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Involvement of Innate and Adaptive Immunity in a Murine Model of Coronary Arteritis Mimicking Kawasaki Disease¹

Danica J. Schulte,^2* Atilla Yilmaz,² Kenichi Shimada,^* Michael C. Fishbein, Emily L. Lowe,^* Shuang Chen,^* Michelle Wong,^* Terence M. Doherty,^* Thomas Lehman, Timothy R. Crother,^* Rosalinda Sorrentino,^2* and Moshe Arditi^23*

^*Pediatric Infectious Diseases, Cedars-Sinai Medical Center, University of California, Los Angeles, CA 90048; Clinic of Internal Medicine I, Department of Cardiology, University Hospital Jena, Germany; Pathology, University California, Los Angeles, CA 90095; and Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY 10021

Kawasaki disease (KD) is the most common cause of acquired cardiac disease and acute vasculitis in children in the developed world. Injection of a cell wall extract isolated from Lactobacillus casei (LCCWE) into mice causes a focal coronary arteritis that histopathologically mimics the coronary lesions observed in KD patients. In this study we used this model to investigate the participation of T cells, B cells, and dendritic cells (DC) in the development of coronary arteritis. RAG1^–/–, B cell^null, and wild-type (WT) mice were injected with a single dose of LCCWE (500 µg/mouse i.p.). None of the RAG1^–/– mice developed coronary arteritis, whereas 70% of WT and 100% of B cell^null mice developed coronary lesions, indicating that T cells were required for lesion formation. When splenocytes isolated from LCCWE-treated mice were restimulated with LCCWE, we observed significant IFN- secretion in WT but not in RAG1^–/– mice. Immunohistochemical staining showed F4/80⁺ macrophages, activated MIDC-8⁺ myeloid DCs (mDC), plasmacytoid DCs, and colocalization of CD3⁺ T cells with mDCs in coronary artery lesions, suggesting an Ag-driven process. T cells but not B cells are required for LCCWE-induced coronary arteritis. Similar to human lesions, the coronary lesions contain macrophages, activated mDCs, and plaslmacytoid DCs all in close proximity to T cells, further strengthening the relevance of this mouse model to the immunopathology of coronary disease in KD. These studies are consistent with the interpretation that macrophages and DCs may collaborate with T cells in the pathological mechanisms of coronary arteritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01AI072726-01A (to M.A.) and 1 K08 A1070162-01 (to D.J.S.).

² D.J.S., A.Y., R.S., and M.A. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Moshe Arditi, Cedars-Sinai Medical Center, Division of Pediatric Infectious Diseases and Immunology, 8700 Beverly Boulevard, Room 4220, Los Angeles, CA 90048. E-mail address: moshe.arditi{at}cshs.org

⁴ Abbreviations used in this paper: KD, Kawasaki disease; IVIG, i.v. Ig; LCCWE, cell wall extract isolated from Lactobacillus casei; mDC, myeloid dendritic cell; pDC, plasmacytoid DC; WT, wild type; IHC, Immunohistochemical(ly); OCT, optimal cutting temperature; EC, endothelial cell.