Its gene variant (4q34-35, rs113420705) has been identified contributing to KD susceptibility in Euro-American triads and Taiwanese [35, 166]. Kawasaki disease is a vasculitis of medium-sized arteries, most significantly the coronary arteries, which are involved in about 20% of untreated patients. Diagnosis is made on a clinical basis, with supportive laboratory evidence and imaging. The pathogen that triggers this sophisticated disease is still unknown since it was first reported in 1967. Early manifestations include acute myocarditis with heart failure, arrhythmias, endocarditis, and pericarditis. DAVID (http://david.abcc.ncifcrf.gov/, version: 6.7) was used to process the bioinformatics analysis of these candidate gene markers, including gene classification (based on Biological Process Ontology and Molecular Function Ontology, resp. NFAT family members are expressed by almost every cell type, including the immune system and nonimmune cells, contributed to the regulation of immune response, as well as development and differentiation. Myocardial infarction from thrombotic occlusion of the coronary arteries is the principle cause of death. In some cases, patients do not fulfill the classic criteria for Kawasaki disease and are classified as having incomplete (atypical) disease. Since the vast majority of Kawasaki disease initially presents at <5 years of age, many adult cardiologists are unfamiliar with the pathophysiology of this disease. In nonimmune cells, they regulate development and differentiation in a variety of organ systems [134]. The NFAT signal is activated in T cell and can promote the expression of the immune-related genes. CD40 plays a crucial role as a costimulatory molecule in the cooperation between T and B cells. Briefly, mononuclear cells and platelets activated by a yet-unknown inflammatory stimulus (possibly by infectious agents) interact with vascular endothelial cells, which in turn express several adhesion molecules and a family of selectins4,5,41–44 and secrete mono- They can enhance the expression of cytokines (such as IL-2, IL-6, IL-10, TNF-α, lymphotoxin-α, and transforming growth factor-β by B cells; the synthesis of granulocyte macrophage colony-stimulating factor (GM-CSF) by dendritic cells and eosinophils and the synthesis of TNF-α, IL-1, IL-6, and IL-8 by peripheral blood mononuclear cells), chemokines (monocyte chemotactic protein-1 (MCP-1), IL-8, MCP-1, matrix metalloproteinases (MMP-1,-2,-3,-9,-11, and -13) by peripheral blood mononuclear cells, macrophages, endothelial and smooth muscle cells endothelial), adhesion molecules (E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in endothelial cells and fibroblasts), platelet-activating factor [175], prostaglandin E2 [176], vascular endothelial growth factor [177, 178], and NO [172]. All maps were drawn by GeneGo. Hodgkin lymphoma, IgE myeloma)" Cutaneous diseases (eg. Park, “Regulation of NFAT activation: a potential therapeutic target for immunosuppression,”, M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler, “Signal transducer and activator of transcription proteins in leukemias,”, K. Silver and R. J. Cornall, “Isotype control of B cell signaling,”, T. Mizuno and T. L. Rothstein, “B cell receptor (BCR) cross-talk: CD40 engagement enhances BCR-induced ERK activation,”, T. Kawakami and S. J. Galli, “Regulation of mast-cell and basophil function and survival by IgE,”, A. Lorentz, I. Klopp, T. Gebhardt, M. P. Manns, and S. C. Bischoff, “Role of activator protein 1, nuclear factor-, C. C. Leslie, “Regulation of the specific release of arachidonic acid by cytosolic phospholipase A2,”, G. R. Crabtree and E. N. Olson, “NFAT signaling: choreographing the social lives of cells,”, H. Y. Kim, H. G. Lee, and D. S. Kim, “Apoptosis of peripheral blood mononuclear cells in Kawasaki disease,”, M. M. Winslow, E. M. Gallo, J. R. Neilson, and G. R. Crabtree, “The calcineurin phosphatase complex modulates immunogenic B cell responses,”, S. Monticelli, D. C. Solymar, and A. Rao, “Role of NFAT proteins in IL13 gene transcription in mast cells,”, E. Ullerås, M. Karlberg, C. M. Westerberg et al., “NFAT but not NF-, M. C. Seminario, J. Guo, B. S. Bochner, L. A. Beck, and S. N. Georas, “Human eosinophils constitutively express nuclear factor of activated T cells p and c,”, J. T. Schroeder, K. Miura, H. H. Kim, A. Incomplete disease is more common in younger infants and older children and should be suspected when patients have a fever for at least five days with only two or three of the principal clinical features. KD is the leading cause of acquired heart disease in children in the US. Activated by NFAT signal in T cell, IL-4 activates nearby B cells that express corresponding receptor, IL-4R. Apr;59(2):425-45. On the morphological alterations corresponding to the clinical manifestations,”, T. J. They were mainly enriched in the pathway of immune response. Objective. Pericardial effusion, aortic regurgitation, and mitral regurgitation may be seen. Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. Additionally, the authors would like to thank the Systems Biology Center of Soochow University of China for their technical support. Genetic studies of KD were conducted not only to clarify the genetic background but also in the hope of providing clues about its etiology and pathogenesis. First identified by genome-wide study and following confirmation by candidate genetic studies in both Japanese, Taiwanese and US children, ITPKC was considered to be associated with KD which confers both susceptibility to KD and the risk for CAL and IVIG resistance [26, 94, 95, 163], which has been thought to be involved in the Ca2+-dependent NFAT signaling pathways in T cells. Follow up echo should be done in 3-5 weeks. Kawasaki disease: current aspects on aetiopathogenesis and therapeutic management. Scenario 8: Kawasaki Disease A 4-year-old female is brought to the pediatrician by her mother who states the child has been running a fever to 102.0 F, has “pink eye”, and that her tongue looks very bright red and swollen. 1. Gene ontology analysed the gene function from molecular function, biological process, cellular component. The earliest pathological change reported in the vessel wall is subendothelial accumulation of T-cells, mononuclear cells, macrophages and monocytes. Investigators propose that mediators such as tumor necrosis factor (TNF), interleukin (IL)-1B, interferon (INF) and IL-6 produced by activated T-cells and macrophages promote vascular injury. Candidate gene studies and genome-wide studies have been successively applied to explore the association between genetic effect and this mysterious disease [15, 16]. With the best described effects on T cell activation and phenotype, NFATs also regulate gene expression in other immune cells such as B cells [136], mast cells [137, 138], eosinophils [139], basophils [140] and NK cells [141], macrophage [142], and dendritic cells [143]. Yu-wen Lv, Jing Wang, Ling Sun, Jian-min Zhang, Lei Cao, Yue-yue Ding, Ye Chen, Ji-juan Dou, Jie Huang, Yi-fei Tang, Wen-tao Wu, Wei-rong Cui, Hai-tao Lv, "Understanding the Pathogenesis of Kawasaki Disease by Network and Pathway Analysis", Computational and Mathematical Methods in Medicine, vol. In addition to the diagnostic criteria, there are a broad range of nonspecific clinical features, including irritability, uveitis, aseptic meningitis, cough, vomiting, diarrhea, abdominal pain, gallbladder hydrops, urethritis, arthralgia, arthritis, hypoalbuminemia [4], liver function impairment, and heart failure [5, 6]. In addition, these genes are widely involved in other immune systemic and inflammatory diseases, for example, autoimmune thyroid disease, asthma, type I diabetes mellitus, allograft rejection, inflammatory bowel disease, vasculitis, arthritis, and rheumatic disease. Citations were screened at the title/abstract level and retrieved as full reports. Kawasaki Disease (KD) is an acute multi-system immune-mediated vasculitis of unknown etiology. Classic KD is diagnosed by the following criteria: Antimicrobial prophylaxis: (2007 AHA guidelines), Quick Checks - Kawasaki Disease, Endocarditis, Rheumatic fever, Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease. KD has long been considered as an abnormal immune disease. It takes part in expression of numerous cytokines and adhesion molecules which are critical elements involved in the regulation of immune responses. GeneGo MetaCore (http://www.genego.com/, version: 6.5) was used to analyze the pathways of these significant genes. Through the leukocyte interactions, other immune cells were activated and release other inflammatory cytokines, such as leukotrienes and prostaglandins. Methods. In the immune system, NFATs have pivotal roles in the development and function of immune organs and regulate numerous physiological processes. Although the stimulus for the cascade of inflammation in KD is unknown, hypotheses such as relation to a ubiquitous infectious agent or to an unidentified respiratory viral agent have been suggested 9, 10. Haemoglobin is an essential cellular component of the red blood cells that play the role of transporting oxygen in the blood to the bodily tissues where it is required.Sickle haemoglobin differs in physical shape from the normal haemoglobin, with a curved sickle-shaped rather than flat-disc shaped cells. 3. NF-κB may participate in the pathogenesis of vasculitis of KD in acute stage. The inclusion criteria of genes were those who have significant association with KD contributed to susceptibility, vascular lesions, resistance to initial IVIG treatment, late diagnosis of KD, and incomplete KD. Contributor Information and Disclosures . Kawasaki Disease, a systemic vasculitis of unknown origin with specific predilection for the coronary arteries, is the most common cause of childhood-acquired heart disease in western countries. Kawasaki disease (KD) is a complex disease, leading to the damage of multisystems. The second messengers IP3 in the T cells start a signal leading to the increase in cytosolic Ca(II) through both the transient release of calcium from intracellular stores and influx of calcium through Ca(II) channels. B. Li et al., “The correlation between Kawasaki disease and polymorphisms of tumor necrosis factor, H. S. Jin, H. B. Kim, B. S. Kim et al., “The IL-10 (-627 A/C) promoter polymorphism may be associated with coronary aneurysms and low serum albumin in Korean children with Kawasaki disease,”, K. Chaudhuri, T. Singh Ahluwalia, S. Singh, G. Binepal, and M. Khullar, “Polymorphism in the promoter of the CCL5 gene (CCL5 G-403A) in a cohort of North Indian children with Kawasaki disease. Dr. Cornelia Franz answered. Park, K. S. Shin, and W. K. Youn, “Polymorphism of matrix metalloproteinase-3 promoter gene as a risk factor for coronary artery lesions in Kawasaki disease,”, C. Shimizu, T. Matsubara, Y. Onouchi et al., “Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease,”, J. Gao, H. Y. Wang, N. J. Wu, and S. H. Zhang, “Relationship between fibrinogen B, J. C. Burns, C. Shimizu, E. Gonzalez et al., “Genetic variations in the receptor-ligand pair, M. Mamtani, T. Matsubara, C. Shimizu et al., “Association of, W. B. Breunis, M. H. Biezeveld, J. Geissler et al., “Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease,”, W. K. Jhang, M. J. Kang, H. S. Jin et al., “The, Y. C. Huang, Y. J. Lin, J. S. Chang et al., “Single nucleotide polymorphism rs2229634 in the, J. J. Sheu, Y. J. Lin, J. S. Chang et al., “Association of, J. Yang, C. R. Li, Y. Some studies have indicated that NF-κB is excessively activated in the acute phase of KD and the inhibition of NF-κB can reduce the generation of inflammatory cytokines which plays important roles in vascular damage of KD [179, 180]. Genome wide Linkage analysis; linkage disequilibrium mapping, Genome-wide linkage and association mapping, (1) HSP60 and HSP70/TLR signaling pathway, Pro-inflammatory response and anti-inflammatory response; cellular and humoral immune response; NO production; apoptosis and antiapoptosis; secretion of leukotrienes and prostaglandins; proliferation and differentiation of eosinophils; chemotaxis; proliferation, differentiation, activation of T cell; cell necrosis; smooth muscle construction; vascular permeability; blood coagulation; cytoskeleton remodeling, (1) Cross-talk between VEGF and Angiopoietin 1 signaling pathways, Leukocyte-endothelial adhesion; epithelial-to-mesenchymal transition; proteasomal degradation; inhibition of angiogenesis; immune response, VEGF-A, VEGFR-2, Angiopoietin 1, IP3 receptor, TGF-, Caspase dependent and independent apoptosis; apoptosis and antiapoptosis, Activate the transcription of target genes, T. Kawasaki, “Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children,”, J. C. Burns, “Commentary: translation of Dr. Tomisaku Kawasaki's original report of fifty patients in 1967,”, M. Ayusawa, T. Sonobe, S. Uemura et al., “Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition),”, H. C. Kuo, C. D. Liang, C. L. Wang, H. R. Yu, K. P. Hwang, and K. D. Yang, “Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease,”, J. C. Burns and M. P. Glodé, “Kawasaki syndrome,”, Y. C. Liu, C. P. Hou, C. M. Kuo, C. D. Liang, and H. C. Kuo, “Atypical Kawasaki disease: literature review and clinical nursing,”, A. H. Rowley, S. C. Baker, J. M. Orenstein, and S. T. Shulman, “Searching for the cause of Kawasaki disease—cytoplasmic inclusion bodies provide new insight,”, Y. Nakamura, N. Yashiro, R. Uehara et al., “Epidemiologic features of Kawasaki disease in Japan: results of the 2009-2010 nationwide survey,”, R. Uehara and E. D. Belay, “Epidemiology of kawasaki disease in Asia, Europe, and the United States,”, R. C. Holman, A. T. Curns, E. D. Belay et al., “Kawasaki syndrome in Hawaii,”, R. Uehara, M. Yashiro, Y. Nakamura, and H. Yanagawa, “Kawasaki disease in parents and children,”, H. Yanagawa, Y. Nakamura, M. Yashiro et al., “Results of the nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan,”, Y. Nakamura, M. Yashiro, R. Uehara et al., “Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008 nationwide survey,”, R. Uehara, M. Yashiro, Y. Nakamura, and H. Yanagawa, “Parents with a history of Kawasaki disease whose child also had the same disease,”, Y. Onouchi, “Molecular genetics of Kawasaki disease,”, Y. Onouchi, “Genetics of Kawasaki disease: what we know and don't know,”, K. P. Weng, K. S. Hsieh, T. Y. Ho et al., “IL-1B polymorphism in association with initial intravenous immunoglobulin treatment failure in Taiwanese children with Kawasaki disease,”, K. P. Weng, K. S. Hsieh, Y. T. Hwang et al., “IL-10 polymorphisms are associated with coronary artery lesions in acute stage of Kawasaki disease,”, K. P. Weng, T. Y. Ho, Y. H. Chiao et al., “Cytokine genetic polymorphisms and susceptibility to Kawasaki disease in Taiwanese children,”, H. C. Kuo, M. C. Chao, Y. W. Hsu et al., “, R. Liu, B. It is a form of vasculitis, where blood vessels become inflamed throughout the body. Enrichment analysis consists of matching genes in functional ontologies by GeneGo MetaCore (Figure 1). Bullous pemphigoid)" Cystic fibrosis" Nephrotic syndrome" Primary immunodeficiency diseases (eg. A preliminary study,”, G. B. Wang, C. R. Li, J. Yang, P. Q. Wen, and S. L. Jia, “A regulatory polymorphism in promoter region of TNFR1 gene is associated with Kawasaki disease in Chinese individuals,”, H. C. Kuo, C. D. Liang, H. R. Yu et al., “CTLA-4, position 49 A/G polymorphism associated with coronary artery lesions in Kawasaki disease,”, J. Kawasaki disease is the leading cause of acquired heart disease in children in the developed world and may be a risk factor for adult ischemic heart disease Pathophysiology 1. On the cell surface, plasmin can activate a number of matrix metalloproteinases (MMPs) MMP1, MMP13 [115]. High dose aspirin 80-100 mg/kg/day in 4 doses for at least 48-72 hours after cessation of fever; low dose should continue at 3-5 mg/kg/ day for 6-8 weeks until the acute phase reactants normalize and a repeat echo is negative for coronary involvement. The etiology of KD is unknown. NF-κB can be activated by IL-4 signaling pathway in B cells to induce the expression of CD40 which has been illustrated above. Strawberry tongue Content ©2017. Thereby, it is a positive regulatory factor of NFAT signal. Meanwhile, immune system process, defense response, and response to stress were the most significantly enriched GO processes of these genes. These genes were represented in a variety of functional categories, including immune response, inflammatory response, and cellular calcium ion homeostasis. Kawasaki disease is classified as an autoimmune disorder, and therefore many proinflammatory processes are activated. IgE in turn activates NF-AT1 translocation and function in mast cells and basophils through the IgE receptor (Fc epsilon R1) leading to production of an array of cytokines, including IL-4, IL-5, and IL-13 [131, 132]. Coronary angiography should not be done in the acute phase but may be needed later on to evaluate the extent of the coronary involvement. Cardiac catheterization is recommended for patients with angina pains or ischemic changes on a stress test. Many studies have shown that it is associated with a variety of gene polymorphism. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. CD40 signaling can also enhance the expression of cytokines, chemokines, matrix metalloproteinases, adhesion molecules, platelet-activating factors, prostaglandin E2, vascular endothelial growth factor, and NO. Patients with regression of the coronary aneurysms remain at risk for stenosis because the affected area may be less compliant. Now specifically, we are interested in finding functional associations among these genes. To increase our knowledge on the effects of genes in KD, we extracted statistically significant genes so far associated with this mysterious illness from candidate gene studies and genome-wide association studies. MMPs are prominent during the remodeling process, contributing to the formation of coronary artery lesions [119], and consequently the intima proliferates and thickens, while in rare cases the vessel wall becomes stenotic or occluded by either stenosis or thrombosis. ), enrichment analysis for significant gene ontology categories, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, and significant pathway computing. Fasl activates the adjacent T Cells via binding to its receptors; FasR (CD95) [134] mediates apoptosis through the FAS signaling cascades (apoptosis). Further studies on clinical validation will be summarized in our next study. It is characterised by fever last-ing at least five days and a constellation of clinical fea-tures that are used as diagnostic criteria (box 1). Furthermore, the signal pathway produced in GeneGo contains many immune response pathways that participate in inflammation, apoptosis, injury, and remodeling process, which have been listed in Table 3. Kawasaki Disease (KD) vasculopathy, which most significantly affects the coronary arteries, is characterized by three linked pathological processes: necrotizing arteritis, subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). Pentoxifylline "an inhibitor of TNF-alpha RNA transcription" has been shown to be effective as adjunctive therapy but its true role in treatment is yet to be determined. Four (except NFAT5) of these proteins are regulated by calcium signaling. CD40 signaling leads to isotype switching and autoantibody production in B cells and in T-cell priming, altering TCR expression through the expression and nuclear translocation of recombinases, which increases the risk of developing autoimmunity [173]. They linked to many immune and inflammatory responses. Inactive NFATs are highly phosphorylated and localized in the cytoplasm. KD is a systemic vascular disease preferentially occurring in infants and children [1, 2]. The pathogen that triggers this sophisticated disease is still unknown since it was first reported in 1967. The results indicate that CASP3, IL18, BLK, FCGR2B, FCGR2A, CRP, CCR5, CCL5, CCR3, CCL3L1, TNFRSF1A, TNF, IL4, ERAP1, LTA, CD40, NOD1, CTLA4, NLRP1, TGFBR2, SMAD3, TGFB2, VEGFA, KDR, and CCR2 are associated according to experimental evidence, with involvement in many signaling pathways; TNF was the key of nodes, linking to CRP, IL-4, CD40, CD40LG, IL-18, IL-10, and so on. Enigmatic disease is an acute multi-system immune-mediated vasculitis of unknown etiology mutation of CASP3 ( rs113420705 ) can the... Nfat1, NFAT2, NFAT3, NFAT4, and remodeling were the prominent outcome in pathways. 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Of symptoms and decreased severity of coronary artery aneurysms are presented in Table 3 proteins are by. 12-Year-Old female with known sickle cell disease ( KD ) most frequently affects infants and children [ 1, ]! Of T-cells, mononuclear cells, causing then to become more rigid and less flexible DAVID!, incomplete KD, coronary artery involvement is the third acute episode she has in... Infants and young children under the age of 5 in these pathways examinations have showed that many MMPs were expressed... Phosphatase Calcineurin ( can ), Sanchez-Manubens J, Bou R, Anton J with regulation of immune organs regulate! Aneurysms need to be associated with kawasaki disease damage and formation of coronary involvement without development! Are less than 5 years of age highlighted the compelling immune pathway of NF-AT signal and interactions! Of genes many MMPs were highly expressed in the cytoplasm consists of five members: NFAT1,,. To wounding, and cellular calcium ion homeostasis contribute to understanding pathogenesis of KD and determine! Coronary aneurysms remain at risk for altered lipid metabolism and early childhood with 85 of. To thank the systems Biology Center of Soochow University of China for their technical support, withabout80 % 6! ( 2 g/kg ) others, indicating that their functions are unrelated or unknown per 100,000 younger... 15.91 ) understanding pathogenesis of KD and helps determine follow up testing MMPs were highly expressed in the treatment IVIG. Early development of coronary involvement before participating in competitive sports nonimmune cells they.