Research Letter
Abstract
Authors
Hiva Fassihi, Shehla Mohammed, Yuka Nakazawa, Heather Fawcett, Sally Turner, Joanne Palfrey, Isabel Garrood, Adesoji Abiona, Ana M.S. Morley, Mayuko Shimada, Kana Kato, Alan R. Lehmann, Tomoo Ogi
Abstract
Authors
Steven Q. Le, Alexander Sorensen, Soila Sukupolvi, Gianna Jewhurst, Grant L. Austin, Balraj Doray, Jonathan D. Cooper, Patricia I. Dickson
Abstract
Authors
Mindy K Graham, Sarki A. Abdulkadir
Abstract
Authors
Masahiko Shigemura, Felix L. Nunez-Santana, S.Marina Casalino-Matsuda, David Kirchenbuechler, Radmila Nafikova, Fei Chen, Zhan Yu, Yuliana V. Sokolenko, Estefani Diaz, Suchitra Swaminathan, Suror Mohsin, Rizaldy P. Scott, Lynn C. Welch, Chitaru Kurihara, Emilia Lecuona, G.R. Scott Budinger, Peter H. S. Sporn, Jacob I. Sznajder, Ankit Bharat
Abstract
Authors
Alireza Raissadati, Xuanyu Zhou, Harrison Chou, Yuhsin Vivian Huang, Shaheen Khatua, Yin Sun, Anne Xu, Sharon Loa, Arturo Hernandez, Han Zhu, Sean M. Wu
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Authors
Nathalie Baumlin, Sumedha Gunewardena, Scott H. Randell, Frank Horrigan, Matthias Salathe
Abstract
Authors
Alyssa M. Duffy, Anshika Goenka, Maryam I. Azeem, Azmain Taz, Sayalee V. Potdar, Sara A. Scott, Ellen Marin, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Vikas A. Gupta, Sagar Lonial, Ajay K. Nooka, Madhav V. Dhodapkar, Kavita M. Dhodapkar
Abstract
Authors
Elena Godoy-Molina, Natalia L. Serrano, Aquilina Jiménez-González, Miquel Villaronga, Rosa M. Marqués Pérez-Bryan, Rubén Varela-Fernández, Stephanie Lotz-Esquivel, Alba Hevia Tuñón, Prachi P. Trivedi, Nina Horn, Joseph F. Standing, Víctor Mangas-Sanjuan, Mercè Capdevila, Aurora Mateos, Denis Broun, Svetlana Lutsenko, Ines Medina-Rivera, Rafael Artuch, Cristina Jou, Mònica Roldán, Pedro Arango-Sancho, Mónica Saez-Villafañe, Juan J. Ortiz-de-Urbina, Angela Pieras-López, Marta Duero, Rosa Farré, Jordi Pijuan, Janet Hoenicka, James C. Sacchettini, Michael J. Petris, Vishal M. Gohil, Francesc Palau
Abstract
Authors
Macee C. Owen, Vinay R. Penna, Hao Dun, Wenjun Li, Benjamin J. Kopecky, Kenneth M. Murphy, Daniel Kreisel, Kory J. Lavine
Abstract
Perianal fistulizing Crohn’s disease (PCD) is a common and debilitating complication with elusive pathophysiology. To define actionable immunologic targets in PCD, we recruited patients with PCD (n = 24), CD without perianal disease (NPCD, n = 10), and idiopathic/cryptoglandular perianal fistulas (IPF, n = 29). Biopsies from fistula tracts, fistula opening, and rectal mucosa were analyzed using single-cell RNA-sequencing (scRNA-seq), mass cytometry (CyTOF), and spatial transcriptomics (ST). Global hyperactivation of IFN-g pathways distinguished PCD from idiopathic perianal fistulas and CD without perianal disease in the fistula tracts and/or intestinal mucosa. IFN-g and TNF-a signaling directly induced genes involved in epithelial-to-mesenchymal transition in PCD rectal epithelial cells. Enhanced IFN-g signaling in PCD was driven by pathogenic Th17 (pTh17) cells, which were recruited and activated by myeloid cells overexpressing LPS signature (LPS_myeloid). pTh17 and LPS_myeloid cells co-localized adjacent to PCD fistula tracts on ST and drove local IFN-g signaling. Anti-TNFs facilitated fistula healing by downregulating T and myeloid cell signatures, while promoting mucosal barrier repair and immunoregulatory processes. Key single-cell findings were validated by bulk RNA-seq data of an independent CD cohort. To summarize, we identified IFN-g-driven mechanisms contributing to pathogenesis and highlighted its blockade as a therapeutic strategy for PCD.
Authors
Siyan Cao, Khai M. Nguyen, Kaiming Ma, Tingyi Tan, Xin Yao, Ta-Chiang Liu, Malek Ayoub, Jalpa Devi, Sami Samaan, Yizhou Liu, Radhika Smith, Matthew L. Silviera, Steven R. Hunt, Paul E. Wise, Matthew G. Mutch, Sean C. Glasgow, William C. Chapman Jr, Michelle L. Cowan, Mathew A. Ciorba, Marco Colonna, Parakkal Deepak
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ISSN: 0021-9738 (print), 1558-8238 (online)