Kawasaki syndrome (KS) is currently the most common cause of acquired heart disease in children. Early treatment of KS with intravenous gammaglobulin significantly reduces, but does not eradicate, the occurrence of cardiovascular complications. Thus, discovery of the etiology and pathogenesis of KS is of critical importance. The current proposal will expand upon preliminary data from our lab that suggests the marked immune activation associated with acute KS is caused by a superantigen(s), e.g., a variant staphylococcal toxic shock syndrome toxin (TSST-KS) or streptococcal pyrogenic exotoxin C (SPEC) that activates macrophages and induces the selective stimulation of T cells bearing Vbeta2 gene segments.
The specific aims will be: First, to assess the role of antibody repertoire as a risk factor for KS. We will assay anti-toxin antibody levels in sera from acute vs convalescent KS patients, their family members and age-matched controls by using both functional assays of toxin neutralization and ELISA. We postulate that the selective deficiency of antibodies against TSST-KS and/or SPEC predispose to acute KS> Second, to correlate the isolation of toxin-producing bacteria with various established parameters of immune activation in acute KS. The demonstration that isolation of toxin secreting S. aureus is accompanied by the activation of macrophages and Vbeta2+ T cells will strengthen the argument that superantigens play a role in the pathogenesis of KS. Third, to determine whether the selective stimulation of T cells in patients with KS, complicated by the development of coronary artery disease, is oligoclonal or diverse, we will clone and sequence their T Cell Receptor Vbeta2 and control Vbeta gene transcripts amplified PCR. Fourth, to determine whether TSST-KS has different immunologic properties than staphylococcal TSST1 when tested on T cells, B cells, and/or vascular endothelial cells. We postulate that as the result of several critical mutations between variant TSST-KS vs staphylococcal TSST1, the cause of Toxic Shock Syndrome (TSS), that TSST-KS may exhibit different immunologic properties which account for at least some of the differences in the immunologic features distinguishing acute KS vs TSS. The importance of our proposed studies is that it should contribute directly to an understanding of the pathogenesis and etiology of KS. The elucidation of immune mechanisms underlying this disease will have important implications for the development of more effective therapeutic approaches to the treatment of KS as well as other diseases where similar pathologic mechanisms may exist. Furthermore, identification of the causative agent and unique populations of T cells associated with KS may allow us to more readily diagnose this disease and institute early therapy to prevent heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL037260-12
Application #
2609247
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-12-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
12
Fiscal Year
1998
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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