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Helminth Antigens Modulate Immune Responses in Cells from Multiple Sclerosis Patients through TLR2-Dependent Mechanisms¹

Dr. Raúl Carrea Institute for Neurological Research, Foundation for the Fight against Childhood Neurological Diseases (FLENI), Department of Neurology, Buenos Aires, Argentina

To better understand the link between parasite infections and the course of multiple sclerosis (MS), we studied the role of TLRs in helminth product recognition by dendritic cells (DCs) and B cells. Baseline expression of TLR2 was significantly higher in infected-MS patients compared with uninfected MS subjects or healthy controls. Moreover, cells exposed to TLR2 agonists or to soluble egg Ag (SEA) from Schistosoma mansoni resulted in significant TLR2 up-regulation. SEA suppressed the LPS-induced DCs production of IL-1β, IL-6, IL-12, and TNF- and enhanced TGF-β as well as IL-10 production. Similarly, after exposure to SEA, anti-CD40-activated B cells increased IL-10 production. Both processes were MyD88 dependent. In addition, SEA down-regulated the expression of LPS-induced costimulatory molecules on DCs in a MyD88-independent manner. DCs stimulation by SEA and TLR2 agonists induced increasing phosphorylation of the MAPK ERK1/2. Neither stimulus showed an effect on p38 and JNK1/2 phosphorylation, however. Addition of the ERK1/2 inhibitor U0126 was associated with dose-dependent inhibition of IL-10 and reciprocal enhancement of IL-12. Finally, cytokine effects and changes observed in DCs costimulatory molecule expression after SEA exposure were lost when TLR2 expression was silenced. Overall, these findings indicate that helminth molecules exert potent regulatory effects on both DCs and B cells through TLR2 regulation conducted via different signaling pathways. This knowledge could prove critical in developing novel therapeutic approaches for the treatment of autoimmune diseases such as MS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Dr. Raúl Carrea Institute for Neurological Research, Foundation for the Fight against Childhood Neurological Diseases (FLENI) (to J.C.).

² Address correspondence and reprint requests to Dr. Jorge Correale, Raúl Carrea Institute for Neurological Research, FLENI, Montañeses 2325, (1428) Buenos Aires, Argentina. E-mail address: jcorreale{at}fleni.org.ar

³ Abbreviations used in this paper: MS, multiple sclerosis; DC, dendritic cell; MBP, myelin basic protein; MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; PPD, purified protein derivative; rh, recombinant human; SEA, soluble egg Ag; siRNA, small interfering RNA.