthermore, parasite antigens were able to induce TLR2 expression on both B cells and DCs. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicating helminth-mediated signaling induced changes in cytokine secretion in a MyD88-dependent manner. In addition, helminth antigens significantly enhanced co-stimulatory molecule expression, effects not mediated by MyD88. Parasite antigens acting on MyD88 induced significant ERK kinase phosphorylation in DC. Addition of the ERK inhibitor U0126 was associated with dose-dependent IL-10 inhibition and reciprocal enhancement in IL-12, both correlating with ERK inhibition. Finally, cytokine effects and changes observed in co-stimulatory DC molecules after helminth antigen exposure were lost when TLR2 was silenced. Overall, the data described indicate that helminth molecules exert potent regulatory effects on both DCs and B cells from MS patients through TLR2 regulation.
Highlights
Multiple Sclerosis (MS) is a chronic autoimmune mediated disease of the Central Nervous System (CNS) characterized by inflammation, demyelination, and axonal loss (McFarland and Martin, 2007)
The cytoplasmic tail of CD1d is linked to signaling cascades associated to IL-10 transcription, suggesting yet another immune regulatory mechanism (Colgan et al, 1999). These results provide clear evidence that persistent helminth infections can induce an anti-inflammatory regulatory network, altering the course of MS, intervention studies are necessary to establish whether a direct link between parasites and the autoimmune response observed in MS exists
We have shown that soluble egg antigen (SEA) and TLR2 agonists modulate intracellular pathways resulting in suppression of IL-12, IL-6, IL-1β, and TNF-α dendritic cells (DC) production, and activation of TGF-β, as well as IL-10 production by both DCs and B cells through a MyD88-dependent pathway (Correale and Farez, 2009)
Summary
Does helminth activation of toll-like receptors modulate immune response in multiple sclerosis patients?. Reduced infectious disease prevalence in particular has been proposed as the cause In agreement with this hypothesis, we recently demonstrated significantly better clinical and radiological outcome in helminth-infected MS patients, compared to uninfected ones. Parasite antigens were able to induce TLR2 expression on both B cells and DCs. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicating helminth-mediated signaling induced changes in cytokine secretion in a MyD88-dependent manner. Helminth antigens significantly enhanced co-stimulatory molecule expression, effects not mediated by MyD88. Cytokine effects and changes observed in co-stimulatory DC molecules after helminth antigen exposure were lost when TLR2 was silenced. The data described indicate that helminth molecules exert potent regulatory effects on both DCs and B cells from MS patients through TLR2 regulation
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