scholarly journals DC-SIGN(CD209) Promoter −336 A/G (rs4804803) Polymorphism Associated with Susceptibility of Kawasaki Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Hong-Ren Yu ◽  
Wei-Pin Chang ◽  
Lin Wang ◽  
Ying-Jui Lin ◽  
Chi-Di Liang ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Adhesion Molecule ◽  
Risk Allele ◽  
Systemic Vasculitis ◽  
Intercellular Adhesion Molecule ◽  
Unknown Etiology ◽  
High Dose ◽  
Lectin Receptor ◽  
Ivig Resistance ◽  
Intracellular Adhesion Molecule

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism ofDC-SIGN(CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (P=0.004under the dominant model). However, the promoter variant ofDC-SIGNgene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele ofDC-SIGNpromoter −336 (rs4804803) is a risk allele in the development of KD.

scholarly journals Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Takashi Inoue ◽  
Shokei Murakami ◽  
Kenji Matsumoto ◽  
Akio Matsuda
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Combination Therapy ◽  
Molecular Mechanisms ◽  
Ivig Therapy ◽  
Unknown Etiology ◽  
High Dose ◽  
Ivig Resistance ◽  
Tnf Α ◽  
Clinical Benefits

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD. Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities. Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG. Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

scholarly journals Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

2020 ◽  
Author(s):  
Takashi Inoue ◽  
Shokei Murakami ◽  
Kenji Matsumoto ◽  
Akio Matsuda
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Combination Therapy ◽  
Molecular Mechanisms ◽  
Ivig Therapy ◽  
Unknown Etiology ◽  
High Dose ◽  
Ivig Resistance ◽  
Tnf Α ◽  
Clinical Benefits

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD.Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities.Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1s (IL-1α and IL-1β) was resistant to high-dose IgG.Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

Abstract 16564: Analysis of the Mechanisms of Intravenous Immunoglobulin-Resistant Kawasaki Disease Using iPS Cell Technology

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazuyuki Ikeda ◽  
Tomonaga Ameku ◽  
Yui Nomiya ◽  
Masahiro Nakamura ◽  
Satoshi Matsui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kawasaki Disease ◽  
Intravenous Immunoglobulin ◽  
Expression Profiles ◽  
Systemic Vasculitis ◽  
Dermal Fibroblasts ◽  
Gene Set Enrichment Analysis ◽  
Recurrent Fever ◽  
Ips Cell ◽  
Ivig Resistance

Introduction: Kawasaki disease (KD) is a systemic vasculitis of unknown origin. Although the treatment of intravenous immunoglobulin (IVIG) significantly resolves inflammation, 10-20% of KD patients have persistent or recurrent fever after the administration of IVIG, and IVIG-resistant patients have a particularly high risk of developing coronary artery abnormalities. Hypothesis: The mechanisms of IVIG-resistant KD have been analyzed using the patients’ leukocyte samples. However, vascular endothelial cells (ECs), closely related to the vasculitis of KD, have not been examined in the previous reports. We propose a hypothesis that ECs are mainly involved in the etiology of IVIG-resistance. Methods: The purpose of this study is to establish new in vitro disease models of vasculitis using induced pluripotent stem cell (iPSC) technology, and clarify the mechanisms of IVIG-resistance in KD. Dermal fibroblasts or T cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by episomal vectors encoding Oct3/4, Sox2, Klf4, L-Myc, LIN28, and p53 shRNA. The iPSC lines were then differentiated into ECs by using a previously-reported differentiation method, and the EC samples were subjected to the microarray analyses. Results: The KD patient-derived iPSCs could be differentiated into ECs. The gene expression profiles were compared between iPS-derived ECs (iPS-ECs) generated from IVIG-resistant and IVIG-responsive KD patients. We found that 107 genes were at least two fold up-regulated and 101 genes were at least two fold down-regulated in iPS-ECs from IVIG-resistant KD patients compared with those from IVIG-responsive patients. The Principle Component Analysis (PCA) was performed, but the gene expression levels showed no significant differences between the groups. The Gene Set Enrichment Analysis (GSEA) revealed that the gene sets related to IL-6, NRAS (a member of the RAS oncogene family) and breast cancer were up-regulated in iPS-ECs from IVIG-resistant KD patients. Conclusions: Taking into account that the concentration of IL-6 has been reported to be elevated in acute phase of IVIG-resistant KD, our results suggest that the up-regulation of IL-6 related genes in ECs might be involved in the pathogenesis of IVIG-resistant KD.

CD209 (DC-SIGN) – role in the work of the innate immunity and pathogen penetration

2020 ◽  
Vol 1 (9) ◽  
pp. 64-71
Author(s):  
E. A. Klimov ◽  
◽  
E. K. Novitskaya ◽  
S. N. Koval’chuk ◽  
◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Adhesion Molecule ◽  
Immune Evasion ◽  
Intercellular Adhesion Molecule ◽  
Lectin Receptor

Intercellular adhesion molecule CD209 (DC-SIGN) is a membrane C-type lectin receptor expressed on the surface of dendritic cells and macrophages. CD209 plays an important role in innate immunity. Many studies have shown the possibility of interaction of the CD209 molecule with a number of dangerous pathogens of humans and animals. This review summarizes information on the structure of the CD209 gene and its product, describes the role of the CD209 protein in the immune response, in the migration of dendritic cells from the blood to the tissue, and their interaction with neutrophils. The currently known signaling pathway of activation through the CD209 inflammatory response is presented. The role of CD209 as an endocytic antigen receptor and the participation of the protein in immune evasion of pathogens are discussed. The mechanisms known to date for the development of infections caused by pathogens of various nature in animals are described.

scholarly journals CD40Gene Polymorphisms Associated with Susceptibility and Coronary Artery Lesions of Kawasaki Disease in the Taiwanese Population

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Ho-Chang Kuo ◽  
Mei-Chyn Chao ◽  
Yu-Wen Hsu ◽  
Ying-Chi Lin ◽  
Ying-Hsien Huang ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Systemic Vasculitis ◽  
Recessive Model ◽  
Unknown Etiology ◽  
Nucleotide Polymorphisms ◽  
Taiwanese Population ◽  
Allelic Discrimination Assay ◽  
Allelic Discrimination ◽  
First Time

Background. Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression ofCD40ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role ofCD40Lin the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate theCD40polymorphism in KD and CAL formation.Methods. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) ofCD40(rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay.Results. A significant association was noted with regards toCD40tSNPs (rs1535045) between controls and KD patients (P=0.0405, dominant model). In KD patients, polymorphisms ofCD40(rs4810485) showed significant association with CAL formation (P=0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms ofCD40and susceptibility/disease activity of KD.Conclusions. This study showed for the first time that polymorphisms ofCD40are associated with susceptibility to KD and CAL formation, in the Taiwanese population.

Intercellular adhesion molecule-1 gene polymorphisms in patients with familial mediterranean fever

Open Medicine ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. 679-682
Author(s):  
Senol Kobak ◽  
Arzu Celebi ◽  
Fahrettin Oksel ◽  
Yasemin Kabasakal ◽  
Ulus Akarca
Keyword(s):  
Familial Mediterranean Fever ◽  
Healthy Volunteers ◽  
Adhesion Molecule ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Unknown Etiology ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Conditions ◽  
Allele Specific ◽  
Mediterranean Fever

AbstractFamilial Mediterranean fever (FMF) is a disease of unknown etiology characterized by recurrent attacks of polyserositis and fever. Intercellular adhesion molecule-1 (ICAM-1) is known to contribute inflammatory conditions by regulating leukocyte localization at inflammatory sites. The aim of this study was to evaluate the probable association of ICAM-1 G/R 241 and ICAM-1 E/K 469 polymorphisms according to susceptibility with FMF. Sixty-seven FMF patients and 83 healthy volunteers were included in the study. Genomic DNA was extracted from EDTA-preserved whole blood of whole series of patients and controls, and genotyped by polymerase chain reaction (PCR) and allele-specific oligonucleotide techniques for ICAM-1 polymorphisms G/R at codon 241 and E/K at codon 469. The ICAM-1 241 genotype and allele frequencies of FMF patients and healthy volunteers were similar. The frequency of ICAM-1 K469 homozygosity was significantly lower in FMF patients than in the controls (32.8% vs 50.7% subsequently, p=0.03). Moreover, ICAM-1 E469 allele was more frequent in FMF patients than in controls (44.8% vs 32.3%, p:0.03). Our results showed that ICAM-1 469 gene polymorphism could contribute to the pathogenesis of FMF.

scholarly journals Incomplete Kawasaki disease in Egypt

2018 ◽  
Vol 2017 (3) ◽  
Author(s):  
Hala M Agha ◽  
Hala S Hamza
Keyword(s):  
Kawasaki Disease ◽  
Viral Infections ◽  
Systemic Vasculitis ◽  
Vascular Inflammation ◽  
Clinical Findings ◽  
Unknown Etiology ◽  
Cervical Lymphadenitis ◽  
Barr Virus ◽  
Childhood Illnesses ◽  
Epstein Barr

[first paragraph of article]Kawasaki disease (KD) is a hybrid condition at the junction of infectious diseases, immunology, rheumatology, and cardiology.1 KD is a systemic vasculitis of unknown etiology predominately affecting medium-sized vessels such as the coronary arteries, which mainly affects infants and children2. The disease itself may be the characteristic manifestation of a common pathway of immune-mediated vascular inflammation in genetically susceptible hosts3. Untreated KD may lead to the formation of coronary artery aneurysms and sudden cardiac death in children. The diagnosis of KD is based on the clinical features of fever of at least 5 days together with at least 4 or 5 other features including rash, bilateral conjunctival injection, changes in peripheral extremities, lymphadenopathy and oropharyngeal changes4. The diseases that must be differentiated from KD because of similar clinical findings include viral infections (measles, adenovirus, enterovirus, and Epstein-Barr virus), scarlet fever, staphylococcal scaled skin syndrome, toxic shock syndrome, polyarteritis nodosa, bacterial cervical lymphadenitis, and juvenile rheumatoid arthritis5,6. Because each of the symptoms commonly occurs in other childhood illnesses, the disease can be difficult to diagnose, especially in children who present with an incomplete form of the disease. KD has not been previously reported from Egypt and there are special challenges in recognizing complete KD in a country where physicians have limited experience with the disease. The diagnosis of incomplete KD is thus even more challenging in this setting. 

Abstract 12638: Autophagy-mitophagy Induction Improves Cardiovascular Inflammation in a Murine Model of Kawasaki Disease Vasculitis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Stefanie Marek-iannucci ◽  
Angela Gomez ◽  
Debbie Moreira ◽  
Malcolm Lane ◽  
Rebecca Porritt ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Excision Repair ◽  
Systemic Vasculitis ◽  
Unknown Etiology ◽  
Recent Experimental Data ◽  
Intermittent Fasting ◽  
Autophagic Flux ◽  
Clinical Genetic ◽  
Mtdna Damage ◽  
Mitochondrial Fractions

Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Recent experimental data from mouse models, as well as clinical, genetic and transcriptome evidence from KD patients suggest a key role of the NLRP3-IL-1β pathway in the pathogenesis of KD. NLRP3 can be activated by mitochondrial (mt) DNA released in the setting of defective autophagy/mitophagy, but a potential role for autophagy/mitophagy in KD cardiovascular inflammation has not been determined. In the Lactobacillus casei cell wall extract (LCWE) mouse model of KD vasculitis, LCWE injection in WT mice results in coronary arteritis, aortitis and myocarditis, mimicking human KD. We found that expression of the autophagy/mitophagy markers Parkin and p62 was significantly higher in whole lysate and mitochondrial fractions of heart tissue of LCWE-injected mice than controls, indicating impaired autophagic flux and mitophagy. Parkin -/- mice developed significantly more LCWE-induced cardiovascular lesions than control mice, and treatment of WT mice with a GLP-1 receptor agonist, known to activate Parkin, significantly reduced LCWE-induced inflammation. LCWE-induced cardiovascular lesions were amplified in mice deficient in OGG1, a base excision repair protein sensitive to mtDNA damage. Finally, inhibiting autophagy with chloroquine exacerbated LCWE-induced KD vasculitis, whereas inducing autophagy by intermittent fasting decreased cardiovascular inflammation in the model. Altogether, our data suggest that impaired autophagy/mitophagy exacerbates KD and supports a role for mtDNA damage in the disease. These findings enhance our understanding of KD pathogenesis and may provide novel therapeutic targets.

Abstract 12698: Sodium-containing versus Sodium-trace Preparations of Ivig for Children With Kawasaki Disease in Acute Phase

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Takanori Suzuki ◽  
Nobuaki Michihata ◽  
Tetsushi Yoshikawa ◽  
Kazuyoshi Saito ◽  
Kiyohide Fushimi ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Length Of Stay ◽  
Propensity Score ◽  
Acute Phase ◽  
Medical Cost ◽  
Instrumental Variable ◽  
Systemic Vasculitis ◽  
Developed Countries ◽  
Recommended Treatment ◽  
Ivig Resistance

Objectives: Kawasaki disease (KD) is an acute systemic vasculitis that most commonly causes acquired cardiac disease in children in developed countries. The most highly recommended treatment for KD is 2 g/kg intravenous immunoglobulin (IVIG). Hyponatremia in patients with KD in the acute phase is known to be associated with IVIG resistance and coronary artery abnormalities (CAA). There are two types of IVIG, sodium-containing (high Na) and sodium-trace (low Na) preparations. However, few studies have compared the effects of these two preparations for superiority. The purpose of this study was to compare outcomes between high and low Na IVIG preparations in KD children using a national inpatient database in Japan. Methods: We used the Diagnostic Procedure Combination database to identify KD patients treated with IVIG between 2010 and 2017. We identified those receiving high and low Na preparations of IVIG as an initial treatment. Outcomes included proportion of CAA, IVIG resistance, adverse effects, length of stay, and medical cost. Propensity score-matched analyses were conducted to compare the outcomes between the two groups. Instrumental variable analyses were performed to confirm the results. Results: We identified 47,292 patients with KD and created 23646 propensity score-matched pairs between the high and low Na IVIG groups. There were significant differences in proportions of CAA (2.5% vs. 2.9%; p=0.016) and IVIG resistance (23.8% vs. 24.9%; p=0.006) between the two groups. However, there were no significant differences in length of stay or medical cost. The instrumental variable analyses confirmed that high Na IVIG was significantly associated with lower proportion of CAA compared with low Na IVIG (odds ratio, 1.69; p<0.001). Conclusions: The present study suggests that high Na IVIG is potentially effective for reducing the proportion of CAA in KD patients. Prospective studies are warranted to confirm the effectiveness observed in this study.

scholarly journals Torticollis as Presentation for Atypical Kawasaki Disease Complicated by Giant Coronary Artery Aneurysms

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Tracey Dyer ◽  
Paul Dancey ◽  
John Martin ◽  
Suryakant Shah
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Systemic Vasculitis ◽  
Cervical Lymphadenopathy ◽  
Febrile Illness ◽  
High Dose ◽  
Coronary Artery Aneurysms ◽  
Low Dose Aspirin ◽  
Atypical Kawasaki Disease ◽  
Mucosal Changes

Kawasaki disease (KD) is an acute systemic vasculitis of childhood. The diagnosis can be made in a patient who presents with a prolonged high fever and meeting at least four of five criteria including polymorphous rash, mucosal changes, extremity changes (including swelling and/or palmar and plantar erythema), bilateral nonsuppurative conjunctivitis, and unilateral cervical lymphadenopathy. Atypical KD refers to patients who have not met the full criteria and in whom atypical features may be present. We discuss a case of a 6-year-old male who presented to the Emergency Department with torticollis. A series of investigations for elevated inflammatory markers revealed dilated coronary artery aneurysms on echocardiogram, and thus he was diagnosed with atypical KD. His only other criteria were bilateral nonsuppurative conjunctivitis and a prior brief febrile illness. He was treated with high-dose intravenous immune globulin (IVIG) and low-dose aspirin. Low-molecular-weight heparin and atenolol were added due to the presence of giant aneurysms.

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