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2 results on '"Steve M Holland"'

1. Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-kB pathway

Author

Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Audrey Parent, Axel Cederholm, Darawan Rinchai, Lucy Bizien, Gonca Hancioglu, Quentin Philippot, Mame Sokhna Gueye, Majistor Raj Luxman, Maglorius Renkilaraj, Masato Ogishi, Camille Soudée, Mélanie Migaud, Flore Rozenberg, Mana Momenilandi, Quentin Riller, Luisa Imberti, Ottavia Delmonte, Gabriele Müller, Bärbel Keller, Julio Orrego, William Alexander Gallego, Tamar Rubin, Melike Emiroglu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda-Guillen, David I Berrios, Linda Vong, Connie H Katelaris, Peter Mustillo, Johannes Rädler, Jonathan Bohlen, Jale Bengi Celik, Camila Astudillo, Sarah Winter, Audrey Guichard, Vivien Béziat, Jacinta Bustamante, Qiang Pan-Hammarström, Yu Zhang, Lindsey B Rosen, Steve M Holland, Heather Kenney, Kaan Boztuğ, Nizar Mahlaoui, Sylvain Latour, Roshini Abraham, Vassilios Lougaris, Fabian Hauck, Anna Sediva, Faranaz Atschekzei, M Cecilia Poli, Mary A Slatter, Boaz Palterer, Michael D Keller, Alberto Pinzon-Charry, Anna Sullivan, Luke Droney, Daniel Suan, Nathalie Aladjidi, Miguel Hie, Estibaliz Lazaro, Jose Franco, Sevgi Keles, Marion Malphette, Marlene Pasquet, Maria Elena Maccari, Andrea Meinhardt, Aydan Ikinciogullari, Mohammad Shahrooei, Fatih Celmeli, Patrick Frosk, Christopher C Goodnow, Paul E Gray, Alexandre Belot, Hye Sun Kuehn, Sergio D Rosenzweig, Francesco Licciardi, Amélie Servettaz, Vincent Barlogis, Guillaume Le Guenno, Vera-Maria Herrmann, Taco Kuijpers, Grégoire Ducoux, Françoise Sarrot-Reynauld, Catharina Schuetz, Charlotte Cunningham-Rundles, Frédéric Rieux-Laucat, Stuart G Tangye, Cristina Sobacchi, Rainer Doffinger, Klaus Warnatz, Bodo Grimbacher, Claire Fieschi, Laureline Berteloot, Vanessa Bryant, Sophie Trouillet Assant, Luigi D Notarangelo, Helen Su, Benedicte Neven, Laurent Abel, Qian Zhang, Bertrand Boisson, Aurélie Cobat, Emmanuelle Jouanguy, Olle Kampe, Paul Bastard, Chaim Roifman, Nils Landegren, Mark S Anderson, Jean-Laurent Casanova, and Anne Puel

Abstract

Patients with inborn errors of the alternative NF-κB pathway have low thymic AIRE expression, leading to the development of auto-Abs neutralizing type I IFNs, and severe viral diseases.

Published
2023
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2. Dysregulation of CD8+ T cell function in the setting of altered cytokine signaling due to inborn errors of immunity

Author

Jose S. Campos Duran, Peyton E. Conrey, Samir Sayed, Chao Di, Elena N. Gonzalez, Neil D. Romberg, Jenna R.E. Bergerson, Steve M. Holland, Alexandra F. Freeman, Helen C. Su, Jennifer W. Leiding, Lisa R. Forbes, Tiphanie P. Vogel, and Sarah E. Henrickson

Subjects
Immunology, Immunology and Allergy
Abstract

A key outcome of chronic antigenic stimulation in the setting of sustained inflammation is the development of CD8+ T cell exhaustion. However, the relative roles of inflammation and antigen stimulation on T cell dysfunction remain unclear. Inborn errors of immunity (IEIs) provide an opportunity to study the effect of genetic alterations in signaling pathways on immune function. Here, we focus on an IEI resulting from genetically amplified cytokine signaling: gain-of-function mutations in STAT3 (STAT3 GOF). STAT3 signals downstream of multiple inflammatory cytokines (e.g., IL-6 and IL-27) and we used STAT3 GOF as a genetic mimic of chronic inflammation. To assess how amplified STAT3 signaling impacts immune cell subset distribution and activation status, PBMCs from STAT3 GOF patients and age-matched healthy controls were profiled via mass cytometry (CyTOF). This revealed altered states of CD8+ T cell activation including increased expression of immunoregulatory receptors (e.g., PD-1 and CD39). STAT3 GOF CD8+ T cells also showed impaired cytokine production and reduced proliferative capacity. Bulk RNA sequencing of naïve STAT3 GOF CD8+ T cells identified an exhausted-like transcriptional profile. Quantitation of metabolic function shows alterations in glucose use and oxidative phosphorylation in STAT3 GOF. Our studies suggest that inflammation alone may directly impair CD8+ T cell function. Understanding the mechanisms by which inflammation impacts T cell function may identify components of T cell dysregulation that can be targeted therapeutically in these rare patients, as well as those with more common inflammatory diseases (e.g., obesity) with shared aspects of T cell dysfunction. Supported by CHOP Research Institute, The Primary Immune Deficiency Treatment Consortium (PIDTC) and Immune Deficiency Foundation (IDF).

Published
2022
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