SummaryKawasaki disease (KD) is an acute systemic vasculitis of childhood that does not have a known cause or aetiology. The epidemiological features (existence of epidemics, community outbreaks and seasonality), unique age distribution and clinical symptoms and signs of KD suggest that the disease is caused by one or more infectious environmental triggers. However, KD is not transmitted person-to-person and does not occur in clusters within households, schools or nurseries. KD is a self-limited illness that is not associated with the production of autoantibodies or the deposition of immune complexes, and it rarely recurs. Regarding the underlying pathophysiology of KD, innate immune activity (the inflammasome) is believed to play a role in the development of KD vasculitis, based on the results of studies with animal models and the clinical and laboratory findings of KD patients. Animal studies have demonstrated that innate immune pathogen-associated molecular patterns (PAMPs) can cause vasculitis independently of acquired immunity and have provided valuable insights regarding the underlying mechanisms of this phenomenon. To validate this concept, we recently searched for KD-specific PAMPs and identified such molecules with high specificity and sensitivity. These molecules have structures similar to those of microbe-associated molecular patterns (MAMPs), as shown by liquid chromatography-tandem mass spectrometry. We propose herein that KD is an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe-derived innate immune stimulants and that it is not a typical infectious disease.

Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.

Objective-The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries. Methods and Results-Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/ cytokine and matrix metallopeptidase (Mmp) genes in each tissue in vivo by microarray analysis. Conclusion-This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans. Key Words: coronary artery disease Ⅲ immune system Ⅲ Kawasaki disease Ⅲ pathology Ⅲ coronary arteritis Ⅲ inflammation G erm-line encoded pattern-recognition receptors of the innate immune system sense exogenous microbial components and endogenous danger signals to protect the host. [1][2][3][4] The pattern-recognition receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors, the leucine-rich repeat-containing (NLR) protein family, and as-yet-unidentified pattern-recognition receptors that recognize double-stranded DNA. 1,3 The TLR, RIG-I-like receptor, and NLR families consist of 10 (human), 3, and more than 20 members, respectively. 1,3,4 In the cardiovascular system, endothelial cells are usually the first among the structural cells to sense microbial components through pattern-recognition receptors. Human endothelial cells express functional innate immune receptors, such as TLRs and NLRs. 5,6 There is a line of evidence that activation of TLRs, especially TLR4 and TLR2, contributes to the development and progression of cardiovascular diseases, including atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure. 7 With respect to NLRs, only a limited number of studies have shown that human endothelial cells express functional NLRs, nucleotide-binding oligomerization domain 1 (NOD1) and NOD2. Chlamydophila pneumoniae and Listeria monocytogenes elicited NOD1-dependent interleukin (IL)-8 production in endothelial cells. 8,9 A selective NOD1 ligand, FK565, ...