Kawasaki disease: a matter of innate immunity

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis of childhood that does not have a known cause or aetiology. The epidemiological features (existence of epidemics, community outbreaks and seasonality), unique age distribution and clinical symptoms and signs of KD suggest that the disease is caused by one or more infectious environmental triggers. However, KD is not transmitted person-to-person and does not occur in clusters within households, schools or nurseries. KD is a self-limited illness that is not associated with the production of autoantibodies or the deposition of immune complexes, and it rarely recurs. Regarding the underlying pathophysiology of KD, innate immune activity (the inflammasome) is believed to play a role in the development of KD vasculitis, based on the results of studies with animal models and the clinical and laboratory findings of KD patients. Animal studies have demonstrated that innate immune pathogen-associated molecular patterns (PAMPs) can cause vasculitis independently of acquired immunity and have provided valuable insights regarding the underlying mechanisms of this phenomenon. To validate this concept, we recently searched for KD-specific PAMPs and identified such molecules with high specificity and sensitivity. These molecules have structures similar to those of microbe-associated molecular patterns (MAMPs), as shown by liquid chromatography-tandem mass spectrometry. We propose herein that KD is an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe-derived innate immune stimulants and that it is not a typical infectious disease.

Keywords: Kawasaki disease; innate immunity; liquid chromatography-mass spectrometry; pathogen-associated molecular patterns.

Figure 1

Nucleotide‐binding oligomerization domain‐containing protein (NOD1) ligand (FK565)‐induced coronary arteritis. (a) Administration of FK565 (100 μg/day p.o. for 2 weeks) induces coronary arteritis. This Kawasaki disease (KD) model is characterized by panarteritis with dense inflammatory cell infiltration involving neutrophils and macrophages, but is not associated with fibrinoid necrosis. This histopathology recapitulates the coronary artery lesions of KD. (b) Control solvent: no arteritis. (c) FK565‐induced coronary arteritis in a severe combined immunodeficient (SCID) mouse. This panel shows that FK565 also induces a milder form of coronary arteritis in SCID mice than that induced in wild‐type mice. Most of the infiltrating inflammatory cells are neutrophils and macrophages, as is the case in wild‐type mice. These data show that the coronary artery lesions of KD are mediated by the innate immune system (PAMPs) and develop independently of acquired immunity. (d) Absence of vasculitis in a NOD1‐knock‐out mouse from Nishio et al. 58.

Figure 2

Schematic representation of the molecular and cellular mechanisms underlying nucleotide‐binding oligomerization domain‐containing protein (NOD1)‐induced arteritis. A NOD1 ligand, FK565, activates endothelial cells which produce large amounts of chemokines, including CCL2. In response to CCL2 and other chemokines, CCR2 (chemokine receptor)‐expressing precursor cells (monocytes) in the peripheral blood are recruited to FK565‐activated endothelial cells. This process subsequently induces the differentiation of cardiac CD11c⁺ macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis. MMP = matrix metalloproteinase.

Figure 3

Human coronary artery endothelial cells (HCAECs)‐stimulatory activities of biofilm extracts from Yersinia pseudotuberculosis. HCAECs‐stimulatory activities of Y. pseudotuberculosis extracts were measured by interleukin (IL)‐6 production from HCAECs. Y. pseudotuberculosis extracts were prepared from culture supernatants (□) or biofilms (▪) of Y. pseudotuberculosis cultured in the presence (+) or absence (–) of butter. Medium alone, ethyl acetate alone or ethyl acetate extract from glass slides cultured in the absence of microbes was used as a negative control. FK565 (10 µg/ml) was used as a positive control. Data are expressed as the fold change in induction of IL‐6 production compared to positive control levels. Modified from the data of Kusuda et al. 71.

Figure 4

Innate immune‐mediated vasculitis as a pathogenic model for Kawasaki disease (KD). Microbes produce massive amounts of pathogen‐associated molecular patterns /microbe‐associated molecular patterns (PAMPs/MAMPs) under certain biofilm‐like conditions. PAMPs/MAMPs induce damage‐associated molecular pattern (DAMP) [S100 proteins and high mobility group box 1 (HMGB1)] production by and release from host cells. These molecules activate endothelial and immune cells co‐operatively through innate immune pattern recognition receptors (PRRs). Recruitment of immune cells to activated endothelial cells and destruction of vascular structures result in the development of KD vasculitis and aneurysms. These molecular scenarios may be even more prominent in genetically predisposed individuals.