Dataset Information

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

ABSTRACT:

Background

Resistance to intravenous immunoglobulin (IVIG) occurs in 10-20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.

Method

We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.

Results

Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.

Conclusions

Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5176264 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

Wang Yue Y Li Zhen Z Hu Guang G Hao Shiying S Deng Xiaohong X Huang Min M Ren Miao M Jiang Xiyuan X Kanegaye John T JT Ha Kee-Soo KS Lee JungHwa J Li Xiaofeng X Jiang Xuejun X Yu Yunxian Y Tremoulet Adriana H AH Burns Jane C JC Whitin John C JC Shin Andrew Y AY Sylvester Karl G KG McElhinney Doff B DB Cohen Harvey J HJ Ling Xuefeng B XB

PloS one 20161221 12

<h4>Background</h4>Resistance to intravenous immunoglobulin (IVIG) occurs in 10-20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.<h4>Method</h4>We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expres ...[more]

PMID: 28002448

Similar Datasets

Project description:Kawasaki disease (KD) is an acute, self-limited febrile illness of young children. The etiology of KD remains to be poorly understood. There has been limited research on longitudinal examination of peripheral blood leukocytes for immune profiling particularly in relation to treatment response with intravenous immunoglobulin (IVIG). This study profiles immune cells at the time of diagnosis and over the disease course. In addition, we identified the characteristics of the immune cells in IVIG-responsive patients with KD. We enrolled patients diagnosed with KD between May 1, 2017, and January 1, 2020. Blood was taken at least three times from all enrolled patients: at diagnosis (before IVIG infusion) and immediately and 2 weeks after IVIG infusion. We evaluated the laboratory findings and results of flow cytometry analysis of immune cells at all stages, focusing on CD4+ T lymphocytes, CD8+ T lymphocytes, CD19+ B lymphocytes, granulocytes, classical monocytes, and natural killer (NK) cells. Non-febrile healthy controls (NFCs) and other febrile controls (OFCs) were also enrolled. A total of 68 patients were enrolled and divided into two groups according to IVIG resistance status: IVIG-responsive (n = 55) and IVIG-resistant (n = 13). The total fever duration was significantly longer in the IVIG-resistant group (9.7 ± 5.3 days) than in the IVIG-responsive group (6.7 ± 3.0 days; P = 0.02). There was a significant difference in intermediate CD14+CD16+ monocytes between KD patients and both NFC and OFCs; they were significantly higher and lower in KD patients than NFC and OFCs, respectively (P < 0.001). The levels of all three subtypes of NK cells were significantly lower in KD patients than in both NFC and OFCs (P < 0.001). Regarding IVIG responsiveness, CD14+CD16+ intermediate monocyte levels were significantly lower in the IVIG-resistant group (P < 0.001). In addition, CD56-CD16+ NK cell expression was significantly lower in the IVIG-resistant group than in the IVIG-responsive group (P = 0.002). In conclusion, our results suggest CD56-CD16+N NK cells and CD14+CD16+ intermediate monocytes might play an essential role in immunopathogenesis of KD. Further studies are warranted to explore the role of these subpopulations particularly for the observed association with coronary artery lesions (CAL) and treatment response.

Dataset Information

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

Background

Method

Results

Conclusions

Publications

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets