The Roles of Ca2+/NFAT Signaling Genes in Kawasaki Disease: Single- and Multiple-Risk Genetic Variants

Wang, Wei; Lou, Jiao; Zhong, Rong; Qi, Yan-qi; Shen, Na; Lu, Xuzai; Wang, Yujia; Zhang, Qing; Zou, Li; Duan, Jiayu; Ke, Juntao; Miao, Xiaoping; Gong, Fangqi

doi:10.1038/srep05208

Cited by 20 publications

(22 citation statements)

References 56 publications

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“…Furthermore, unlike these common genes, ITPKC and CASP3 variants are specific to KD disease. T-cell activation is strongly involved in endothelial cell damage by eliciting proinflammatory reactions, including the Ca 2 +/nuclear factor of activated T-cell (NFAT) signaling pathway at the onset of KD [25,26]. ITPKC negatively regulates T-cell activation, while CASP3 is involved in the execution phase of apoptosis and also negatively regulates the Ca 2 +/NFAT pathway [26].…”

Section: The Infectious Trigger Hypothesismentioning

confidence: 99%

Autoimmune Aspects of Kawasaki Disease

Sakurai¹

2019

J Investig Allergol Clin Immunol

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Kawasaki disease (KD) is classified as a medium-sized vasculitis of systemic vasculitis syndrome characterized by hypercytokinemia. Although the etiology of KD remains unidentified, epidemiological features point to the role of infection and genetic predisposition. Recent studies revealed endothelial damage and resultant thrombin generation, as well as B-cell activation during the acute phase of KD. Several anti-endothelial cell autoantibodies (AECAs) have been identified in KD patients. Taken together with the recently developed concept of immunothrombosis, a potential pathogenic mechanism for KD emerges. First, some polyclonal antibodies generated against invading microorganisms would exhibit cross-reactivity toward endothelial cell components and become dominant during affinity maturation. AECA binding to endothelial cells would cause endothelial activation or damage, with proinflammatory cytokine release, fostering a hypercoagulable state by leukocyte activation by proinflammatory cytokines. This, in turn, would lead to coronary artery lesions. KD vasculitis might be initiated upon AECA binding to the vasa vasorum and progress to panvasculitis and a vulnerable vessel wall, resulting in an aneurysm. The aneurysm would cause flow recirculation and alteration of wall shear stress. Consequently, platelets activated by shear stress, along with ultra-large von Willebrand factor (VWF) released by endothelial cells, would cause platelet-driven arterial thrombosis. Autoimmunity-associated thrombosis initiated by AECA binding to endothelial cells might play a major role in the pathogenesis of certain subtypes of KD. The notion of KD consisting of subtypes, the major one of which is AECA-associated vasculitis, will help facilitate a better understanding of KD and further promote early and accurate diagnosis, which remains challenging.

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Section: The Infectious Trigger Hypothesismentioning

confidence: 99%

Autoimmune Aspects of Kawasaki Disease

Sakurai¹

2019

J Investig Allergol Clin Immunol

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“…Onouchi et al in 2008 reported that single nucleotide polymorphisms (SNPs) in ITPKC on chromosome 19q13.2 were associated with susceptibility to KD and risk of coronary artery abnormalities in Japanese and American children (rs28493229) [30]. Other variants found to be associated with KD were SNP rs2720378 and rs2290692 [31]. Polymorphism of ITPKC might result in increased activation of T cells and consequently increased release of interleukin-2 (IL-2).…”

Section: Etiopathogenesismentioning

confidence: 99%

“…It carries out apoptosis of immature cells [31]. It cleaves Inositol 1,4,5 triphosphate receptor, type 1 in apoptotic T cells and thereby serves as the positive regulator of Ca 2+ /NFAT pathway [28].…”

Section: Etiopathogenesismentioning

confidence: 99%

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Kawasaki disease: etiopathogenesis and novel treatment strategies

Agarwal

Agrawal

2016

Expert Review of Clinical Immunology

164

113

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Introduction-Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity.Areas covered-This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment.Expert Commentary-There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options.

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“…In addition, genetic analysis revealed mutations in 16 sites of key genes of Ca 2+ /NFAT signaling pathway in children with KD; and the mutant rs1561876AA is strongly correlated with vasculitis in KD 15,16 . These findings further suggest that the Ca 2+ /NFAT signaling pathway plays an important role in KD coronary artery injury.…”

mentioning

confidence: 99%

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

Wang

Liu

et al. 2020

Sci Rep

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ca 2+ /nuclear factor of activated t-cells (ca 2+ /NFAT) signaling pathway may play a crucial role in the pathogenesis of Kawasaki disease (KD). We investigated the poorly understood Ca 2+ /nfAt regulation of coronary artery endothelial cells and consequent dysfunction in KD pathogenesis. Human coronary artery endothelial cells (HCAECs) stimulated with sera from patients with KD, compared with sera from healthy children, exhibited significant increases in proliferation and angiogenesis, higher levels of NFATc1 and NFATc3 and some inflammatory molecules, and increased nuclear translocation of NFATc1 and NFATc3. HCAECs stimulated with sera from patients with KD treated with cyclosporine A (CsA) showed decreased proliferation, angiogenesis, NFATc1 and inflammatory molecules levels as compared with results for untreated HCAECs. In conclusion, our data reveal that KD sera activate the Ca 2+ /nfAt in HCAECs, leading to dysfunction and inflammation of endothelial cells. CsA has cytoprotective effects by ameliorating endothelial cell homeostasis via Ca 2+ /NFAT. Kawasaki Disease (KD), also known as mucocutaneous lymph node syndrome (MCLS), is an acute febrile rash that occurs mainly in children under 5 years which is the most common systemic vasculitis syndrome in children 1 . The disease mainly affects small and medium arteries, especially coronary arteries. Coronary artery lesions (CAL) can occur in 25% of patients 2 . Coronary artery injury and coronary aneurysm formation are the most important acute and long-term sequela of KD 3,4 .The pathogenesis of KD remains unclear. Recent studies have confirmed that vascular endothelial cells (VECs) play a very important role in the coronary artery injury of KD 5 . Children with KD have abnormal activation of the immune system; VECs are stimulated to express and release a variety of adhesion factors, which in turn cause inflammatory cells to adhere to the surface of endothelial cells, which resulting in inflammation to damage of VECs 6 . The dysfunction of VECs plays a vital role in vascular tension, lipid metabolism and coagulation mechanism, which in turn activate inflammatory cells, causing inflammation extending deep into the endothelium, leading to destruction of the vascular elastic layer, formation of coronary aneurysm and vascular remodeling 7 .

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The Roles of Ca2+/NFAT Signaling Genes in Kawasaki Disease: Single- and Multiple-Risk Genetic Variants

Cited by 20 publications

References 56 publications

Autoimmune Aspects of Kawasaki Disease

Autoimmune Aspects of Kawasaki Disease

Kawasaki disease: etiopathogenesis and novel treatment strategies

The role of Ca2+/NFAT in Dysfunction and Inflammation of Human Coronary Endothelial Cells induced by Sera from patients with Kawasaki disease

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