Similar results were obtained by Lee et?al. virus.46 SAs are LRRC63 a family of potent immunostimulatory proteins whose particular structures and sequences lead to a shared ability to by-pass the mechanism of conventional major histocompatibility complex (MHC)-restricted antigen processing. When an SA is involved, T cell responses are quantitatively and qualitatively different from conventional T cell activation by normal antigens. In particular, SAs activate T cells in a manner that depends on the T cell receptor variable domain (V), and so a large number of T cells can be simultaneously activated.85 The activation is extremely potent and a number of studies have found that KS is characterised by the marked activation of T cells and monocytes/macrophages, and increased production of IL-1, TNF- and IL-6, which are the same immunological findings as those of TSS.47 Although some attempts to demonstrate the Ansamitocin P-3 presence of SA-producing pathogens in children Ansamitocin P-3 with KS have led to negative results,48, 49, 50, 51 others have provided data suggesting the direct involvement of SAs. Leung et?al. blindly studied bacterial SAs potentially involved in the pathogenesis of KS in cultures of patients in the acute phase and controls,52 and found SA-producing bacteria in 13 of the 16 patients but in only one of the 15 controls (isolated from pharyngeal or rectal cultures, thus suggesting the gastrointestinal tract as the primary entry site. Similar findings of TSST-1-producing and SPEC-producing streptococci in children with acute KS have been recently Ansamitocin P-3 published.47 The SA theory may be supported by anecdotal reports of KS patients with guttate psoriasis because it has been suggested that this form of psoriasis is due to toxin-mediated T cell activation.53 Furthermore, a number of studies analysing the T lymphocyte receptor repertoire and the titres of antibodies against selected SAs have indirectly demonstrated that these proteins may be related to the development of KS.52, 54, 55, 56 In addition, Suenaga et?al. examined five SA genes in the stools of KS patients, febrile Ansamitocin P-3 controls and healthy children,57 and found at least one of the genes in 42 specimens from the patients with KS (70%), in 14 from the febrile group (38.9%), and in seven from the healthy group (26.9%). The detection rate between subjects with and without KS was of at least one of the 5 SA genes (expression in immune effecter cells influences susceptibility to KS. Interesting results were Ansamitocin P-3 also reported by Shimizu et?al. that investigated genetic variation in 15 genes belonging to the TGF-B pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands.101 Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KS susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KS susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338; locus may have implications for understanding immune activation in KS pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease. More recently, Japanese and Taiwanese groups independently reported a significant association between KS and polymorphisms in the intergenic region on chromosome 8p23-p22 between B lymphoid kinase ( em BLK /em ), a tyrosine kinase involved in B-cell receptor signal transduction and FAM167A, a functionally uncharacterized gene.116, 117 Onouchi et?al. undertook a GWAS involving 428 Japanese individuals with KS and 3379 Japanese controls genotyped at 473,803 SNPs.116 They validated the results in two independent replication panels of 754 cases and 947 controls, and observed significant associations in the FAM167A-BLK region (rs2254546, em p /em ?=?8.2??10?21). Similar results were obtained by Lee et?al. in 622 individuals with KS and 1107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls.117 They found that polymorphisms at BLK gene together with genetic abnormalities at CD40, were associated with KS at genome-wide significance ( em p /em ? ?5.5??10?8) confirming the role of immune activation and inflammation in the pathogenesis of the syndrome. However, despite these findings, the correlations between genetic markers the risk of developing and severity of KS are far from clear. At the moment the most convincing evidences of a strict correlation between genetic abnormalities and KS regards polymorphisms of ITPKC, FCGR, CASP3 and TGFB genes. Conclusions Although various data suggest that KS is an infection-related clinical syndrome that can only develop in children with predisposing genetic backgrounds, our knowledge of the infectious agent(s) involved and the genetic characteristics of susceptible.