Abstract
KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2–3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.
Highlights
Lactobacillus casei is a probiotic commensal bacterium that is naturally found in the gut and has an important role in maintaining mucosal homeostasis by activating T cells that “sense” other pathogens and serve as a by-stander source of lymphokines and co-stimulatory signals [1]
We addressed the T cell response to Lactobacillus casei cell wall extract (LCWE) in Kawasaki disease (KD) subjects compared to healthy children and healthy adult donors
LCWE induces a vasculitis in mice following intraperitoneal injection, which is defined by the activation and infiltration of innate cells and CD8+ cytotoxic T cells into vascular tissues and the development of acute inflammation of the coronary arteries and the aorta
Summary
Lactobacillus casei is a probiotic commensal bacterium that is naturally found in the gut and has an important role in maintaining mucosal homeostasis by activating T cells that “sense” other pathogens and serve as a by-stander source of lymphokines and co-stimulatory signals [1]. In many therapeutic settings including neoplasms, L. casei serves as an adjuvant to facilitate the activation of tumor-specific T cells [2, 3]. An intraperitoneal injection of its cell wall extract, L. casei cell wall extract (LCWE), induces vasculitis in mice and is a wellrecognized murine model to study KD, an acute pediatric vasculitis of the coronary arteries that affects infants and young children [4,5,6]. The cascade of events in the LCWE-induced KD murine model include abnormalities of mucosal permeability and intestinal leakage and the subsequent release of proinflammatory cytokines such as IL-1β, IL-6, and TNF that recruit monocytes, macrophages, and T cells to the inflamed vascular tissues [5, 7]. We characterized in vitro the pro-inflammatory CD8+ and CD4+ T and regulatory T (Treg) cell responses to LCWE in peripheral blood mononuclear cells (PBMC) isolated from subacute KD children, healthy children with a history of KD, and healthy adults
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