A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis.

Alma-Martina Cepika
Romain Banchereau
Elodie Segura
Marina Ohouo
Brandi Cantarel
Kristina Goller
Victoria Cantrell
Emily Ruchaud
Elizabeth Gatewood
Phuong Nguyen
Jinghua Gu
Esperanza Anguiano
Sandra Zurawski
Jeanine M Baisch
Marilynn Punaro
Nicole Baldwin
Gerlinde Obermoser
Karolina Palucka, The Jackson Laboratory
Jacques Banchereau, The Jackson Laboratory
Sebastian Amigorena
Virginia Pascual

Abstract

The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases. J Exp Med 2017 Sep 21 [Epub ahead of print]