Immunity
Volume 51, Issue 3, 17 September 2019, Pages 508-521.e6
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Article
Intestinal Permeability and IgA Provoke Immune Vasculitis Linked to Cardiovascular Inflammation

https://doi.org/10.1016/j.immuni.2019.05.021Get rights and content
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Highlights

  • IL-1β-driven increased intestinal permeability is observed in murine KD model

  • Blocking intestinal permeability or IgA production decreases murine KD vasculitis

  • IgA and IgA-C3 are observed in cardiovascular lesions of murine KD model

  • KD vasculitis may be a form of IgA vasculitis involving a gut-vascular axis

Summary

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.

Keywords

Kawasaki disease
IgA
intestinal permeability
coronary arteritis
vasculitis
complement
interleukin-1β

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These authors contributed equally

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