Kawasaki Disease (KD) is the leading cause of acquired heart disease in children in developed nations. At Ann & Robert H. Lurie Children’s Hospital of Chicago, we diagnose 60-70 new cases annually. KD is an acute febrile illness with clinical features commonly observed in infectious diseases, can result in coronary artery aneurysms that can be particularly severe in infants &lt;6 months of age, has highest incidence in young children &lt;5 years of age, is extremely rare in adults, occurs in epidemics with geographic wavelike spread of illness, and only rarely recurs. These features support an infectious cause rather than an autoimmune process, and the etiology that best explains the specific epidemiologic features of KD is a ubiquitous infectious agent that is usually asymptomatic but can result in KD in genetically susceptible children. However, no known infectious agent is associated with KD. My laboratory reported an antigen-driven IgA arterial immune response in acute KD. Synthetic antibodies made from oligoclonal immunoglobulin heavy chains from KD arterial tissue in combination with random kappa light chains detect antigen by immunohistochemistry in acute KD but not infant control lung and in a subset of macrophages in inflamed KD tissues, but cognate light and heavy chains for the antibodies could not be determined, limiting their usefulness in specific antigen identification. My laboratory also found that type I interferon-induced genes were upregulated in lungs of KD patients, and that activated cytotoxic T lymphocyte and type I interferon-induced genes were upregulated in KD arterial tissues, consistent with an antiviral immune response. Based on these data, we hypothesize that KD is an immune-mediated illness occurring in genetically predisposed children infected with a presently unidentified virus. Using new methods to rapidly clone and produce high-affinity antigen-specific synthetic antibodies incorporating cognate light and heavy immunoglobulin chains, we plan to prepare a panel of KD-specific monoclonal antibodies and use them to identify KD-specific antigens. In preliminary studies, we have identified an oligoclonal, antigen-driven plasmablast response in peripheral blood of an acute KD patient who developed a coronary artery aneurysm, prepared a synthetic antibody from the most prevalent oligoclonal KD plasmablasts from this patient, and demonstrated binding of this antibody to KD tissues by immunohistochemistry and Western blot assays. We have gathered a multidisciplinary team including experts in KD, virology, immunology, and biostatistics to perform the following specific aims: 1) Identify and clone the peripheral blood plasmablast response in KD, and 2) Identify antigenic targets of oligoclonal KD peripheral blood plasmablasts. Identification of the etiology of KD would have a major impact on the field of pediatrics, by allowing for improved diagnosis, development of specific and more effective therapies, and by ultimately enabling prevention, which would reduce pediatric health care costs, morbidity, and mortality from the long-term consequences of coronary artery aneurysms that are acquired during young childhood.
|Effective start/end date||5/4/18 → 6/1/19|
- National Institute of Allergy and Infectious Diseases (5R21AI140029-02 REVISED)