Discussion
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.
In summary, our data showed significantly increased numbers of Th22 and
Th17 cells, but not Th1 cells, as well as higher levels of
Th22/Th17-type cytokines in KD patients. More importantly, serum IL-17A
and IL-22 levels were positively correlated with the ESR, CRP and
NT-proBNP. Meanwhile, treatment with IVIG not only effectively improved
clinical symptoms, but also reduced the numbers of Th22 and Th17 cells
and their cytokines in KD patients. The presented data might provide new
insights into understanding the pathogenesis of KD and aid in developing
an effective therapy for use in the patients who have already developed
coronary artery lesions. However, we recognized that our study had
limitations, such as a relative small sample size and the absence of
functional study of Th22 and Th17 cells in the pathogenic process of KD.
Therefore, further longitudinal studies of the real function of Th22 and
Th17 cells in the pathogenic process of KD with a bigger population are
warranted.