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Delayed apoptosis of circulating neutrophils in Kawasaki disease
H Tsujimoto1, S Takeshita, K Nakatani
1Department of Paediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan.
Abstract:
Circulating 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+ 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.
Insights
Polymorphonuclear neutrophil (PMN) apoptosis is inhibited in Kawasaki disease (KD). This delay is linked to Fas-mediated resistance and altered Bcl-2 protein expression, impacting immune response in KD patients.
Area of Science:
- Immunology
- Cell Biology
- Pediatrics
Background:
- Circulating polymorphonuclear neutrophils (PMNs) are activated during Kawasaki disease (KD).
- The role of PMN apoptosis in KD pathogenesis remains unclear.
- Investigating PMN apoptosis deregulation is crucial for understanding KD.
Purpose of the Study:
- To investigate the regulation of polymorphonuclear neutrophil (PMN) apoptosis in Kawasaki disease (KD).
- To determine if PMN apoptosis is inhibited in acute KD patients.
- To explore the mechanisms underlying delayed PMN apoptosis in KD.
Main Methods:
- Isolated PMNs from KD patients, bacterial infection, viral infection, and healthy children were cultured in vitro.
- Flow cytometry was used to assess spontaneous apoptosis (annexin V+, DNA fragmentation) and Fas expression.
- Intracellular expression of anti- and pro-apoptotic proteins (A1/Bax ratio) was analyzed.
Main Results:
- PMN apoptosis was significantly lower in acute KD patients compared to other groups.
- Circulating Fas-positive PMNs were reduced in acute KD patients.
- PMN apoptosis resistance in KD was associated with Fas-mediated signaling and altered Bcl-2 family protein expression (higher A1/Bax ratio).
Conclusions:
- PMN apoptosis is inhibited during the acute phase of Kawasaki disease.
- Resistance to Fas-mediated apoptosis and mitochondrial pathway dysregulation contribute to delayed PMN apoptosis in KD.
- These findings offer insights into KD immunopathogenesis and potential therapeutic targets.