PT  - JOURNAL ARTICLE
AU  - JC Martin
AU  - G Boschetti
AU  - C Chang
AU  - R Ungaro
AU  - M Giri
AU  - LS Chuang
AU  - S Nayar
AU  - A Greenstein
AU  - M. Dubinsky
AU  - L Walker
AU  - A Leader
AU  - JS Fine
AU  - CE Whitehurst
AU  - L Mbow
AU  - S Kugathasan
AU  - L.A. Denson
AU  - J. Hyams
AU  - JR Friedman
AU  - P Desai
AU  - HM Ko
AU  - I Laface
AU  - Guray Akturk
AU  - EE Schadt
AU  - S Gnjatic
AU  - A Rahman
AU  - M Merad
AU  - JH Cho
AU  - E Kenigsberg
TI  - Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy
AID  - 10.1101/503102
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 503102
4099  - http://biorxiv.org/content/early/2018/12/20/503102.short
4100  - http://biorxiv.org/content/early/2018/12/20/503102.full
AB  - Clinical benefits to cytokine blockade in ileal Crohn’s disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.