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

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

To solve these puzzles, we propose a new hypothesis based on the premise of a "protein homeostasis system" in the host. Mammals, including humans, have evolved through genes which code for proteins. All living activities from embryonic development to the aging process are strictly controlled by a variety of proteins at the molecular level. The numbers and kinds of genes (kinds of proteins) that are activated differ according to the different organ tissue cells and timing of their activation. An organ specific cell produces its own specific proteins. Also, some proteins are produced only during the embryonic stage while some proteins are produce in later stages of the life cycle of mammals. For example, in genetic diseases such as neurofibromatosis or rare genetic prion diseases including fatal familial insomnia, the expression or progression of these diseases appears after 2-5 decades of age. 88 The pathogenesis of these genetic diseases may be associated with transformed proteins, including prions, which may be toxic to nerve cells, and the toxic proteins should be controlled for avoidance of the disease in vivo. On the other hand, mammals have also strawberry tongue, cervical lymphadenopathy, skin rashes and desquamation of skins after defervescence, mimicking those of KD. Although some patients with GAS infection complain of severe clinical phenotypes including streptococcal toxic shock syndrome and necrotizing fasciitis, scarlet fever is a self-limited disease, with a mean historical fever duration of 6 days without antibiotic treatment. 83 If enough doses of GAS are inoculated to every individual, nearly all individuals who do not have antibodies to toxins would be affected with scarlet fever. The immunopathogenesis of severe GAS infections such as streptococcal toxic shock syndrome and necrotizing fasciitis remains unknown. It is suggested that the streptococcal superantigens, including pyrogenic exotoxins, stimulate an intense proliferation and activation of the immune cells (T cells and macrophages), resulting in the production of large quantities of cytokines. The cytokine imbalance of a local environment may be responsible for tissue injuries and many of the clinical manifestations of severe, invasive GAS infections. 84, 85 As nonsuppurative complications, ARF and acute poststreptococcal glomerulonephritis (APSGN) are well-documented after GAS infections. 83 ARF is an acute febrile disease characterized with prolonged fever, carditis, arthritis, skin rash (erythema marginata) and chorea. 86,87 ARF occurs 2-4 wks after the primary GBS infections of the pharynx. The majority of GAS infected patients recover uneventfully, and only some patients who have genetic susceptibility may be affected with ARF, similar to KD. Although ARF is a disease of which the etiologic agent has been proven, the immunopathogenesis of the disease remains unsolved with speculation as to an immunemediated disease triggered by infectious insults. One hypothesis suggests that bacterial exotoxins or superantigens may be involved in the cardiac tissue injury through the direct toxic effect on target tissues or through activated cytokines. Others suggest that autoimmune reaction of immune cells that are sensitized to bacterial antigens may attack the target cells that may share epitopes with bacterial antigens ("molecular mimicry"). 86, 87 The clinical manifestations of ARF can appear without symptomatic GAS infections (pharyngitis) in a third of patients. 86