Single-cell analysis of peripheral blood mononuclear cells to reveal of cellular etiology of Kawasaki disease based on hygiene hypothesis

Abstract

AbstractKawasaki disease (KD) is an acute systemic vasculitis that can lead to acquired heart disease in children mostly from developed countries. Its cause is still obscure and one explanation for its emergence is called “hygiene hypothesis” stating that the immune system of a newborn must be trained by common pathogens in order to reach its full development. In this study, we analyzed peripheral blood mononuclear cells from three febrile patients and KD patients to investigate the evidence for “hygiene hypothesis” of KD. Overall single-cell expression profiles show that the biological processes of immunity, B cell activation pathway and their related entities are upregulated in febrile patients and KD patients after IVIG treatment. The differentially expressed gene analyses further demonstrate that the cell cycle genes and MYC target genes are over expressed in KD patients before treatment. Paradoxically, hematopoietic stem and progenitor cells (HSPCs) in KD patients before IVIG treatment exhibit a high expression pattern of the genes involved in immunity, immune response and B cell signaling pathway, i.e., a premature immune activation propensity. The cell differentiation trajectory is also shortened in KD patients before treatment compared with those in febrile patients and KD patients after treatment. Two cell cycle genes (HSPD1 and HSPE1) and MYC gene are early expressed in KD patients before treatment according pseudo-time analyses of cell development. The pseudo-time analyses of B cell development in three datasets indicate that a large proportion of B cells in KD patients before treatment are actually arrested in transitional state. Here, we argue that the HSPCs with a premature immune activation propensity is probably the cellular etiology behind Kawasaki disease, which lead to the symptoms of B cell dysplasia and malfunctional immune responses. Lacking of common pathogens in surroundings may be the cause of immune hyperactive HSPCs which treat everything as pathogen. Thus, our findings in this study are an affirmative support of “hygiene hypothesis”.