The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model.
OBJECTIVE
Induction of tissue-specific experimental autoimmune diseases involves the use of complete Freund adjuvant containing Mycobacterium tuberculosis, whose recognition by the innate immune system depends on Toll-like receptors (TLRs) that signal through the adaptor molecule MyD88. The authors' previous study showed that MyD88(-/-) mice, but not TLR2(-/-), TLR4(-/-), or TLR9(-/-) mice, were resistant to experimental autoimmune uveitis (EAU).


METHODS
The EAU induction in mice deficient in TLR3 or mice double deficient in TLR2+4, TLR2+9, and TLR4+9 was examined and the role of the TLR agonists in the adjuvant effect involved in the induction of EAU was assessed.


RESULTS
TLR3-deficient and TLR2+4, TLR2+9, and TLR4+9 double-deficient mice were as susceptible to EAU as their control littermates. However, in mice immunized with a low-dose EAU regimen, TLR4 agonist lipopolysaccharide (LPS) enhanced EAU scores, delayed-type hypersensitivity responses, and antigen-specific T-cell proliferation. Antigen-specific IL-17 and IFN-gamma production by T lymphocytes was markedly increased in the LPS-treated group. The effects of LPS on EAU were abolished by treatment with an LPS deactivator polymyxin B. Inclusion of agonists for TLR2, TRL3, or TRL9 in immunization also enhanced EAU scores.


CONCLUSIONS
These results suggest that signaling of TLR2, TRL3, TRL4, and TRL9 is highly redundant in the adjuvant effect needed to induce EAU and that diverse microbial infections may contribute to the pathogenesis of diseases such as uveitis.
Fang
Jiazhu
J
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Fang
Dan
D
Silver
Phyllis B
PB
Wen
Feng
F
Li
Bing
B
Ren
Xiangrong
X
Lin
Qing
Q
Caspi
Rachel R
RR
Su
Shao Bo
SB
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D012177:Retinol-Binding Proteins / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology*; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D001324:Autoantigens; D005136:Eye Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D012177:Retinol-Binding Proteins; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000099214:Retinol-Binding Proteins, Interstitial; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse