Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Several lines of evidence point to an important role of genetic variation in KD susceptibility. Acute KD is associated with systemic immune activation, including elevated serum levels of IL-1, IL-4, IL-6, IL-8, IL-10, TNF£\, and decreased serum levels of TGF£], as well as a variety of other cytokines that are believed to play important roles in the onset of KD. This study aims to investigate the association of 14 various polymorphisms of nine cytokine genes (IL-1A, IL-1B, IL-1RN, IL-4, IL-6, IL-8, IL-10, TNFA and TGFB) with the risk of KD. A total of 213 KD children and 226 sex-matched infection disease-free adult controls were recruited in the hospital-based case-control study. The polymorphisms of IL-1 RN intron2 VNTR and IL-4 intron3 VNTR were determined by PCR. The polymorphisms of IL-1B T-31C and IL-1B C-511T were determined by PCR-RFLP. The other single nucleotide polymorphisms (SNPs) of IL-1A C-889T, IL-4 T-590C, IL-6 G-174C, IL-8 T-251A, IL-8 C+781T, IL-10 A-1082G, IL-10 T-819C, IL-10 A-592C, TNFA G-308A and TGFB C-509T were determined by TaqMan real-time PCR method. We found that there were no associations between the 14 polymorphisms and risk of KD, either in the single locus genetypic analysis or in the multiple loci haplotypic analysis. However, in the combined analysis, subjects with four and five ¡§at risk¡¨ genotypes combined from IL-1A, IL-1B, IL-1RN, IL-4, IL-6, IL-8, IL-10, TNFA and TGFB genetic polymorphisms were with 1.85 fold risk of KD as compared to those with less or equl to four ¡§at risk¡¨ genotypes (AOR=1.85; 95% CI, 1.16-2.97; P=0.011). Additionally, subjects with six and seven ¡§at risk¡¨ genetic polymorphisms were with 2.34 fold risk as compared to those with less or equal to four ¡§at risk¡¨ genotypes (AOR=2.34; 95% CI, 1.45-3.76; P=0.001). In conclusion, no association was found between cytokine genetic polymorphisms and KD risk, except in the combined analysis.

Kawasaki disease (KD) is a multisystem vasculitis leading to coronary artery aneurysm formation. In a superantigen-mediated murine model of KD, the development of coronary arteritis is mediated by T-cells through the production of TNFα. TNFα localizes to the coronary arteries, where it induces the expression of MMP-9, resulting in the breakdown of elastin and the formation of aneurysms. Statins have been recently shown to have anti-inflammatory and immunomodulatory properties as a result of the inhibition of small GTPases. In our murine model of KD, atorvastatin treatment inhibits superantigen mediated T- cell proliferation and cytokine production, including IL-2 and TNFα. Additionally, statin treatment inhibits TNFα-mediated MMP-9 production by vascular smooth muscle cells, through inhibition of the MEK/ERK pathway. Thus, statins modulate each of the critical steps in the pathogenesis of KD in a disease model, suggesting that statin use could alter the outcome and prognosis of children suffering with this disease.

Lactobacillus casei cell wall extract (LCWE)- induced coronary arteritis in mice models Kawasaki disease (KD). LCWE injections consist of T-cell dependent factors that expand superantigen (SAg)-activated T-cell receptor (TCR) Vβ6+ cells, and T-cell independent factors (i.e. TLR2 activity) that localize and sustain the immune response. TLR2 can upregulate costimulatory molecules to rescue SAg-activated T-cells from apoptosis. Accordingly, SAg-activated costimulation-rescued TCRVβ6+ cells are predicted to express activation markers, produce cytokines and be able to induce coronary arteritis. MAM was identified as a SAg able to activate TCRVβ6+ cells in a manner similar to LCWE; however a combination of MAM and TLR2 agonist Pam3Cys could not induce coronary arteritis. As another marker of disease, leukocyte recruitment molecule expression in the hearts of MAM+Pam3Cys- injected mice was found to be lower than in LCWE- injected mice. Therefore, LCWE contains unique features beyond TCRVβ6 stimulation and TLR2 activity that are important for disease induction.

Kawasaki disease (KD) is a multisystem vasculitis leading to coronary artery aneurysm formation. In a superantigen-mediated murine model of KD, the development of coronary arteritis is mediated by T-cells through the production of TNFα. TNFα localizes to the coronary arteries, where it induces the expression of MMP-9, resulting in the breakdown of elastin and the formation of aneurysms. Statins have been recently shown to have anti-inflammatory and immunomodulatory properties as a result of the inhibition of small GTPases. In our murine model of KD, atorvastatin treatment inhibits superantigen mediated T- cell proliferation and cytokine production, including IL-2 and TNFα. Additionally, statin treatment inhibits TNFα-mediated MMP-9 production by vascular smooth muscle cells, through inhibition of the MEK/ERK pathway. Thus, statins modulate each of the critical steps in the pathogenesis of KD in a disease model, suggesting that statin use could alter the outcome and prognosis of children suffering with this disease.

Lactobacillus casei cell wall extract (LCWE)- induced coronary arteritis in mice models Kawasaki disease (KD). LCWE injections consist of T-cell dependent factors that expand superantigen (SAg)-activated T-cell receptor (TCR) Vβ6+ cells, and T-cell independent factors (i.e. TLR2 activity) that localize and sustain the immune response. TLR2 can upregulate costimulatory molecules to rescue SAg-activated T-cells from apoptosis. Accordingly, SAg-activated costimulation-rescued TCRVβ6+ cells are predicted to express activation markers, produce cytokines and be able to induce coronary arteritis. MAM was identified as a SAg able to activate TCRVβ6+ cells in a manner similar to LCWE; however a combination of MAM and TLR2 agonist Pam3Cys could not induce coronary arteritis. As another marker of disease, leukocyte recruitment molecule expression in the hearts of MAM+Pam3Cys- injected mice was found to be lower than in LCWE- injected mice. Therefore, LCWE contains unique features beyond TCRVβ6 stimulation and TLR2 activity that are important for disease induction.

Superantigens (SAgs) are implicated in the initiation of many diseases, including Kawasaki disease (KD), a multi-system vasculitis that leads to persistent inflammation and damage of coronary arteries. T cells are central to the pathogenesis of SAg-mediated diseases. Lactobacillus casei cell wall extract (LCWE) induces a disease in mice that resembles human KD, and contains a novel SAg. Despite the fact that SAg-activated T cells undergo apoptosis, they persist and are necessary for coronary inflammation in this model of KD. We report rescue from apoptosis of SAg-stimulated T cells in vitro by costimulation through CD28 or 4-1BB. CD28- or 4-1BB-mediated signaling stimulated concurrently with SAg upregulated the anti-apoptotic factor Bcl-XL. In vivo, co-injection of LCWE and a 4-1BB agonist aggravated coronary disease. These findings suggest that costimulation of T cells affects extent of illness in this model of KD, and supports targeting costimulation as a therapeutic intervention in SAg-triggered diseases.

Kawasaki disease (KD) is a multisystem vasculitis with predilection for the coronary arteries. Although the cause of KD remains elusive, there is evidence to suggest a superantigenic trigger. When T-cells are activated by a superantigen (SAg) they undergo massive proliferation but eventually apoptose; however, in KD, we hypothesize that these T-cells persist and infiltrate the coronary arteries. Previous studies have shown that enhanced costimulation through CD28 or 4-1BB rescues T-cells from apoptosis and exacerbates disease in a mouse model of KD. Our results suggest that this signal needs to be initiated close in timing to that of the SAg. In addition, the two molecules can act independently of one another, but are not additive. Also, stimulation of the 4-1BB pathway in the presence of a SAg elicits a Th1 phenotype. Lastly, TRAF1 regulates this enhanced survival downstream of 4-1BB. Thus, these results provide new insights into the effects of costimulation in SAg-mediated disease, and suggest that these pathways need to be targeted early to abrogate the enhanced survival of SAg-activated T-cells.

Superantigens (SAgs) are implicated in the initiation of many diseases, including Kawasaki disease (KD), a multi-system vasculitis that leads to persistent inflammation and damage of coronary arteries. T cells are central to the pathogenesis of SAg-mediated diseases. Lactobacillus casei cell wall extract (LCWE) induces a disease in mice that resembles human KD, and contains a novel SAg. Despite the fact that SAg-activated T cells undergo apoptosis, they persist and are necessary for coronary inflammation in this model of KD. We report rescue from apoptosis of SAg-stimulated T cells in vitro by costimulation through CD28 or 4-1BB. CD28- or 4-1BB-mediated signaling stimulated concurrently with SAg upregulated the anti-apoptotic factor Bcl-XL. In vivo, co-injection of LCWE and a 4-1BB agonist aggravated coronary disease. These findings suggest that costimulation of T cells affects extent of illness in this model of KD, and supports targeting costimulation as a therapeutic intervention in SAg-triggered diseases.

Kawasaki disease (KD) is a multisystem vasculitis with predilection for the coronary arteries. Although the cause of KD remains elusive, there is evidence to suggest a superantigenic trigger. When T-cells are activated by a superantigen (SAg) they undergo massive proliferation but eventually apoptose; however, in KD, we hypothesize that these T-cells persist and infiltrate the coronary arteries. Previous studies have shown that enhanced costimulation through CD28 or 4-1BB rescues T-cells from apoptosis and exacerbates disease in a mouse model of KD. Our results suggest that this signal needs to be initiated close in timing to that of the SAg. In addition, the two molecules can act independently of one another, but are not additive. Also, stimulation of the 4-1BB pathway in the presence of a SAg elicits a Th1 phenotype. Lastly, TRAF1 regulates this enhanced survival downstream of 4-1BB. Thus, these results provide new insights into the effects of costimulation in SAg-mediated disease, and suggest that these pathways need to be targeted early to abrogate the enhanced survival of SAg-activated T-cells.

Kawasaki disease (KD) is an acute inflammatory disease characterized by persistent inflammation of the coronary arteries. KD is characterized by the release of cytokines such as tumor necrosis factor alpha (TNFα) and is thought to be initiated by a superantigen (SAg). The Lactobacillus casei cell wall extract model of KD demonstrates a critical requirement for TNFα and its receptor during pathogenesis, although the precise effect of TNFα is unknown. A persistent T cell infiltrate in the coronary artery disagrees with established fates of SAg activated cells, which undergo apoptosis. In this work, TNFα was found to promote the survival of SAg-reactive T cells. The results demonstrate that TNFα regulates B7.2 molecule expression on antigen presenting cells, and that TNFα indirectly promotes the survival of SEB-stimulated T cells by driving costimulation. These observations demonstrate how TNFα prevents T cell apoptosis and lend support to KD therapies which target TNFα and B7.