The Role of T Lymphocytes in the Pathogenesis of Kawasaki Disease in an Animal Model

Abstract

Kawasaki disease (KD) is the most common cause of multisystem vasculitis in children in the developed world. Although KD is widely believed to be the result of an infectious agent, its etiology is still unknown. Past research has reported the possible role for bacterial superantigens in the induction of KD. Our laboratory has characterized a novel superantigen found in Lactobacillus casei cell wall extract (LCWE) which is responsible for triggering the immune response leading to KD-like coronary vasculitis in injected mice. In this study, we investigated the T helper subsets responsible for disease induction by studying expression of signature cytokines. LCWE was injected into susceptible mouse strains and RT-PCR, flow cytometry, and immunohistochemistry were performed on peripheral lymphoid tissue at set time-points. Expression and production of T helper subset associated cytokines were determined. Cardiac tissue was also similarly analyzed to determine the relationship between the immune response in the periphery to that in the heart end organ. Semi-quantitation of cytokine mRNA expression demonstrated a Th1 predominated phenotype in the periphery at days 1 to 3 post LCWE injection (IFNγ). This was followed by Th2 cytokine upregulation after day 3 (IL-4). Flow cytometry confirmed this finding by the detection of intracytoplasmic IFNγ and IL-4 at similar relative timepoints. In the heart end organ, IFNγ expression was found to be abnormally upregulated 42 days after LCWE injection. Infiltrates identified as T lymphocytes were seen as early as 3 days post LCWE injection and observed in all latter time points (up to 6 months). Different T lymphocyte subsets, at different times, are able to mediate the immunologic responses leading to inflammation. Dissecting this immune response to LCWE in mice gives important clues to the etiology of Kawasaki disease in humans.