The up-to-date pathophysiology of Kawasaki disease

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis of an unknown aetiology. A small proportion of children exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or infected by Yersinia reproducibly develop principal symptoms of KD in various ethnic areas, but not in all studies. These microbes provoke a rapid cell-damaging process, called 'pyroptosis', which is characterised by a subsequent release of proinflammatory cellular components from damaged endothelial and innate immune cells. In agreement with these molecular events, patients with KD show elevated levels of damage-associated molecular patterns derived from cell death. In addition, an overwhelming amount of oxidative stress-associated molecules, including oxidised phospholipids or low-density lipoproteins, are generated as by-products of inflammation during the acute phase of the disease. These molecules induce abnormalities in the acquired immune system and activate innate immune and vascular cells to produce a range of proinflammatory molecules such as cytokines, chemokines, proteases and reactive oxygen species. These responses further recruit immune cells to the arterial wall, wherein inflammation and oxidative stress closely interact and mutually amplify each other. The inflammasome, a key component of the innate immune system, plays an essential role in the development of vasculitis in KD. Thus, innate immune memory, or 'trained immunity', may promote vasculitis in KD. Hence, this review will be helpful in understanding the pathophysiologic pathways leading to the development of principal KD symptoms and coronary artery lesions in patients with KD, as well as in subsets of patients with SARS-CoV-2 and Yersinia infections.

Keywords: COVID‐19; Kawasaki disease; damage‐associated molecular patterns; oxidative stress; pyroptosis; vasculitis.

Figure 1

Hypothetical model for the pathophysiology of Kawasaki disease. Innate immune pathogen‐associated molecular patterns (PAMPs) from microbes activate proinflammatory signals in innate immune and vascular cells through pattern recognition receptors (PRR), thereby producing large amounts of chemokines and cytokines. Massively produced damage‐associated molecular patterns (DAMPs) from cell death and oxidative stress in the circulating blood exert pleiotropic effects on platelets, monocytes, neutrophils, endothelial cells and vascular smooth muscle cells through receptor [lectin‐like oxidised LDL receptor‐1 (LOX‐1)]‐mediated and receptor‐independent mechanisms. Soluble pattern recognition molecules (PRMs) are also involved in the pathophysiology of Kawasaki disease. In response to these stimulations, monocytes and neutrophils in the peripheral blood are recruited to stimulated vascular cells. Subsequently, monocytes differentiate into macrophages. These macrophages and neutrophils play a pivotal role in the development of acute coronary arteritis. Inflammation and oxidative stress mutually amplify each other, leading to the induction of acute KD. HMGB1, high‐mobility group box 1; LDL, low‐density lipoprotein.