Clinical Score and Transcript Abundance Patterns Identify Kawasaki Disease Patients Who May Benefit From Addition of Methylprednisolone

Ogata, Shohei; Ogihara, Yoshito; Nomoto, Keiko; Akiyama, Kazumasa; Nakahata, Yayoi; Sato, Kayoko; Minoura, Katsunori; Kokubo, Kenichi; Kobayashi, Hirosuke; Ito, Masahiro

doi:10.1203/pdr.0b013e3181baa3c2

Cited by 39 publications

(33 citation statements)

References 28 publications

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“…16 In contrast, our data suggest that the expressions levels of IL-1R2, IL18R1 and S100A12 in iPSC-ECs were not significantly different between the IVIG responder and IVIG non-responder groups (data not shown). We assume that the discrepancy of these findings may result from differences in the tissue types analyzed.…”

Section: Kd-ipscs Can Be Differentiated Into Ecscontrasting

confidence: 62%

“…Using the Egami scoring system, Ogata et al predicted IVIG responsiveness in KD patients. 16 They found the transcripts for IL-1R2, IL-18R1 and S100A12 protein, which are related to IVIG resistance and the development of coronary artery lesions (CAL), had significantly upregulated mRNA expression levels in the whole blood samples of IVIG-resistant KD patients.…”

Section: Generation Of Ipscs From Kd Patientsmentioning

confidence: 99%

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Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model

Ikeda

Mizoro

Ameku

et al. 2017

Circ J

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vation of the immune system, with elevations in serum pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α. 3-5 The major source of these cytokines and chemokines has remained a mystery. A previous report analyzed the activation status of peripheral blood mononuclear cells (PBMNCs) by flow cytometry, DNA microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR), finding evidence that the innate immune system appeared to play a role in the pathogenesis and pathophysiology of KD, but it also found that PBMNCs had a low expression of pro-inflammatory cytokine genes. 6 It has therefore been K awasaki disease (KD) is an acute febrile disorder characterized by systemic vasculitis and a high predilection for infants and young children. Although ~5 decades have passed since the disease was first described, 1 its etiology still remains unknown. Approximately 25% of untreated KD patients suffer from coronary artery abnormalities, but the frequency of coronary artery sequelae decreases to 2.8% if treatment with high-dose intravenous immunoglobulin (IVIG) is used. 2 However, ~10-20% of KD patients have persistent fever after this treatment and a high risk for coronary artery sequelae.KD in the acute phase is characterized by marked acti- Background: Approximately 10-20% of Kawasaki disease (KD) patients are resistant to intravenous immunoglobulin (IVIG) treatment. Further, these patients are at a particularly high risk of having coronary artery abnormalities. The mechanisms of IVIG resistance in KD have been analyzed using patient leukocytes, but not patient vascular endothelial cells (ECs). The present study clarifies the mechanisms of IVIG resistance in KD using an induced pluripotent stem cell (iPSC) disease model. Methods and Results:Dermal fibroblasts or peripheral blood mononuclear cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by the episomal vector-mediated transduction of 6 reprogramming factors. KD patient-derived iPSCs were differentiated into ECs (iPSC-ECs). The gene expression profiles of iPSC-ECs generated from IVIG-resistant and IVIG-responsive KD patients were compared by RNA-sequencing analyses. We found that the expression of CXCL12 was significantly upregulated in iPSC-ECs from IVIG-resistant KD patients. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that gene sets involved in interleukin (IL)-6 signaling were also upregulated. Conclusions:The first iPSC-based model for KD is reported here. Our mechanistic analyses suggest that CXCL12, which plays a role in leukocyte transmigration, is a key molecule candidate for IVIG resistance and KD severity. They also indicate that an upregulation of IL-6-related genes may be involved in this pathogenesis.

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Section: Kd-ipscs Can Be Differentiated Into Ecscontrasting

confidence: 62%

Section: Generation Of Ipscs From Kd Patientsmentioning

confidence: 99%

Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model

Ikeda

Mizoro

Ameku

et al. 2017

Circ J

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“…Articles surprisingly, the TARC/CCL17 levels were greatly decreased after IVIG treatment in KD patients, which raises the possibility of the activation of negative-feedback loops (23,24). Of note, there were still higher TARC/CCL17 levels at a subacute stage than those in the controls (P < 0.001).…”

Section: Tarc/ccl17 Snps In Kawasaki Diseasementioning

confidence: 94%

TARC/CCL17 gene polymorphisms and expression associated with susceptibility and coronary artery aneurysm formation in Kawasaki disease

et al. 2013

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Background: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Thymus and activation-regulated chemokine/chemokine ligand 17 (TARC/CCL17) is one of the Th2 chemokines and has been suggested as a candidate gene for conferring susceptibility to Th2 associated with allergy diseases. This study examined the correlation between gene polymorphisms and plasma levels of TARC/CCL17 in patients with KD and the outcomes of KD. Methods: A total of 381 KD patients and 564 controls were subjected to determination of five tagging single-nucleotide polymorphisms of TARC/CCL17. In addition, plasma TARC/ CCL17 levels were measured by enzyme-linked immunosorbent assay. results: Polymorphisms of TARC/CCL17 were significantly different between normal children and patients with KD. A allele of rs4784805 has better intravenous immunoglobulin (IVIG) treatment response to KD. Furthermore, plasma TARC/ CCL17 levels were higher in KD patients than that in controls before IVIG treatment. After IVIG treatment, plasma TARC/ CCL17 levels decreased significantly. conclusion: This study provides the first evidence supporting the association between TARC/CCL17 polymorphisms, susceptibility of KD, and IVIG responses in KD patients. k awasaki disease (KD), also known as mucocutaneous lymph node syndrome, is an acute febrile systemic vasculitis that was first described by Kawasaki et al. in 1974 in English (1), but its etiology remains unknown till now. It occurs most commonly in children younger than 5 y of age, particularly in children younger than 2 y of age, and the clinical presentation of KD is prolonged fever, conjunctivitis, diffuse mucosal inflammation, polymorphous skin rashes, indurative edema of the hands and feet associated with peeling of finger tips, and nonsuppurative lymphadenopathy (2). In developed countries, KD has been the leading cause of acquired heart diseases in children (2,3). The most serious complication of KD is the occurrence of coronary artery lesions (CALs), including myocardial infarction, coronary artery fistula formation (4), coronary artery dilation, or coronary artery aneurysm (CAA) (5). In addition, KD is the major cause of acquired CAA in childhood (6). The prevalence of KD in children is the highest in Japan, followed by Korea and Taiwan, and the lowest in Europe (5). Therefore, it is possible that a genetic background plays an important role in the pathogenesis of KD.Thymus and activation-regulated chemokine/chemokine ligand 17 (TARC/CCL17) is a member of the CC chemokine group (7). It is a ligand of the CC chemokine receptor (8), which is selectively expressed on Th2 cells (9) and serves for the recruitment and migration of cells bearing this receptor (7-9). TARC/CCL17 has been suggested as a candidate gene for conferring susceptibility to Th2 associated with allergy diseases and is highly implicated in the pathogenesis of atopic dermatitis (10,11) and bronchial asthma (12). There are several lines of evidence pointing out an abnormal Th1/Th2 balance in KD patients (13). Recently, it has b...

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“…The most utilized treatment is the application of Intravenous gammaglobulin (GGIV) at a dose of 2 per kg in a sole dose for a 12-infusion; this is the most accepted treatment and has allowed to the reduction of prevalence of aneurysms to <5% and a mortality of 2% to 0.3%, although the GGIV scheme is at a dosage of 400 mg × kg × day for 5 days, plus aspirin at 80 to 100 mg × kg × day. According to response, the GGIV dose can be repeated, or corticoids can be added, especially in refractory cases (Cha, 2008;Chung, 2009;Falcini, 2006;Hung, 2009;Miura, 2008;Newbauer, 2004;Ogata, 2009;Okada, 2009;Sano, 2010;Tremoulet, 2008).…”

Section: Treatmentmentioning

confidence: 99%

“…Concerning recommendation for treatment of KD during the past 3 years, it as been mentioned that the greatest effectiveness in cases of relapse or resistance is obtained on utilizing pulses of methylprednisolone in addition to GG. In cases of recurrence of fever or resistance to GGIV, this combination has even been recommended as initial therapy (Cha, 2008;Chung, 2009;Miura, 2008;Ogata, 2009;Okada, 2009;Sha, 2008). Cardiovascular sequelae of KD in the adult in Japan.…”

Section: Treatmentmentioning

confidence: 99%

Kawasaki Disease, Others Heart Injuries, Not Only Coronary Arteritis

Sotelo-Cruz¹

2011

Advances in the Etiology, Pathogenesis and Pathology of Vasculitis

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Clinical Score and Transcript Abundance Patterns Identify Kawasaki Disease Patients Who May Benefit From Addition of Methylprednisolone

Cited by 39 publications

References 28 publications

Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model

Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model

TARC/CCL17 gene polymorphisms and expression associated with susceptibility and coronary artery aneurysm formation in Kawasaki disease

Kawasaki Disease, Others Heart Injuries, Not Only Coronary Arteritis

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