Delayed apoptosis of circulating neutrophils in Kawasaki disease

Abstract

SUMMARYCirculating polymorphonuclear neutrophils (PMNs) are known to increase in number and are functionally activated in the acute phase of Kawasaki disease (KD). In the present study, we investigated whether the apoptosis of PMNs is deregulated in KD. When the isolated PMNs were cultured in vitro, the proportions of spontaneous apoptotic PMNs (annexin V 1 cells and cells with fragmented DNA) were found to be significantly lower (P , 0´01) in the patients with KD (n 25) than in the patients with a bacterial infection (n 20) or a viral infection (n 20), or in healthy children (n 20). The proportion of circulating Fas-positive PMNs was also significantly lower (P , 0´01) in the acute KD patients than in the other groups. In the acute phase of KD, the proportion of spontaneous apoptotic PMNs showed a significant positive correlation (P , 0´01) with the proportions of circulating Fas-positive PMNs. Furthermore, the agonistic anti-Fas MoAb (CH-11) induced a significant increase in the proportion of apoptotic PMNs in the patients with a viral infection and healthy children, but not in either the patients with KD or the patients with a bacterial infection. In the intracellular expression of anti-and pro-apoptotic proteins, the A1/Bax ratio was significantly higher in acute KD than in the other groups. These findings indicate that PMN apoptosis is inhibited during the acute phase of KD and also suggest that both the resistance against the Fas-mediated death signal and the down-regulation of the mitochondrial apoptotic signalling pathway due to an altered balance of Bcl-2 protein expression are responsible for the delayed PMN apoptosis.

A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease

“…Delayed apoptosis of leukocytes is characteristic of acute KD and may contribute to pathogenesis [27]. Intravenous immunoglobulin (IVIg), standard therapy for KD, induces apoptosis of neutrophils in acute KD [28].…”

Transcript abundance patterns in Kawasaki disease patients with intravenous immunoglobulin resistance

“…Elevated plasma levels of VEGF have been detected in acute KD and immunohistochemistry has demonstrated VEGF in coronary arteries, where it may mediate the prominent neovascularization seen in the arterial wall [43, 44]. Increased CEACAM1 expression has also been associated with delayed neutrophil apoptosis, which suggests that apoptosis may be an important pathway for decreasing inflammation in KD [18, 45, 46]. Therefore, measuring concentrations of the alternatively spliced variants of CEACAM1 in plasma may reveal it to be a useful biomarker in predicting IVIG-resistance.…”

The Role of Neutrophil Activation in the Pathogenesis of Kawasaki Disease

“…Since the prolonged survival of activated neutrophils has autotoxic potential due to the release of proteases and ROS, neutrophil apoptosis may represent a suitable mechanism for resolving inflammation. We previously reported that the apoptosis of neutrophils is inhibited during the acute phase of KD, and that an increase in the number of peripheral neutrophils may be associated with the delayed apoptosis of neutrophils [33]. Furthermore, IVIG can promote apoptosis in activated neutrophils in vitro by an oxygen-dependent pathway via FcγRII and III [34].…”