Although dysregulated activation of effector CD3+CD4+T helper cell are involved in the pathogenic process of KD [7, 12], this specific mechanism remain unknown. In this study, we found that the numbers of circulating Th17 cells in KD patients, but not Th1 cells, were significantly greater than those in the HC, which were consistent with previous studies [7]. However, our finding were different from another report that displayed an equivalent levels of circulating Th17 cells [18]. Conflicting results may be due to enrollment of patients. Morever, these inconsistencies are partly due to differences in methodology, or detection markers of the definition of Th17 cell. Indeed, the pathogenic mechanism of Th17 cells in the development of KD depends on the phase of their disease. Consistently, the concentrations of serum IL-17A, but not IFN-γ, in KD patients were significantly higher than that in the HC, consistent with a previous study [7]. More importantly, we found that the numbers of circulating Th17 cells were correlated positively with the concentrations of serum IL-17A in those patients. These suggest that Th17 cells are major producers of IL-17A in KD patients. Based on our data, serum IL-17A were correlated positively with ESR and CRP, indicating that Th17 cell contribute to innate immune responses. More importantly, our data showed also a high expression level of Th17 cells and serum IL-17A in KD patients with CAL compared to the KD patients with NCAL. Additionally, the concentrations of serum IL-17A in KD patients with CAL were correlated positively with the concentrations of NT-proBNP, which are a hallmark of CAL [19], suggesting Th17 cells contribute to the progression of CALs. This possible mechanism is that the proinflammatory cytokine IL-17A acts on a broad range of cells, including neutrophils and monocytes, to induce the expression of additional proinflammatory cytokines such as TNF-α [20]. Our novel findings may provide new insights into understanding the pathogenesis of CAL.
In addition to Th17 cells, Th22 cells expressing aryl hydrocarbon receptor (AHR) are associated with numerous autoimmune diseases, such as SLE, RA and ankylosing spondylitis (AS) [14–15, 21]. However, the possible mechanisms of Th22 cells in the development of KD remain unclear. In this study, we found that the numbers of circulating Th22 cells and the concentrations of serum IL-22 in KD patients were significantly greater than those in the HC. These results extend previous observations and support the notion that Th22 cells, like Th17 cells, also have major functions in the pathogenesis of KD. It is possible that the inflammatory environment in the development of KD preferably activates naive helper T cells towards Th1 and Th17 directions [22]. Morever, we found that the numbers of circulating Th22 cells were correlated positively with the concentrations of serum IL-22 in KD patients, suggesting that IL-22 is predominantly secreted by Th22 cells in those patients. More importantly, serum IL-22 were correlated positively with ESR and CRP, indicating that Th22 cells might serve as a biomarker for indicating disease severity or prognosis of KD, which, however, should be confirmed in future studies with a larger sample size. There are limitations in our study. Furthermore, we found a high expression level of Th22 cells and serum IL-22 in KD patients with CAL compared to the KD patients with NCAL and the concentrations of serum IL-22 were correlated positively with the concentrations of NT-proBNP in patients with CAL. These suggest that Th22 cells collaborate and contribute to the pathogenesis of CALs. Notably, our data revealed that the numbers of circulating Th22 cells in KD patients were correlated positively with the concentrations of serum TNF-α, which were an independent risk factor associated with a significantly longer median time to recovery of CALs [23]. Therefore, the current data provide a possibility that Th22 cells might induces the secretion of TNF-α, which further cause the occurrence of CAL. We are interested in further investigating the specific mechanism of Th22 cells in the process of CAL.
Treating affected patients with IVIG has been demonstrated to control symptoms and inhibit coronary aneurysm formation effectively in KD patients with CAL [24]. The precise mechanism of IVIG in the treatment of KD remains unclear. We found that the treatment with IVIG reduced significantly the numbers of circulating Th22 and Th17 cells and the concentrations of serum IL-22 and IL-17 in KD patients. It is possible that immunosuppressants mainly induce the proliferation of naive T cells to regulatory T cells, rather than effector T cells. Morever, the treatment with IVIG also reduced significantly the concentrations of serum TNF-α in KD patients. Consequently, these findings suggest that treatment with IVIG may be more effective in modulating the imbalance between effector and Tregs in KD patients.