RESUMO
OBJECTIVE: To identify cytokine genes uniquely expressed in peripheral blood mononuclear cells (PBMNCs) in the acute phase of Kawasaki disease (KD) with coronary artery lesions (CALs). STUDY DESIGN: We screened the mRNA expression levels of PBMNCs from 4 pairs of KD patients with and without CAL using DNA microarray. The result was confirmed by real-time polymerase chain reaction (RT-PCR). The genetic association study was performed to analyze the significance of single nucleotide polymorphisms in the identified gene for the development of CAL in KD patients (184 controls, 144 KD patients with CAL, 64 KD patients without CAL). RESULTS: The microarray analysis showed that tissue inhibitor of metalloproteinases 2 (TIMP2) was expressed at higher levels in PBMNCs of KD patients with CAL than in KD patients without CAL. Quantitative RT-PCR confirmed that the expression levels were significantly higher in the KD patients with CAL than in those without CAL (P < .05). Among KD patients, TIMP2 promoter polymorphisms were significantly associated with a risk of CAL (P < .01). There was a significant difference in the transcriptional activities between the haplotypes of the TIMP2 promoter polymorphisms by reporter assay using U-937. CONCLUSIONS: TIMP2 overexpression and the promoter polymorphisms might play a role in the development of CALs.
Assuntos
Doença das Coronárias/genética , Predisposição Genética para Doença , Metaloproteinase 2 da Matriz/genética , Síndrome de Linfonodos Mucocutâneos/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/fisiopatologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Probabilidade , RNA Mensageiro , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To investigate whether the CD25 + CD4 + regulatory T-cell population, which plays important roles not only in maintaining immunologic self-tolerance but also in controlling the magnitude and character of antimicrobial immune responses, is related to the pathophysiology of Kawasaki disease (KD). STUDY DESIGN: The patient group consisted of 54 patients (median age, 30 months; 27 female and 27 male patients) fulfilling the criteria for KD. Age-matched control subjects included 17 patients with active infections and 24 healthy children. We analyzed CD25 + CD4 + cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and transforming growth factor beta in peripheral blood mononuclear cells and purified CD4 + T cells. RESULTS: The proportions of CD25 + CD4 + cells in patients with acute-phase KD (median, 2.35% of total lymphocytes) were significantly lower than those in healthy control subjects (median, 3.14%) and control subjects with disease (median, 3.15%). The proportions returned to the normal level after intravenous gammaglobulin treatment (median, 3.86%). The mRNA expression of Foxp3, CTLA4, and GITR showed similar tendencies. CONCLUSIONS: The decrease of CD25 + CD4 + regulatory T cells in the acute phase might have a role in the development of KD.