The first case of KD in Taiwan was described in 1979. Although Japan has the highest incidence and the United Kingdom has the lowest, the incidence of KD has been steadily increasing all over the world . However, a definitive disease pathogenesis remains uncertain. A practical biomarker may help us stratify therapy for KD according to the likelihood of developing CAL. To the best of our knowledge, our study is the first to survey the correlation of tight junction ZO-1 protein in KD patients. Notably, the ZO-1 level may be related to the development of CAL in KD.
The TJ is a complex located in epithelial cells that regulates the paracellular movement of ions, macromolecules, and immune cells . The cytosolic proteins ZO-1 and ZO-2 are multi-domain polypeptides required for the formation of the TJ  and are essential during TJ assembly. The depletion of either ZO-1 or ZO-2 from epithelial cells results in the delayed formation of TJs and a mild increase in permeability, whereas depletion of both ZO-1 and ZO-2 disrupts the localization of the transmembrane proteins at the tight junction and causes a dramatic alteration of TJ barrier function [17-19]. TJ dysfunction can lead to the disruption of intestinal barrier integrity. Changes in pH, osmotic load, or cytoskeleton function can all affect the barrier function of TJs . About 30% of KD patients presented with gastrointestinal manifestations, such as vomiting, diarrhea, abdominal distension or pain, jaundice, paralytic ileus, hepatomegaly, gallbladder hydrops, and related echographic findings [5, 21, 22]. In their case series, Zulian et al. reported an incidence of 4.6% of atypical KD with a clinical onset characterized by acute surgical abdomen . One study reviewed 33 articles reporting 48 cases of KD with intestinal involvement . Small bowel obstructions may occur as a result of ischemia with stricture with adhesion formation . The most frequent symptoms observed were fever, abdominal pain, and vomiting, and, in all cases, typical KD signs and symptoms appeared following the intestinal complaints.
Growing evidence has suggested that the development of KD may resemble that of an immune/autoimmune process . Marked T-cell and monocyte/macrophage activation is found during the acute phase . Furthermore, KD affects mucosal intestinal immune responses, and KD patients have an increased number of activated T cells and macrophages present in the small intestine [6, 8]. A recent multicenter study that enrolled over 300 patients revealed that KD patients with gastrointestinal symptoms at onset had a complicated KD diagnosis, therapeutic delay, or risk for IVIG-unresponsiveness and coronary aneurysms . New evidence has shown that endothelial dysfunction caused by the vigorous development of immune responses is vital to CAL development in KD patients [28-30].
In one animal study of mice, Lactobacillus-cell wall extract (LCWE)-injected mice developed KD vasculitis and exhibited a significant increase in intestinal leakage. This intestinal barrier dysfunction was associated with increased serum levels of Zonulin. Blocking intestinal permeability by using an anti-Zonulin peptide (AT-1001) protected mice in the study from LCWE-induced KD coronary arteritis .
Some studies have reported that tight junction ZO-1 protein was related to some diseases and could be used as an inflammatory marker. Ram et al. reported that the systemic concentration of ZO-1 was significantly elevated in hepatocellular carcinoma patients and was positively correlated with inflammatory markers . Meanwhile, Boer at el. reported that the lower epithelial α-catenin, E-cadherin, and (or) ZO-1 expression in patients with atopic asthma contributed to a defective airway epithelial barrier and a higher influx of eosinophils in the epithelium . Significantly lower expressions of ZO-1 and α-catenin were detected in irritable bowel syndrome-like symptoms in quiescent inflammatory bowel disease . However, we found no difference in ZO-1 expression in KD compared to the controls. Our results also showed no difference between groups of IVIG responsiveness and resistance in KD patients. Nevertheless, lower ZO-1 levels were noted in CAL patients in the IVIG responsive group of KD. We may interpret this result as CAL being potentially associated with intestinal barrier dysfunction.