Identifying Specific Antigenic Targets of Kawasaki Disease - PROJECT SUMMARY/ABSTRACT
Kawasaki Disease (KD) is the leading cause of acquired heart disease in children in developed nations. KD
can result in coronary artery aneurysms that can lead to lifelong heart disease, myocardial infarction, and
death. The clinical and epidemiologic features support an infectious etiology in genetically susceptible children,
but the cause has eluded more than 50 years of study. Delayed and missed diagnoses increase the risk of
coronary artery aneurysms. The development of urgently needed diagnostic tests and improved therapies are
dependent upon identifying the etiology. In preliminary studies, we analyzed the peripheral blood plasmablast
response at 1-3 weeks after KD fever onset using single cell RT-PCR and made 60 monoclonal antibodies
(Mab) from these plasmablasts. We used these Mab to determine their target antigens. We found that 32/60
Mab, derived from 9/11 KD patients, identify intracytoplasmic virus-like inclusion bodies (ICI) in ciliated
bronchial epithelium of KD children but not infant controls. Using peptide arrays to identify binding epitope(s),
amino acid substitution arrays, and ELISA, we found that 5 of the 32 (16%) Mab, derived from 3 KD patients
with coronary artery aneurysms, recognize KD peptide epitope 1. KD peptide 1 completely blocks binding of
these Mab to KD ICI, indicating that a protein with the binding epitope sequence is present in the ICI.
Moreover, pre-treatment sera from 5/8 KD patients >day 8 after fever onset but 0/17 infant control sera have
IgG antibody to the peptide epitope. We recently identified two additional epitopes using this approach that
require further study. These findings support our hypothesis that at least a subset of KD cases results from
infection with a presently unidentified, ubiquitous viral causative agent containing the KD peptide epitope 1
sequence. In this proposal, we hypothesize that identification of antigens targeted by the plasmablast response
to KD can lead to identification of the etiology(ies) and development of KD serologic tests. To test these
hypotheses, we will: 1) identify the specific proteins recognized by our panel of KD Mab that bind to KD
tissues, 2) screen for additional antigenic targets recognized by the immune response to KD, and 3) evaluate
the antibody responses of KD and control sera to KD antigens. Our findings will inform pathogenesis of KD,
with the long-term goals of improving diagnosis and treatment of KD, enabling prevention, and reducing
healthcare costs from the long-term consequences of coronary artery aneurysms arising in young childhood.
