Research Letter
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
Abstract
Authors
James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson
Abstract
Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.
Authors
Sadia Saeed, Anna-Maria Siegert, YC Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y. H. Lam, Sherine Awad, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas Imran Khan, Nosheen Ramzan, Vladimir Saudek, Stephen O'Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo
Abstract
Authors
Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz, Jr.
Abstract
Authors
Rudy J. Castellani, Hinda Najem, Amy B. Heimberger, Pouya Jamshidi
Abstract
Authors
Lara Haase, Anouar Belkacemi, Laura Neises, Nicole Kiweler, Christine Wesely, Rosanna Huchzermeier, Maja Bozic, Arefeh Khakdan, Marta Sánchez, Arnaud Mary, Nadja Sachs, Hanna Winter, Enrico Glaab, Michael T. Heneka, Emiel P.C. van der Vorst, Michel Mittelbronn, Johannes Meiser, Jochen G. Schneider
Abstract
Authors
Nishanth S. Sadagopan, Rushmin Khazanchi, Rishi Jain, Amy B. Heimberger, Stephen T. Magill
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