Kawasaki disease: pathophysiology and insights from mouse models

Abstract

Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.

Fig. 1. Environmental and genetic factors implicated in the development of Kawasaki disease.

Different aetiological agents, from viruses to environmental toxins, have been proposed as triggering agents for Kawasaki disease; however, none has been corroborated, and the aetiological agent remains unidentified. Increased numbers of IgA⁺ plasma cells have been detected in the pancreas, the kidneys, the coronary artery wall and the respiratory tract of patients with Kawasaki disease. Patients with Kawasaki disease have increased concentrations of secretory IgA in their serum, indicative of defective intestinal barrier function and increased intestinal permeability. Changes in the gut microbiota composition (dysbiosis) have also been suggested to have a role in the development of Kawasaki disease. Single nucleotide polymorphisms in the genes listed have been associated with susceptibility to Kawasaki disease and disease severity. The current understanding is that Kawasaki disease is triggered in genetically predisposed children by a ubiquitous environmental stimulus that typically would not result in an uncontrolled immune response and development of vasculitis.

Fig. 2. Pathophysiology of Kawasaki disease vasculitis.

The normal coronary artery is composed of three general layers: the tunica intima, tunica media and tunica adventitia. The intima is mainly composed of endothelial cells, the media of smooth muscle cells and the adventitia of loose connective tissue. In Kawasaki disease, necrotizing arteritis develops in the first 2 weeks of the disease and is associated with neutrophilic infiltration, which gradually destroys the intima, media and some portions of the adventitia of the coronary artery. CD8⁺ T cells, IgA⁺ plasma cells, monocytes and macrophages compose the inflammatory infiltrate during subacute chronic arteritis. These cells release pro-inflammatory cytokines such as IL-1β and TNF, which contribute to luminal myofibroblast proliferation, in which myofibroblasts, mainly derived from smooth muscle cells, and their matrix products progressively obstruct the coronary lumen.

Fig. 3. Existence of a ‘gut–vascular’ axis in Kawasaki disease vasculitis.

In healthy individuals, intestinal epithelial cells are sealed together by intestinal tight junctions, and the intestinal epithelium acts as a barrier that prevents the passage of commensal bacteria and pathogens while permitting intercellular flux of ions, molecules and metabolites. Lactobacillus casei cell wall extract (LCWE)-induced Kawasaki disease vasculitis and human Kawasaki disease are associated with increased IL-1β production, which leads to decreased expression of intestinal tight junctions, resulting in increased intestinal permeability. Differences in intestinal microbiota composition have been observed in patients with Kawasaki disease, and intestinal dysbiosis might contribute further to the inflammatory process. LCWE injection is also associated with a dysregulated intestinal immune response characterized by increased numbers of IgA⁺ B cells in the gastrointestinal tract and elevated secretory IgA (sIgA) concentrations. Intestinal barrier dysfunction results in sIgA leakage to the systemic circulation and pathogenic IgA–C3 immune complex deposition in the vascular tissues.

Fig. 4. Histological and morphological findings in the LCWE-induced mouse model of Kawasaki disease vasculitis.

Wild-type mice underwent intraperitoneal injection with Lactobacillus casei cell wall extract (LCWE), and heart tissues were harvested 2 weeks later. Haematoxylin and eosin (H&E) and trichrome staining were performed on heart sections. a | Inflammatory cell infiltration in the aortic route (H&E staining; ×40). b | Arteritis development in epicardial muscular coronary artery (H&E staining; ×20). c | Luminal myofibroblast proliferation (LMP) and non-specific neointimal proliferation injury to the arterial wall (trichrome staining; ×200). d | Complete occlusion of the coronary artery by LMP (trichrome staining; ×20). e | Organized thrombus in the coronary artery (H&E staining; ×200). f | Myocarditis (H&E staining; ×200). Ao; aorta, CA; coronary artery.