Kawasaki Disease: Laboratory Findings and an Immunopathogenesis on the Premise of a ""Protein Homeostasis System

Lee, Kyung-Yil; Rhim, Jung-Woo; Kang, Jin-Han

c antibodies initially, until the specific T cell clones and specific antibodies that can efficiently control pathogenic proteins are produced. The activated immune cells during this immune reaction (in the process of protein control) produce various inflammatory cytokines and counter-inflammatory cytokines, and a cytokine imbalance may be associated with the endothelial cell injury in KD. The substances from the injured cells recruit more immune cells with more cytokine production. Some cytokines such as TNF-α induce other proteins including matrix metalloproteinase (MMP) 9, which is toxic to neighboring cells, and aggravate tissue injuries (Fig. 3C) . Other substances released from the initial focus and/or the substances released from the injured lesions and cytokines spread via systemic circulation and induce the initial clinical manifestations of KD, including fever and other diagnostic clinical signs, and other rare manifestations of KD. The substances inducing extra-coronary manifestations including skin rashes and arthritis in KD are controlled by immune cells, and they may not contain the pathogenic proteins which induce a signal to tissue injury. After the emergence of specific T cell clones and specific antibodies for pathogenic proteins, inflammation ceases and a repair reaction begins with the immune cells and regenerating cells (Fig. 3D) . Briefly, the genetic determination of KD susceptibility may depend on a defect in the immune cells to detect and remove pathogenic proteins from initial infections. Also, severity of the disease may depend on the amount of pathogenic proteins with corresponding hyperactivity of immune cells and the time-period for emergence of specific immune cells against pathogenic proteins. The immunopathogenesis of ARF or other immune-mediated disease could be explained similarly by this hypothesis. Accordingly, pathogenic proteins, affected target cells, the subset of corresponding immune cells and the kinds of cytokines and other sub-rameters may help shorten the fever duration of the severely affected patients. A hypothetical pathogenesis of KD is proposed using the premise of a "protein homeostasis system" of the host. Hyperactive immune cells, especially T cells, with excessive cytokines may be responsible for tissue injury as well as for tissue reconstruction according to this hypothesis. Further developed tools including bioinformatics of candidate genes and proteomics may be needed for establishing more detailed explanations on the pathogenesis as well as developing diagnostic tests and improved treatments for the prevention of KD. α-chain deficiency mice cannot produce vasculitis. 15, 102 We previously described similar phenomena in M. pneumoniae and influenza virus infections. In these infections, T cell deficiency mice or T cells depressed mice had less severe pneumonia with prolonged survival time and little pathologic findings compared to control mice. 98, 99 Recently, Rowley and Shulman 16 proposed a model on the pathogenesis of KD. The agent of KD may be a ubiquitous infectious agent, most probably a single virus or a group of closely related viruses that lead to KD only in a small subset of genetically susceptible children. The initial infection site of the agent may exist in the respiratory tract including ciliated bronchial epithelium, and both innate and adaptive immune responses ensue including B lymphocytes switching to IgA lymphocytes. The KD agents in circulating macrophages rea