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Research on Changes of Serum HMGB1, MIF, IL-6 Associated with Kawasaki Disease

Author: LvJie
Tutor: PuJinHua
School: Jilin University
Course: Pediatrics
Keywords: Kawasaki disease high-mobility group box 1 protein macrophage migration inhibitory factor Interleukin-6
CLC: R725.4
Type: Master's thesis
Year: 2010
Downloads: 103
Quote: 0
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Abstract


Now, with increasing trend of incidence rate in Kawasaki disease (KD), it has become one of the more common diseases in children. Coronary artery lesion of complicated in KD is a acquired to become the most common causes of heart disease in children. The etiology and pathogenesis of Kawasaki disease is not clear, but the overall tendency is: with a genetic susceptibility factor of the individual in the effect of various pathogenic, pathogenic factors, through direct damage or superantigen-mediated cause immune disorder, T cell subsets and generated of cytokines in body. So, KD is systemic small vessel-based inflammatory response mediated by inflammatory factors such as cytokins and chemical molecules.HMGB1 is an important inflammatory mediator. In a variety of acute inflammatory stimuli, HMGB1 can be found expression in the extracellular or cytoplasmic and have many extracellular functions. Nuclear factor-κB (NF-κB) of macrophages translocate to nuclear in damaged cells and macrophages, and cause after the inflammation by creating a similar tissue necrosis. When damaged cells and macrophages of mouse were knockouted HMGB1, its inflammatory response will be significantly lower. Increased of HMGB1 levels are closely related with cardiovascular disease, especially coronary heart disease. When Recombinant human HMGB1 and microvascular endothelial cells are pregnant, HMGB1 can increase expression of the ICAM-1, VCAM-1, and RAGE; promote secretion TNF, MCP-1, IL-8, PAI-1 and t-PA. It also make phosphorylate of MAP kinase JNK, ERK kinase, transfer core transcription factor NF-κB and SP1, and affect vascular endothelial cells in normal functions.The main function of MIF inhibite monocyte/macrophage migration and promote accumulation of IV-type hypersensitivity in macrophage. The high affinity binding groups of HMGB1 and CD74 molecules in the extracellular part of the 73-232 amino acid residues, active extracellular signal-regulated kinase(ERK) phosphorylation cascade, cause a variety of cell proliferation and synthesized and released of inflammatory transmitters, result varieties of physiological effects. The soluble extracellular part of CD74 fragment sCD7473-232 and anti-CD74 neutralizing antibody can inhibit the CD74 molecule on the cell membrane combined with the MIF, then inhibit the pro-inflammatory role of MIF. Because possessing many biological activities, IL-6 is an important member in complex cytokine network. It can promote B cell differentiation, immunoglobulin secretion and re-immune response; the other thing, it can promote differentiation of cytotoxic T lymphocytes, enhance expression it with IL-2 in perforin gene, increase production T cell IL-2 and IL-2 expression and regulate many cell proliferation and differentiation in the inflammatory response.In this study, we selected thirty patients of Kawasaki disease in our hospital from June 2008 to September 2009 as the case group (of which 18 males, 12 females, ratio 1.5: 1, average age 6 month to 6 years, mean 2.54 years), heat control group (20 cases over the same period of hospitalized with fever, but not KD, 12 cases were male and 8 female, ratio 1.5, an average of 2.37 years), normal control group (20 case out-patient health examination, 11 cases were male, 9 female, ratio was 1.2, an average of 1.89 years, excluding inflammatory disease, physical examination and laboratory tests were normal). The experiments used enzyme-linked immunosorbent assay (ELISA) to detect HMGB1, MIF, IL-6 serum levels, analysis results with statistical methodology. In the end, we can discuss the dysfunction of KD immunological and systemic inflammatory lesions of the mechanism, observate association with the three groups of factors and coronary artery damage and intravenous immunoglobulin (IVIG) for therapy.The results showed: in the acute phase of KD, the level of HMGB1, MIF, IL-6 increase significantly than recovery phase of KD, heating and control groups. There are some statistically significant differences between recovery phase of KD and the control group. Though comparison CAL group and NCAL group of KD, three groups of factors of CAL group elevate significantly, differences are statistically (P <0.05). During the acute phase, IVIG no reactivity Group of HMGB1 levels are significantly elevated IVIG sensitive groups, but no significant decline in recovery. The results showed: in the acute phase of KD, the level of HMGB1,MIF, IL-6 increase significantly, but it decreased in recovery phase. It shows that children with KD have immune dysfunction, imbalance of coagulation and fibrinolysis system in acute stage, and it have immunosuppression and vascular endothelial function in recovery phase. The levels of HMGB1, MIF, IL-6 in the CAL-group were higher than NCAL-group. It indicate that coronary artery lesion group have significant inflammatory response and damaged vascular endothelial cells, so three groups of factors may be forecast the occurrence CAL.Correlation analysis also showed that three groups factor and coronary artery dilatation was positively correlated, in children with acute KD.To examine as a prognostic marker in acute phase of KD, clinical profiles and laboratory findings were compared between responders and poor- responders. In this study, the level HMGB1 of six IVIG non-responsiveness children with KD were significantly higher than the sensitive group and the difference was statistically significant. So, detection HMGB1 may be become a potential tool in IVIG non-responsiveness KD. The levels of MIF and IL-6 were significantly increased, especially in the acute period (P<0.05). The decreased level in recovery phase were higher than heat control group. Il-6, MIF cytokine Involve in the pathogenesis of KD, cytokine cascade effect is base of inflammatory vascular injuring. Serum level of MIF and IL-6 is expected indicators in the acute phase of KD. In analysis of between IVIG non-responsiveness group and IVIG-sensitive, MIF and IL-6 were no significant difference.The level of HMGB1, MIF and IL-6 in KD may be relate to increase the immune vasculitis. The detection is helpful for understanding the development of KD, and through it, the disease is expected in early diagnosis and early treatment. By antibody blocking the expression or activity of the way, it maybe reduce the probability of coronary complication and become a major target for the treatment of KD.

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CLC: > Medicine, health > Pediatrics > Children within the science > Pediatric cardiac and vascular disease
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