Pathogenesis Of Kawasaki Disease Research Articles

An Update on Kawasaki Disease.

To summarize advances in research on the epidemiology, pathogenesis, diagnosis, and treatment of Kawasaki Disease (KD), a systemic inflammatory illness of unknown etiology that affects children globally. The epidemiology of KD was affected by the COVID-19 pandemic and advances in molecular immunology and machine learning have enabled research into its pathogenesis. There is ongoing research into agents that can be used to intensify initial treatment and accumulating evidence supporting the use of certain rescue regimens for refractory disease over others. There is promise surrounding a new coronary artery aneurysm prediction model. Research into the post-acute morbidity of KD continues. The COVID-19 pandemic temporarily reduced the incidence of KD. The NLRP3 inflammasome plays a key role in KD pathogenesis. Intensified initial treatment benefits high-risk patients, yet no intensification regimen shows superiority over another. Corticosteroids, infliximab, or combination therapy with IVIg plus another agent may be superior rescue regimens compared to IVIg alone for refractory KD. The Son score, developed in North America, predicted coronary artery lesions in Japanese and Italian cohorts. Patients with a history of KD may carry long-term physical and emotional burdens that persist into adulthood yet appear to have typical neurocognitive development. Successful transition to adult healthcare presents a challenge.

Illuminating the enigmatic pathogenesis of Kawasaki disease: Unveiling novel therapeutic avenues by targeting FCGR3B-S100A12 pathway

Kawasaki disease (KD) primarily affects the pediatric population and exhibits a notable incidence of drug resistance, resulting in coronary artery damage and thrombosis. This study aimed to identify innovative therapeutic targets for KD treatment. By harnessing single-cell data derived from peripheral blood mononuclear cells, we identified differentially expressed genes. Through the integration of eQTL data and Mendelian randomization analysis, we identified FCGR3B and S100A12 were causally linked to KD. The DrugBank database showed their potential as drug target candidates. GSEA further elucidated their roles on coronary artery damage and thrombosis. Furthermore, we have confirmed that the ligand-FCGR3B complex enhances the intracellular calcium concentration (Ca2+) within the cytoplasm, which in turn accelerates the secretion of S100A12, a pro-inflammatory cytokine that targets endothelial cells, from neutrophils. By integrating existing research, we proposed a synergistic effect that FCGR3B-S100A12 pathway positively modulates the development of coronary artery damage and thrombus formation, suggesting their perspectives in clinical treatment.

Unraveling the gut: the pivotal role of intestinal mechanisms in Kawasaki disease pathogenesis

Kawasaki disease (KD), an acute systemic vasculitis that primarily affects children under 5 years of age, is the leading cause of acquired heart disease in this age group. Recent studies propose a novel perspective on KD’s etiology, emphasizing the gastrointestinal (GI) tract, particularly the role of gut permeability. This review delves into how disruptions in gut barrier function trigger systemic inflammatory responses, exacerbate vascular inflammation, and contribute to coronary artery aneurysms. Evidence suggests that children with KD often exhibit increased gut permeability, leading to an imbalance in gut immunity and subsequent gut barrier damage. These changes impact vascular endothelial cells, promoting platelet aggregation and activation, thereby advancing severe vascular complications, including aneurysms. Additionally, this review highlights the correlation between GI symptoms and increased resistance to standard treatments like intravenous immunoglobulin (IVIG), indicating that GI involvement may predict therapeutic outcomes. Advocating for a new paradigm, this review calls for integrated research across gastroenterology, immunology, and cardiology to examine KD through the lens of GI health. The goal is to develop innovative therapeutic interventions targeting the intestinal barrier, potentially revolutionizing KD management and significantly improving patient outcomes.

Identification of key ferroptosis‑related biomarkers in Kawasaki disease by clinical and experimental validation.

Kawasaki disease (KD) is an acute febrile rash that is primarily characterized by systemic vasculitis and is the leading cause of childhood-acquired heart disease. At present, a KD diagnosis is solely dependent on clinical symptoms and effective diagnostic markers are unavailable. Ferroptosis, a novel form of programmed cell death, contributes to the pathophysiology of infectious diseases. The present study aimed to identify key ferroptosis-related genes (FRGs) involved in the pathological process of KD and thus potential diagnostic biomarkers for this disease. For this purpose, differentially expressed-FRGs (DE-FRGs) between patients with KD and healthy controls were screened. The least absolute shrinkage and selection operator (LASSO) algorithm and a logistic regression model combined with receiver operating characteristic analysis were then used to identify and assess ferroptosis-related markers. Additionally, immune cell infiltration landscapes in the KD and control groups were evaluated using CIBERSORT. Moreover, the predictive value of the identified markers was validated in the clinical samples as well as vascular endothelial cells. A total of 10 DE-FRGs were screened from the KD and control samples. These 10 DE-FRGs were then applied to the LASSO model and 6 key ferroptosis-related markers were obtained. The subsequent Gene Set Variation Analysis results suggested that high expression levels of these markers were closely associated with innate immune activation and metabolism, while low expression was mainly linked to adaptive immune-related pathways. In addition to validating each gene in the training and validation sets, the diagnostic potential of these markers was assessed utilizing KD samples obtained from Shenzhen Baoan Women's and Children's Hospital. As a result, MAPK14, SLC2A3 and PGD were selected as potential diagnostic markers for KD. Additionally, changes in the expression of marker genes during inflammatory activation of vascular endothelial cells were measured by reverse transcription-quantitative PCR. The results of the present study will help to understand the role of FRGs in the pathogenesis of KD. Moreover, the identified FRGs may serve as diagnostic biomarkers, providing new strategies for KD prediction and treatment.

Role of leukocyte-associated Ig-like receptor-1 in the pathogenesis of Kawasaki disease and coronary artery aneurysms

ObjectiveTo elucidate the relationship between leukocyte-associated Ig-like receptor-1 (LAIR-1) and the pathogenesis of Kawasaki disease (KD) and coronary artery aneurysms(CAA). MethodsThe study cohort comprises children who were diagnosed with KD and were categorized into two groups: KD patients with CAA (KD-CAA) and KD without CAA (KD-NCAA), with healthy children serving as control group (HC). LAIR-1 on leukocytes was examined via flow cytometry, while serum LAIR-1 (sLAIR-1) was quantified using ELISA. IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-α, IFN-γ and TNF-α were examined by Immunofluorescence assay. ResultssLAIR-1 levels were elevated in the KD and KD-CAA groups compared with those in the HC and KD-NCAA groups (P < 0.05). sLAIR-1 exhibited an area under the curve value of 0.858 for predicting KD (P < 0.001) and 0.628 for predicting CAA (P = 0.055, borderline significance). LAIR-1 was increased on the neutrophils in KD group, whereas it was lower in KD-CAA than that in KD-NCAA, and decreased in KD after IVIG treatment. In contrast, LAIR-1 was reduced on CD4+ and CD8+ T lymphocyte in KD group, and increased in KD after IVIG treatment (all P < 0.05). LAIR-1 on neutrophils showed a positive correlation with IL-5, while on CD4+ T cells, it was negatively correlated with IL-2, IL-6, IL-10, IFN-γ, and IL-8. On CD8+ T cells, LAIR-1 was negatively correlated with IL-2 and IFN-γ. ConclusionsLAIR-1 may serve as a potential biomarker for KD and CAAs, while LAIR-1 might be implicated in KD pathogenesis and CAA.

Characteristics of intestinal microbiota in the acute phase of Kawasaki disease in infants and children

To study the composition, abundance, and functional profiles of the intestinal microbiota in infants and young children with Kawasaki disease (KD) during the acute phase, and to explore the potential role of intestinal microbiota in the pathogenesis of KD. Six children aged 0-3 years with acute KD admitted to the Department of Cardiology, Children's Hospital Affiliated to Capital Institute of Pediatrics from July to October 2021 were prospectively included as the KD group. Six age- and sex-matched healthy children who underwent physical examinations at the hospital during the same period were selected as the healthy control group. Metagenomics sequencing was used to detect and compare the differences in the microflora structure and functional profiles of fecal samples between the two groups. There were significant differences in the structural composition and diversity of intestinal microbiota between the two groups (P<0.05). Compared with the healthy control group, the abundance of Listeria_monocytogenes (family Listeriaceae and genus Listeria), Bifidobacterium_rousetti, Enterococcus_avium, and Enterococcus_hirae was significantly higher in the intestinal microbiota in the KD group (|LDA|>2.0, P<0.05). The steroid degradation and apoptosis pathways were significantly upregulated in the KD group compared with the healthy control group, while the Bacterial_secretion_system, Sulfur_metabolism, Butanoate_metabolism, Benzoate_degradation, β-alanine metabolism, and α-linolenic acid pathways were significantly downregulated (|LDA|>2, P<0.05). There are significant differences in the structure and diversity of intestinal microbiota between children aged 0-3 years with acute KD and healthy children, suggesting that disturbances in intestinal microbiota occur during the acute phase of KD. In particular, Listeria_monocytogenes, Enterococcus_avium, and Enterococcus_hirae may be involved in the pathogenesis of KD through steroid degradation and apoptosis pathways.

ScRNA+TCR-seq reveals the pivotal role of dual receptor T lymphocytes in the pathogenesis of Kawasaki disease and during IVIG treatment.

Kawasaki disease (KD), a common cause of acquired heart disease in children in developed countries, is primarily treated with intravenous immunoglobulin (IVIG), but some children demonstrate IVIG resistance with increased coronary artery injury risk. T cells have been demonstrated to be involved in the pathogenesis of KD and its treatment with IVIG. However, the role and mechanism of dual TCR T lymphocytes in the occurrence of KD and IVIG therapy remain unclear. This study, based on scRNA-seq combined with TCR-seq technology, clustered the peripheral blood mononuclear cells of 3 healthy controls and 6 KD patients before and after IVIG treatment. Comparative analysis was conducted to investigate the differences in the proportion of single/dual receptor T cells, the characteristics of CDR3 repertoires, cell types, and the expression of transcription factors among the three groups. The study aimed to explore the correlation between dual TCR T cells and KD as well as IVIG treatment. In our experimental results, we observed the presence of dual TCR T cells in all three groups. However, compared to the healthy control group and the IVIG-treated group, the KD patients before IVIG treatment exhibited a lower proportion of dual TCR T cells, with variability between samples, ranging from 4% to 15%. Notably, after IVIG treatment, the proportion of dual TCR T cells significantly increased, stabilizing above 12%, and these T cells also exhibited clonal expansion and a preference for V gene usage. In addition we found differences in dual TCR T cell subsets among the three groups, for example, IVIG treatment increases the proportion of dual TCR Treg cells, but it still remains below that of healthy control groups, significantly higher proportions of both dual TCR CD8 central and effector memory T cells in IVIG-treated KD patients, and differences in the expression of transcription factors between single and dual TCR T cells. These results suggest dual TCR T cells correlate with KD and IVIG treatment. Dual TCR T lymphocytes, especially dual TCR CD8 T cells and Treg cells, play crucial roles in the pathogenesis of KD and during IVIG treatment, providing strong support for further elucidating KD pathogenesis and optimizing treatment strategies.

Small-for-Gestational-Age Status and the Risk of Kawasaki Disease: A Nationwide Birth Cohort in Japan.

Kawasaki disease (KD) is a pediatric disease of unknown etiology that commonly affects infants in East Asia. Infants born small for gestational age (SGA) have weaker immune systems and are more susceptible to infection. Using data from a nationwide Japanese birth cohort study conducted in 2010 (n=34,579), we investigated whether SGA increases the risk of KD. SGA was defined as birth weight below the 10th percentile for gestational age. The outcome was hospitalization for KD between 6 and 30 months of age. The association between SGA and hospitalization for KD, adjusted for child and maternal factors, was examined using logistic regression. Of the 231 children hospitalized for KD, 9.5% were SGA. Further statistical analysis showed that SGA did not increase the odds ratio (OR) of hospitalization for KD (adjusted OR 1.12, 95% confidence interval 0.71-1.75). This result was not changed with stratification by early daycare attendance and preterm status. Reasons for the lack of association may include the multifactorial pathogenesis of KD; in addition, the types of infections to which SGA infants are predisposed may differ from those triggering KD. Overall, our large nationwide study found no association between SGA and KD.

Frequencies of Human Leukocyte Antigen Alleles in Turkish Children with Kawasaki Disease

Abstract Objective Kawasaki disease (KD) is an acute systemic vasculitis that is one of the major causes of acquired heart disease especially in young children. The pathogenesis of KD is still unclear. The increased incidence of the disease among Japanese children and siblings of affected patients suggests a genetic component to KD susceptibility. Several reports have studied human leukocyte antigen (HLA) polymorphisms in different populations with KD and found various results. In the present study, we aimed to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in Turkish children with KD. Methods The study was conducted between January 2016 and February 2018. HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) alleles of patients and healthy controls were studied using the low-resolution DNA-based sequence-specific oligonucleotide method. Results Fifty children with KD and 500 healthy controls were included in this study. In the analysis of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, no statistical difference was found in the frequency of alleles between the patients with KD and the control group. However, a significantly lower frequency of the HLA-DQB1*03 allele was observed in the KD group than in the control group (p &lt; 0.001, odds ratio [OR]: 0.29, 95% confidence interval [CI]: 0.15–0.55). When the patients with KD were divided into two subgroups with or without coronary artery lesions (CALs), the frequency of the HLA-DQB1*03 allele was also found lower in the KD group with CALs than the KD group without CALs (p = 0.008, OR: 0.19, 95% CI: 0.05–0.68). Conclusion The study may guide future studies on HLA-DQB1*03 whether it is a protective allele for KD and CALs in Turkish children.

Redundant role of PAD2 and PAD4 in the development of cardiovascular lesions in a mouse model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. While circulating neutrophils are increased and activated during acute KD, it is unclear whether neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of KD. Peptidylarginine deiminase 4 (PAD4), an enzyme involved in protein citrullination and essential for NETs formation, is implicated in the pathogenesis of various diseases. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced mouse model of KD vasculitis to determine the contribution of PAD4 in KD vasculitis. We found that the pan-PADs inhibitor, Cl-amidine, significantly reduced LCWE-induced cardiovascular lesions, but neutrophil-specific Padi4 KO mice did not impact the development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1β secretion, macrophage-specific Padi4 KO mice did not reduce the lesions. Padi4-/- mice also developed KD vasculitis, AFM30a, a PAD2 inhibitor, significantly reduced KD vasculitis in Padi4-/- mice, indicating a compensatory role of PAD2 in PAD4 deficiency. We also identified several citrullinated proteins in macrophages with constitutively active NLRP3 inflammasome that were inhibited by Cl-amidine treatment, suggesting that protein citrullination participates in NLRP3 inflammasome activation. These data indicate a dispensable role for PAD4-dependent NETs formation, and a redundant role of PAD2 and PAD4 in this murine KD vasculitis. The cardioprotective effects of Cl-amidine to reduce the severity of murine KD vasculitis are not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.

Resurgence of Kawasaki Disease Following Relaxation of Coronavirus Disease 2019 Pandemic Restrictions in Japan

ObjectivesTo compare the number and incidence of Kawasaki disease (KD) patients in years 2 through 4 of the coronavirus disease 2019 (COVID-19) pandemic, and determine the impact of 3 years of implementation infection control measures and their subsequent relaxation on the epidemiology of KD in Japan. Study designWe conducted a population-based, cohort study including consecutive KD patients in Kobe City between 2021 and 2023. We compared the incidence of KD cases, in relation to timing of infection control measures, as well as infectious disease cases based on a regional surveillance system. Data from a previous 2016 through 2020 study were used for comparison. ResultsA total of 566 children with KD were identified during the study period. During the infection control period in 2021 to 2022, the incidence of KD remained low compared with the pre-pandemic level (281.3 and 327.5/100,000 children aged 0-4 years in 2021to 2022 and 2016 through 2019, respectively), but a recovery trend began in the 0-1-year age group. During the relaxation period in 2023, the incidence of KD increased across a wide age range, reaching the highest recorded in Japan (426.7/100,000 children aged 0-4 years), and the median age of onset increased to age 30 months. The resurgence of KD coincided with the patterns for multiple infectious diseases in 2023. The seasonality of KD observed before the pandemic was altered. ConclusionsKD resurged in 2023 after relaxation of the prolonged COVID-19 pandemic restrictions in Japan. This phenomenon coincided with the rise of multiple infectious diseases, and supports the pathogenesis of KD being triggered by infectious agents.

Metagenomic analysis demonstrates distinct changes in the gut microbiome of Kawasaki diseases children.

Kawasaki disease (KD) has been considered as the most common required pediatric cardiovascular diseases among the world. However, the molecular mechanisms of KD were not fully underlined, leading to a confused situation in disease management and providing precious prognosis prediction. The disorders of gut microbiome had been identified among several cardiovascular diseases and inflammation conditions. Therefore, it is urgent to elucidate the characteristics of gut microbiome in KD and demonstrate its potential role in regulating intravenous immunoglobulin (IVIG) resistance and coronary artery injuries. A total of 96 KD children and 62 controls were enrolled in the study. One hundred forty fecal samples had been harvested from KD patients, including individuals before or after IVIG treatment, with or without early coronary artery lesions and IVIG resistance. Fecal samples had been collected before and after IVIG administration and stored at -80°C. Then, metagenomic analysis had been done using Illumina NovaSeq 6000 platform. After that, the different strains and functional differences among comparisons were identified. First, significant changes had been observed between KD and their controls. We found that the decrease of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides uniformis, and Bacteroides ovatus and the increase of pathogenic bacteria Finegoldia magna, Abiotrophia defectiva, and Anaerococcus prevotii perhaps closely related to the incidence of KD. Then, metagenomic and responding functional analysis demonstrated that short-chain fatty acid pathways and related strains were associated with different outcomes of therapeutic efficacies. Among them, the reduction of Bacteroides thetaiotaomicron, the enrichment of Enterococcus faecalis and antibiotic resistance genes had been found to be involved in IVIG resistance of KD. Moreover, our data also revealed several potential pathogenetic microbiome of that KD patients with coronary artery lesions. These results strongly proved that distinct changes in the gut microbiome of KD and the dysfunction of gut microbiomes should be responsible for the pathogenesis of KD and significantly impact the prognosis of KD.

Risks of Kawasaki disease and multisystem inflammatory syndrome in pediatric patients with COVID-19 infection: A TriNetX based cohort study.

The associations of coronavirus disease (COVID-19) with Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) remain unclear. Few large-scale studies have estimated the cumulative incidence of MIS-C and KD after COVID-19 in children. Data were obtained from TriNetX. After propensity score matching was completed, data from 258 645 patients with COVID-19 (COVID-19 group) and 258 645 patients without COVID-19 (non-COVID-19 group) were analyzed using Cox regression. Hazard ratio (HR), 95% CI, and cumulative incidence of MIS-C and KD were calculated for both groups. A stratified analysis was performed to validate the results. After matching for age at baseline and sex, the risks of MIS-C and KD were higher in the COVID-19 group than in the non-COVID-19 group (HR: 3.023 [95% CI, 2.323-3.933] and 1.736 [95% CI, 1.273-2.369], respectively). After matching for age at baseline, sex, race, ethnicity, and comorbidities, the risks of MIS-C and KD remained significantly higher in the COVID-19 group than in the non-COVID-19 group (HR: 2.899 [95% CI, 2.173-3.868] and 1.435 [95% CI, 1.030-2.000]). When stratified by age, the risk of MIS-C was higher in the COVID-19 group-for patients aged >5 years and ≤5 years (HR: 2.399 [95% CI, 1.683-3.418] and 2.673 [95% CI, 1.737-4.112], respectively)-than in the non-COVID-19 group. However, the risk of KD was elevated only in patients aged ≤5 years (HR: 1.808; 95% CI, 1.203-2.716). When stratified by COVID-19 vaccination status, the risks of MIS-C and KD were elevated in unvaccinated patients with COVID-19 (HR: 2.406 and 1.835, respectively). Patients with COVID-19 who are aged <18 and ≤5 years have increased risks of MIS-C and KD, respectively. Further studies are required to confirm the role of COVID-19 in the pathogenesis of MIS-C and KD.

Respiratory viral infections and Kawasaki disease: A molecular epidemiological analysis

Background/PurposeRecent large-scale epidemiological studies have revealed significant temporal associations between certain viral infections and the subsequent development of Kawasaki disease (KD). Despite these associations, definitive laboratory evidence linking acute or recent viral infections to KD cases remains elusive. The objective of this study is to employ a molecular epidemiological approach to investigate the temporal association between viral infections and the development of KD. MethodsWe analyzed 2460 patients who underwent the FilmArray® Respiratory Panel test between April 2020 and September 2021. ResultsFollowing the application of inclusion criteria, 2402 patients were categorized into KD (n = 148), respiratory tract infection (n = 1524), and control groups (n = 730). The KD group exhibited higher positive rates for respiratory syncytial virus (RSV), human rhinovirus/enterovirus (hRV/EV), parainfluenza virus (PIV) 3, and adenovirus (AdV) compared to the control group. Additionally, coinfections involving two or more viruses were significantly more prevalent in the KD group. Notably, RSV-positive, hRV/EV-positive, and PIV3-positive KD patients exhibited a one-month delay in peak occurrence compared to non-KD patients positive for corresponding viruses. In contrast, AdV-positive KD cases did not show a one-month delay in peak occurrence. Moreover, anti-RSV, anti-PIV3, and anti-AdV antibody-positive rates or antibody titers were higher in RSV-, PIV3-, and AdV-positive KD cases, respectively, compared to non-KD cases with the same viral infections. ConclusionRecent infection with RSV, PIV3, or AdV, occasionally in conjunction with other viruses, may contribute to the pathogenesis of KD as infrequent complications.

Abstract 1116: IL-33 Promotes Cardiovascular Lesion Development In A Murine Model Of Kawasaki Disease By Boosting IL-1β Production

Kawasaki Disease (KD), a pediatric acute febrile systemic vasculitis, is the leading cause of acquired heart diseases in children. Coronary artery aneurysms (CAAs) occur in up to 25% of untreated children, which is reduced to 5% with intravenous immunoglobulin (IVIG) treatment. However, up to 20% of KD patients are refractory to IVIG and at higher risk of developing CAAs. This highlights the need to characterize the immune mechanisms mediating KD to develop more efficient therapies. IL-1β plays a key role in KD pathogenesis. IL-33, a member of the IL-1 cytokine family, is released upon inflammation and tissue damage and exerts its effects by binding to its receptor ST2 ( Il1rl1 ). Circulating levels of IL-33 are elevated in KD patients during the acute phase of the disease. However, if and how IL-33 contributes to cardiovascular lesion development in KD remains unknown. Using the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, we observed increased Il33 mRNA expression in hearts and abdominal aorta aneurysms of LCWE-injected mice. While ST2 was detected by immunofluorescence in the hearts of both control and LCWE-injected mice, its expression was increased in the abdominal aortas of LCWE-injected mice. In contrast, IL-33 expression was only increased in inflamed cardiovascular tissues of LCWE-injected mice. Single-cell RNA-sequencing and flow cytometric analysis of abdominal aortas, as well as spatial transcriptomics of heart tissues from LCWE-injected mice, indicated that Il33 transcripts were expressed primarily by stromal cells, such as fibroblasts, endothelial cells, and vascular smooth muscle cells. On the other hand, Il1rl1 transcripts were highly expressed by tissue infiltrating immune cells, such as macrophages, eosinophils, and neutrophils. Blocking IL-33, using either Il33 -/- mice or an anti-IL-33 antibody, significantly attenuated LCWE-induced KD vasculitis. In vitro, IL-33 treatment of LCWE-stimulated bone marrow-derived macrophages boosted their IL-1β production. Overall, our results indicate that IL-33, produced by stromal cells, may promote LCWE-induced KD vasculitis by increasing the release of IL-1β by tissue infiltrating immune cells, and this axis could therapeutically be targeted in KD.

Markers of Endothelial Dysfunction in Kawasaki Disease: An Update.

Kawasaki disease (KD) is a medium vessel vasculitis that has a special predilection for coronary arteries. Cardiovascular complications include the development of coronary artery abnormalities (CAAs) and myocarditis. Endothelial dysfunction (ED) is now recognized to be a key component in the pathogenesis of KD and is believed to contribute to the development of CAAs. ED has been evaluated by several clinical parameters. However, there is paucity of literature on laboratory markers for ED in KD. The evaluation of ED can be aided by the identification of biomarkers such as oxidative stress markers, circulating cells and their progenitors, angiogenesis factors, cytokines, chemokines, cell-adhesion molecules, and adipokines. If validated in multicentric studies, these biomarkers may be useful for monitoring the disease course of KD. They may also provide a useful predictive marker for the development of premature atherosclerosis that is often a concern during long-term follow-up of KD. This review provides insights into the current understanding of the significance of ED in KD.

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development.

Kawasaki disease (KD) often complicates coronary artery lesions (CALs). Despite the established significance of STAT3 signaling during the acute phase of KD and signal transducer and activator of transcription 3 (STAT3) signaling being closely related to CALs, it remains unknown whether and how STAT3 was regulated by ubiquitination during KD pathogenesis. Bioinformatics and immunoprecipitation assays were conducted, and an E3 ligase, murine double minute 2 (MDM2) was identified as the ubiquitin ligase of STAT3. The blood samples from KD patients before and after intravenous immunoglobulin (IVIG) treatment were utilized to analyze the expression level of MDM2. Human coronary artery endothelial cells (HCAECs) and a mouse model were used to study the mechanisms of MDM2-STAT3 signaling during KD pathogenesis. The MDM2 expression level decreased while the STAT3 level and vascular endothelial growth factor A (VEGFA) level increased in KD patients with CALs and the KD mouse model. Mechanistically, MDM2 colocalized with STAT3 in HCAECs and the coronary vessels of the KD mouse model. Knocking down MDM2 caused an increased level of STAT3 protein in HCAECs, whereas MDM2 overexpression upregulated the ubiquitination level of STAT3 protein, hence leading to significantly decreased turnover of STAT3 and VEGFA. MDM2 functions as a negative regulator of STAT3 signaling by promoting its ubiquitination during KD pathogenesis, thus providing a potential intervention target for KD therapy.

Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.

Kawasaki disease (KD) is a diffuse vasculitis in children. Response to high dose intravenous gamma globulin (IVIG), the primary treatment, varies according to genetic background. We sought to identify genetic loci, which associate with treatment response using whole genome sequencing (WGS). We performed WGS in 472 KD patients with 305 IVIG responders and 167 non-responders defined by AHA clinical criteria. We conducted logistic regression models to test additive genetic effect in the entire cohort and in four subgroups defined by ancestry information markers (Whites, African Americans, Asians, and Hispanics). We performed functional mapping and annotation using FUMA to examine genetic variants that are potentially involved IVIG non-response. Further, we conducted SNP-set [Sequence] Kernel Association Test (SKAT) for all rare and common variants. Of the 43,288,336 SNPs (23,660,970 in intergenic regions, 16,764,594 in introns and 556,814 in the exons) identified, the top ten hits associated with IVIG non-response were in FANK1, MAP2K3:KCNJ12, CA10, FRG1DP, CWH43 regions. When analyzed separately in ancestry-based racial subgroups, SNPs in several novel genes were associated. A total of 23 possible causal genes were pinpointed by positional and chromatin mapping. SKAT analysis demonstrated association in the entire MANIA2, EDN1, SFMBT2, and PPP2R5E genes and segments of CSMD2, LINC01317, HIVEPI, HSP90AB1, and TTLL11 genes. This WGS study identified multiple predominantly novel understudied genes associated with IVIG response. These data can serve to inform regarding pathogenesis of KD, as well as lay ground work for developing treatment response predictors.

Emerging evidence of microbial infection in causing systematic immune vasculitis in Kawasaki disease.

Kawasaki disease (KD) is a systematic vasculitis that is often complicated by coronary artery lesions and is a leading cause of acquired heart disease in developed countries. Previous studies have suggested that genetic susceptibility, together with an inducing infectious agent, could be involved in KD pathogenesis; however, the precise causative agent of this disease remains unknown. Moreover, there are still debates concerning whether KD is an infectious disease or an autoimmune disease, although many studies have begun to show that various pathogens functioning as critical inducers could activate different kinds of immune cells, consequently leading to the dysfunction of endothelial cells and systematic vasculitis. Here in this review, we attempt to summarize all the available evidence concerning pathogen infections associated with KD pathogenesis. We also discuss the related mechanisms, present a future perspective, and identify the open questions that remain to be investigated, thereby providing a comprehensive description of pathogen infections and their correlations with the host immune system in leading to KD.

Research advances in genetic polymorphisms in Kawasaki disease

Kawasaki disease (KD) is a systemic inflammatory vascular disorder that predominantly affects children and is the leading cause of acquired heart disease in children. Although the etiology of this disease remains unclear, genome-wide association and genome-wide linkage studies have shown that some susceptible genes and chromosomal regions are associated with the development and progression of KD. With the advancement of high-throughput DNA sequencing techniques, more and more genomic information related to KD is being discovered. Understanding the genes involved in the pathogenesis of KD may provide novel insights into the diagnosis and treatment of KD. By analyzing related articles and summarizing related research advances, this article mainly discusses the T cell activation-enhancing genes that have been confirmed to be closely associated with the development and progression of KD and reveals their association with the pathogenesis of KD and coronary artery lesions.