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

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

Immune cells stances including antibodies may be different from KD. We previously used this hypothesis to explain the immunopathogenesis of acute lung injury in Mycoplasma pneumoniae (M. pneumoniae) and influenza virus infections. 98, 99 For the 2009 H1N1 influenza virus infection, the severity of pneumonia was correlated with lymphocyte counts at presentation, and early immune-modulators (corticosteroids or IVIG) induced dramatic recovery of severe pneumonic consolidations within a day. 99, 100 Therefore, it is also acceptable as a new concept that small pathogenic proteins are produced during immune reactions in acute systemic infections (influenza virus or M. pneumoniae), not by viruses or mycoplasmas themselves, and can induce cytopathic effects on lung tissues by hyperactivated immune cells, especially T cells. 99 In these infections, like strong natural toxins, extremely small amounts of pathogenic proteins that have affinity to lung tissues can induce severe lung injury leading to death by amplification of a maladjusted immune reaction. Along with studies for etiologic agents of KD, some investigators have proposed the immunopathogenesis of KD. Recently the study group of Yeung 15 presented an interesting model for the pathogenesis of KD using a mouse model of KD. They created experimental mice which were able to develop coronary arteritis in response to intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE). This murine model of KD is similar to human KD including the aspect of massive activation of immune cells, disease susceptibility in the young and a similar pathology of coronary arteritis, although replication of the disease is not perfect. They observed that immune cells began to appear in cardiac tissue at day 3 after LCWE injection, and then more immune cells, mainly T cells, infiltrated around the arteries and peaked at day 28. Also, disruption of the intima and media as well as aneurysm formation were observed at day 42. 15, 101 They postulated that T cells have a crucial role in the pathogenesis of KD. A superantigen in LCWE activates massive T-cell clones, and T-cells survive from apoptosis by a co-stimulatory signal on coronary endothelial cells as transformed antigen presentation cells. TLR2 on endothelial cells and a corresponding ligand in LCWE may in part intensify co-stimulation expression on the cells. Activated T cells continued to produce cytokines including TNF-α and IFN-γ, causing a cytokine imbalance in local lesions, that may be responsible for vessel wall injuries. It may be true that T cells have crucial roles in animal KD and in human KD, since adaptive immune deficiency mice (recombination activating gene1 knockout mice) and TCR proteins in KD have affinity mainly to endothelial cells of coronary arteries, and bind to the receptors on endothelial cells. This process is directly toxic to the endothelial cells and/or produces new proteins including inflammatory mediators through signal transduction pathways to the nucleus. These mediators from the affected cells are a signal for the recruitment of immune cells (Fig. 3B) . To control the pathogenic proteins and/or the new proteins from the injured cells, immune cells, especially T cells for small proteins, are recruited and activated. Because there is a time-gap for the appearance of specific immune cell clones (specific T cells and B cells) in an immune reaction, this reaction may be conducted by non-specific T cells and non-specifi