It is well known that abnormal activation of effector CD3+CD4+T helper cells play an important role in the pathogenesis of KD [7, 12], this specific mechanism remain unknown. In this study, we found that KD patients had greater numbers of circulating Th17 cells, which were consistent with previous studies . However, our finding were different from another report that displayed an equivalent levels of circulating Th17 cells . Conflicting results may be due to enrollment of patients. Morever, part of the factors for these inconsistencies are the identification methods and surface markers of Th17 cell. Indeed, the pathogenic mechanism of Th17 cells in the development of KD rely on the phase of their disease. Morever, the concentrations of serum IL-17A were significantly higher in KD patients, consistent with a previous study . More importantly, we found that circulating Th17 cells were positively correlated with serum IL-17A in those children. These suggest that Th17 cells are major producers of IL-17A in KD patients. Based on our data, serum IL-17A were positively correlated with ESR and CRP, indicating that Th17 cell contribute to innate immune responses. More importantly, our data showed that a higher expression levels of Th17 cells and serum IL-17A in KD patients with CAL were positively correlated with the concentrations of NT-proBNP, which is a hallmark pathological of CAL , speculating Th17 cells are involved in the formation of coronary aneurysms. This possible mechanism is that the proinflammatory cytokine IL-17A promotes neutrophils and monocytes to secrete the proinflammatory cytokines such as IL-6 and TNF-α . These findings might provide a new perspective on the mechanism of CAL formation.
Like Th17 cells, Th22 cells are also associated with numerous autoimmune diseases, such as SLE, RA and ankylosing spondylitis (AS) [14–15, 21]. However, the underlying specific mechanism of Th22 cells in the pathogenesis of KD is still unclear. In this study, we detect that the numbers of circulating Th22 cells and the serum levels of IL-22 were significantly greater in KD patients compared to those in the HC. These results extend previous observations and support the notion that Th22 cells, like Th17 cells, also play an important role in the pathogenesis of KD. It is possible that the inflammatory environment in the development of KD preferably promotes the differentiation of naive CD4+ T helper cells into Th22 and Th17 cells . Morever, we found that circulating Th22 cells were positively correlated with serum IL-22, suggesting that IL-22 is predominantly released by Th22 cells in KD children. More importantly, serum IL-22 were positively linearly correlated with ESR and CRP at the same time, indicating that Th22 cells might serve as a potential marker for indicating disease activity or prognosis of KD. Furthermore, we found that a higher expression level of Th22 cells and serum IL-22 were positively correlated with the concentrations of NT-proBNP in CAL+KD patients, suggesting that Th22 cells collaborate and contribute to the formation of coronary aneurysms. Notably, our study showed that circulating Th22 cells in KD patients were positively correlated with serum TNF-α, which were an independent risk factor associated with a significantly longer median time to recovery of CALs . 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 . The possible mechanism of action of IVIG in the treatment of KD is still unclear. We found that the treatment with IVIG reduced significantly the numbers of circulating Th22 and Th17 cells as well as the serum levels of 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 serum levels of TNF-α in KD patients. Consequently, our data reveal that treatment with IVIG treatment can effectively regulate the imbalance between effector T and regulatory T cells in KD patients.
In summary, our data showed significantly increased numbers of Th22 and Th17 cells, but not Th1 cells, in KD patients. More importantly, higher levels of serum Th22-type cytokines (IL-22) and Th17-type cytokines (IL-17) were positively correlated with the ESR, CRP and NT-proBNP. Meanwhile, treatment with IVIG not only relieved clinical symptoms quickly and effectively, but also reduced the numbers of Th22 and Th17 cells and their cytokines in KD patients. The presented data might aid in developing a new and effective treatment method for use in the children who have already developed coronary artery lesions. However, we recognized the limitations of our study, such as a relative small sample size and the lack of mechanism research of Th22 and Th17 cells in the pathogenesis of KD. Hence, further longitudinal studies of the specific mechanism of Th22 and Th17 cells in the pathogenesis of KD with a bigger population are urgently needed.