title: Pertussis toxin is superior to TLR ligands in enhancing pathogenic autoimmunity, targeted at a neo-self antigen, by triggering robust expansion of Th1 cells and their cytokine production.
abstract: Microbial products are assumed to play a major role in triggering pathogenic autoimmunity. Recently accumulated data have shown that these products stimulate the immune system by interacting with TLRs, expressed on APCs. To examine the capacity of various TLR ligands to trigger pathogenic autoimmunity, we used a system in which naive CD4 cells, specific against hen egg lysozyme (HEL), are injected into recipient mice expressing HEL in their eyes. Only when stimulated, the naive cells acquire pathogenic capacity and induce ocular inflammation. Seven TLR ligands were tested in this system: lipoteichoic acid/peptidoglycan, zymosan, poly (I:C), LPS, pertussis toxin (PTX), flagellin, and CpG oligodeoxynucleotide. Treatment of recipient mice with HEL alone stimulated proliferation of the transferred cells, but no disease, whereas ocular inflammation did develop in recipient mice coinjected with HEL and any one of the seven TLR ligands. Inflammation induced by PTX surpassed by its severity those induced by all other tested TLR ligands and was accompanied by a dramatic increase in number of the transferred cells that acquired features of effector Th1 lymphocytes. Ocular inflammation and number of transferred cells in recipients injected with PTX and HEL were substantially reduced by treatment with Abs against IFN-gamma or IL-12, thus indicating the role of these cytokines in the PTX effect. Overall, our observations demonstrate that various TLR ligands are capable of triggering pathogenic autoimmunity and that PTX surpasses other microbial products in this activity, by stimulating excessive proliferation and polarization toward Th1 of naive T cells.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institute of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Fujimoto
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.forename: Guangpu
authors.initials: G
authors.lastname: Shi
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Vistica
authors.forename: Eric F
authors.initials: EF
authors.lastname: Wawrousek
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
authors.forename: Igal
authors.initials: I
authors.lastname: Gery
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007905:Lens Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D037342:Pertussis Toxin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008024:Ligands; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma; D037342:Pertussis Toxin; C421864:hen egg lysozyme; D009113:Muramidase