Alteration of CD4⁺CD25⁺Foxp3⁺T cell level in Kawasaki disease

Abstract

PurposeExaggerated pro-inflammatory reactions during the acute phase of Kawasaki disease (KD) suggest the role of immune dysregulation in the pathogenesis of KD. We investigated the profiles of T regulatory cells and their correlation with the clinical course of KD.MethodsPeripheral blood mononuclear cells were collected from 17 KD patients during acute febrile and subacute afebrile phases. T cells expressing CD4, CD25, and Foxp3 were analyzed using flow cytometry, and the results were correlated with the clinical course of KD.ResultsThe percentage of circulating CD4+CD25highFoxp3+ T cells among CD4+ T cells was significantly higher during the subacute afebrile phase than during the acute febrile phase (1.10%±1.22% vs. 0.55%±0.53%, P=0.049). Although levels of CD4+CD25lowFoxp3+ T cells and CD4+CD25-Foxp3+ T cells were only slightly altered, the percentage of CD4+CD25+Foxp3- T cells among CD4+ T cells was significantly lower during the subacute afebrile phase than during the acute febrile phase (2.96%±1.95% vs. 5.64%±5.69%, P=0.036). Consequently, the ratio of CD25highFoxp3+ T cells to CD25+Foxp3- T cells was higher during the subacute afebrile phase than during the acute febrile phase (0.45%±0.57% vs. 0.13%±0.13%, P=0.038).ConclusionDecreased CD4+CD25highFoxp3+ T cells and/or an imbalanced ratio of CD4+CD25highFoxp3+ T cells to CD4+CD25+Foxp3- T cells might play a role in KD development. Considering that all KD patients were treated with intravenous immunoglobulin (IVIG), recovery of CD4+CD25highFoxp3+ T cells during the subacute afebrile phase could be a mechanism of IVIG.

CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract–Induced Murine Model of Kawasaki Disease

“…Several studies demonstrate abnormalities in the Treg cell compartment during KD in humans. Compared to healthy controls or febrile patients with an active non‐KD infection, febrile patients in the acute phase of KD exhibit decreased proportions of circulating CD4+CD25+FoxP3+ Treg cells . In vitro, IVIG treatment enhances the suppressive functions of CD4+CD25+ Treg cells and increases the intracellular expression of FoxP3, IL‐10, and transforming growth factor β (27).…”

Th17‐ and Treg‐related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease

“…Treg cells require TGF‐β for differentiation, specifically express the transcription factor FoxP3, and secrete inhibitory cytokines including IL‐10 and TGF‐β . Most studies to date have shown that IVIG therapy seems to increase FoxP3 expression , but may not affect TGF‐β levels . Although IL‐10 is considered an anti‐inflammatory cytokine, prior studies have shown that IL‐10 is actually elevated in the acute phase of Kawasaki disease and then significantly subsides after IVIG treatment .…”

Important role of CCR2 in a murine model of coronary vasculitis

“…Moreover, Treg/Th17 cell imbalance was correlated with a reduction of IL-10 and TGF-β together with an increase of IL-17 after CAWS administration as in KD [13,14]. Interestingly, genetic inactivation of CCR2, but not CCR5, is protective against CAWS induced-aortic and coronary vasculitis.…”

“…Finally, diverse experimental models implicate CCR2 in the establishment of tolerance or development of autoimmunity [12]. Moreover increasing evidence points towards the loss of regulatory mechanisms (depletion of regulatory T cells, Treg), along with amplification of T cell driven inflammation (expansion of T helper cells producing IL-17, Th17), in KD [13,14]. Our research highlights the critical role of CCR2 in the pathogenesis of coronary vasculitis seen in KD and identifies this chemokine receptor as an important determinant of the Treg/Th17 balance which may be critical for disease initiation and maintenance [13,15].…”