Hygiene Hypothesis as the Etiology of Kawasaki Disease: Dysregulation of Early B Cell Development

Abstract

Kawasaki disease (KD) is an acute systemic vasculitis that occurs predominantly in children under 5 years of age. Despite much study, the etiology of KD remains unknown. However, epidemiological and immunological data support the hygiene hypothesis as a possible etiology. It is thought that more sterile or clean modern living environments due to increased use of sanitizing agents, antibiotics, and formula feeding result in a lack of immunological challenges, leading to defective or dysregulated B cell development, accompanied by low IgG and high IgE levels. A lack of B cell immunity may increase sensitivity to unknown environmental triggers that are nonpathogenic in healthy individuals. Genetic studies of KD show that all of the KD susceptibility genes identified by genome-wide association studies are involved in B cell development and function, particularly in early B cell development (from the pro-B to pre-B cell stage). The fact that intravenous immunoglobulin is an effective therapy for KD supports this hypothesis. In this review, I discuss clinical, epidemiological, immunological, and genetic studies showing that the etiopathogenesis of KD in infants and toddlers can be explained by the hygiene hypothesis, and particularly by defects or dysregulation during early B cell development.

Keywords: B cells; Kawasaki disease; hygiene hypothesis; intravenous immunoglobulin.

Figure 1

The incidence of Kawasaki disease (KD) in Japan and South Korea has increased continuously since 1961. This graph is based on data collected during nationwide surveys in Japan [1,22,23,24,25,26,27,28,29,30,31,32,33,34,35] and South Korea [36,37,38,39,40,41,42,43]. Three nationwide epidemics were observed in Japan (1979, 1982, and 1986).

Figure 2

Immunoglobulin levels in children (A) and age-specific incidence rates of Kawasaki disease (KD) in Japan (B). The immunoglobulin levels in children depicted above were obtained from an immunology textbook [58]. The age-specific incidence rate of Kawasaki disease (KD) by sex was simplified from epidemiological data of Japan [33].

Figure 3

Increased risk of Kawasaki disease (KD) in children with common allergic diseases and vice versa. CI, confidence interval; HR, hazard ratio; OR, odds ratio.

Figure 4

Genetic studies support early B cell–mediated pathogenesis of KD. The effect of risk alleles of KD susceptibility genes on mRNA expression is shown by arrows (↑: upregulation and ↓: downregulation). BCR, B cell receptor; KD, Kawasaki disease.

Figure 5

Proposed mechanism underlying the hygiene-hypothesis-driven etiopathogenesis of KD. IVIG, intravenous immunoglobulin.