Down-regulation of TLR2, 3, 9 and Signaling Mediators, MyD88 and TRIF, Gene Transcript Levels in Patients with Kawasaki Disease Treated with IVIG
Kawasaki disease (KD) is an acute febrile systemic vasculitis of childhood characterized by elevated levels of inflammatory mediators at the acute stage. High-dose intravenous immunoglobulin (IVIG) is well accepted as a conventional therapy for KD. The aim of the present study was to determine the expression level of Toll like receptors (TLRs) and their corresponding signaling mediators in PBMCs of IVIG-treated KD patients. TLR2, 3, 9 and signaling mediators, MyD88 and TRIF transcript levels were determined in PBMCs from 31 KD patients, before (acute phase), 2 weeks later (sub-acute phase) and 6 weeks later (convalescent phase) of IVIG therapy using real time PCR. The mean age of the patients was 3.6 years and 65% of subjects were male and 35% were female. 20 age-matched irrelevant febrile patients and 20 healthy subjects were included as control groups. Elevated levels of TLR2, MyD88, and TRIF gene transcripts were observed in the PBMCs at acute phase of untreated KD patients in compression with normal subjects. IVIG therapy resulted in significant decrease in TLR2, 3 and 9 (60-90%) as well as MyD88 and TRIF (60-70%) transcripts following 2 and 6 weeks. With Regard to significant up-regulation of MyD88 and TRIF at the acute phase of KD, our findings suggest TLR signaling pathway potential in KD pathogenesis and may also support the assumption of an infectious background in KD. Down-regulation of TLR members and corresponding mediators in IVIG treated patient suggest general TLR pathway suppression as a novel anti-inflammatory mechanism of IVIG.
1. Gerding R. Kawasaki disease: a review. J Pediatr Health Care 2011; 25(6):379-87.
2. Son MB, Newburger JW. Kawasaki disease. Pediatr Rev 2013, 34(4):151-62.
3. Cassidy J, Petty R, Laxer R, Lindsley B. The text book of pediatric reumatology 2010:505-15.
4. Yanagisawa M, Kobayashi N, Matsuya S. Myocardial infarction due to coronary thromboarteritis, following acute febrile mucocutaneous lymph node syndrome (MLNS) in an infant. Pediatrics 1974; 54(3):277-80.
5. Kato H, Koike S, Yamamoto M, Ito Y, Yano E. Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J Pediatr 1975; 86(6):892-8.
6. Galeotti C, Bayry J, Kone-Paut I, Kaveri SV. Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin. Autoimmun Rev 2010;9(6):441-8.
7. Ikeda K, Yamaguchi K, Tanaka T, Mizuno Y, Hijikata A, Ohara O, et al. Unique activation status of peripheral blood mononuclear cells at acute phase of Kawasaki disease. Clin Exp Immunol 2010; 160(2):246-55.
8. Matsubara T, Ichiyama T, Furukawa S. Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol 2005; 141(3):381-7.
9. Hui-Yuen JS, Duong TT, Yeung RS. TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease. J Immunol 2006; 176(10):6294-301.
10. Ichiyama T, Yoshitomi T, Nishikawa M, Fujiwara M, Matsubara T, Hayashi T, et al. NF-kappaB activation in peripheral blood monocytes/macrophages and T cells during acute Kawasaki disease. Clin Immunol 2001;99(3):373-7.
11. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and long- term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004; 114(6):1708-33.
12. Ichiyama T, Ueno Y, Isumi H, Niimi A, Matsubara T,Furukawa S. An immunoglobulin agent (IVIG) inhibits NF- kappaB activation in cultured endothelial cells of coronary arteries in vitro. Inflamm Res 2004; 53(6):253-6.
13. Kessel A, Peri R, Haj T, Snir A, Slobodin G, Sabo E, et al.IVIg attenuates TLR-9 activation in B cells from SLE patients. J Clin Immunol 2011; 31(1):30-8.
14. Akira S. Toll-like receptor signaling. J Biol Chem 2003;278(40):38105-8.
15. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002; 168(9):4531-7.
16. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5):373-84.
17. Takeda K, Akira S. Toll-like receptors in innate immunity.Int Immunol 2005; 17(1):1-14.
18. Younesi V, Nikzamir H, Yousefi M, Khoshnoodi J, Arjmand M, Rabbani H, et al. Epstein Barr virus inhibits the stimulatory effect of TLR7/8 and TLR9 agonists but not CD40 ligand in human B lymphocytes. Microbiol Immunol 2010; 54(9):534-41.
19. Ghaderi H, Kiany F, Razmkhah M, Dadras S, Chenari N, Hosseini A, et al. mRNA expression of pattern recognition receptors and their signaling mediators in healthy and diseased gingival tissues. J Indian Soc Periodontol 2014;18(2):150-4.
20. Nejatollahi F, Ranjbar R, Younesi V, Asgharpour M.Deregulation of HER2 downstream signaling in breast cancer cells by a cocktail of anti-HER2 scFvs. Oncol Res 2013; 20(8):333-40.
21. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29(9):e45.
22. Schulte DJ, Yilmaz A, Shimada K, Fishbein MC, Lowe EL, Chen S, et al. Involvement of innate and adaptive immunity in a murine model of coronary arteritis mimicking Kawasaki disease. J Immunol 2009; 183(8):5311-8.
23. Rosenkranz ME, Schulte DJ, Agle LM, Wong MH, Zhang
W, Ivashkiv L, et al. TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease. Circulation 2005;112(19):2966-73.
24. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124(4):783-801.
25. Wang GB, Li CR, Zu Y. [Change of MyD88-independent signal transduction of Toll-like receptor 4 in immunological pathogenesis of Kawasaki disease]. Zhonghua Er Ke Za Zhi 2007; 45(11):818-23.
26. Freeman AF, Shulman ST. Kawasaki disease: summary of the American Heart Association guidelines. Am Fam Physician 2006; 74(7):1141-8.
27. Ichiyama T, Ueno Y, Hasegawa M, Niimi A, Matsubara T, Furukawa S. Intravenous immunoglobulin inhibits NF- kappaB activation and affects Fcgamma receptor expression in monocytes/macrophages. Naunyn Schmiedebergs Arch Pharmacol 2004; 369(4):428-33.
28. Abe J, Jibiki T, Noma S, Nakajima T, Saito H, Terai M.Gene expression profiling of the effect of high-dose intravenous Ig in patients with Kawasaki disease. J Immunol 2005; 174(9):5837-45.
29. Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology (Oxford) 2011; 50(4):689-96.
30. Tadema H, Abdulahad WH, Stegeman CA, Kallenberg CG, Heeringa P. Increased expression of Toll-like receptors by monocytes and natural killer cells in ANCA-associated vasculitis. PLoS One 2011; 6(9):e24315.
31. Giordani L, Quaranta MG, Marchesi A, Straface E, Pietraforte D, Villani A, et al. Increased frequency of immunoglobulin (Ig)A-secreting cells following Toll-like receptor (TLR)-9 engagement in patients with Kawasaki disease. Clin Exp Immunol 2011; 163(3):346-53.
32. Seite JF, Guerrier T, Cornec D, Jamin C, Youinou P, Hillion S. TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. J Autoimmun 2011; 37(3):190-7.
|Issue||Vol 14, No 2 (2015)|
|IVIG Kawasaki disease MyD88 Toll like receptors TRIF|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|