Helminth antigens modulate immune responses in cells from multiple sclerosis patients through TLR2-dependent mechanisms.
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-1beta, IL-6, IL-12, and TNF-alpha and enhanced TGF-beta 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.
Correale
Jorge
J
Dr. Raúl Carrea Institute for Neurological Research, Foundation for the Fight against Childhood Neurological Diseases (FLENI), Department of Neurology, Buenos Aires, Argentina. jcorreale@fleni.org.ar
Farez
Mauricio
M
D000328:Adult; D000818:Animals; D000947:Antigens, Helminth / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D005260:Female; D006801:Humans; D008024:Ligands; D008074:Lipoproteins / Q000494:pharmacology; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D010063:Ovum / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D000947:Antigens, Helminth; D008024:Ligands; D008074:Lipoproteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine