Kawasaki syndrome (KS) is currently the most common cause of acquired heart disease in the United States and Japan. Left untreated, approximately 30% of children develop coronary artery (CA) abnormalities. Early treatment of KS with intravenous gammaglobulin (IVGG) significantly reduces the occurrence of cardiovascular complications due to KS. Thus, the development of an objective laboratory test for diagnosis of KS is critical. The current proposal will test the hypothesis that KS is caused by a superantigen e.g. a bacterial toxin that induces the selective stimulation of T cells bearing specific T cell receptor (TCR) Vbeta gene segments. Furthermore, we postulate that this expansion of T cells will be unique and not found in other diseases associated with systemic inflammation.
The specific aims will be: First, to determine whether KS is associated with the selective expansion of T cells, we will assess the TCR Vbeta gene usage of T cells from peripheral blood and tissue infiltrates of KS patients vs patients with other diseases that may mimic KS. As part of these studies, we will examine whether TCR Vbeta gene usage correlates with disease response in KS patients. Thus, we will compare the TCR Vbeta gene usage with different clinical outcomes e.g. development of CA abnormalities, response to IVGG therapy, ethnic background, etc. Second, to determine whether the selective stimulation of T cells in KS is clonotypic or diverse, we will clone and sequence the KS TCR transcripts amplified by PCR. Third, to determine the capacity of antibodies in KC sera to inhibit the T cell mitogenic effects of various staphylococcal and streptococcal exotoxins. We expect to find that convalescent but not acute sera from KS patients will contain IgG to streptococcal erythrogenic toxin B. Furthermore, the lack of IgG to erythrogenic toxin B during acute KS may predispose to the selective expansion of T cells expressing Vbeta2 and Vbeta8 gene segments. The pathogenesis and etiology of KS is poorly understood. It is hoped that these studies will contribute to an understanding of the pathogenesis of KS. The elucidation of immune mechanisms underlying this disease should have important consequences for the development of more effective therapeutic approaches to the treatment of KS and other diseases where similar pathologic mechanisms may exist. In particular, identification of an unique population of T cells associated with KS may allow us to more readily diagnose and institute early therapy of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL037260-06
Application #
3352794
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-12-01
Project End
1994-11-30
Budget Start
1991-12-23
Budget End
1992-11-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Zhang, Yong; Leung, Donald Y M; Goleva, Elena (2014) Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma. J Allergy Clin Immunol 133:1744-52.e1
Goleva, Elena; Jackson, Leisa P; Harris, J Kirk et al. (2013) The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med 188:1193-201
Zhang, Yong; Leung, Donald Y M; Goleva, Elena (2013) Vitamin D enhances glucocorticoid action in human monocytes: involvement of granulocyte-macrophage colony-stimulating factor and mediator complex subunit 14. J Biol Chem 288:14544-53
Goleva, Elena; Searing, Daniel A; Jackson, Leisa P et al. (2012) Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma. J Allergy Clin Immunol 129:1243-51
Goleva, Elena; Jackson, Leisa P; Gleason, Melanie et al. (2012) Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients. J Allergy Clin Immunol 129:687-693.e1
Zhang, Yong; Leung, Donald Y M; Richers, Brittany N et al. (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 188:2127-35
Li, Ling-Bo; Leung, Donald Y M; Martin, Richard J et al. (2010) Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid-resistant asthma. Am J Respir Crit Care Med 182:877-83
Searing, Daniel A; Zhang, Yong; Murphy, James R et al. (2010) Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 125:995-1000
Goleva, Elena; Li, Ling-Bo; Leung, Donald Y M (2009) IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance. Am J Respir Cell Mol Biol 40:223-30
Goleva, Elena; Hauk, Pia J; Hall, Clifton F et al. (2008) Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol 122:550-9.e3

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