Natalie T Deuitch1, Dan Yang2, Pui Y Lee3, Xiaomin Yu4, Natalia Sampaio Moura5, Oskar Schnappauf5, Amanda K Ombrello5, Deborah Stone5, Hye Sun Kuehn6, Sergio D Rosenzweig6, Patrycja Hoffmann5, Cornelia Cudrici2, Deborah M Levy7, Elizabeth Kessler8, Jennifer B Soep9, Arielle D Hay10, Austin Dalrymple11, Yu Zhang12, Li Sun13, Qiuye Zhang14, Xuemei Tang15, Yuan Wu16, Koneti Rao12, Haibo Li17, Hong Luo18, Yao Zhang16, Jon M Burnham19, Manfred Boehm2, Karyl Barron12, Daniel L Kastner5, Ivona Aksentijevich20, Qing Zhou21. 1. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. Electronic address: Natalie.deuitch@nih.gov. 2. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 3. Boston Children's Hospital, Boston, Mass. 4. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. 5. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. 6. Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, Md. 7. University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. 8. Children's Mercy Hospital, Kansas City, Mo. 9. School of Medicine, University of Colorado, Boulder, Colo. 10. Nicklaus Children's Hospital, Miami, Fla. 11. Saint Louis University School of Medicine, SSM Health Cardinal Glennon Children's Hospital, St Louis, Mo. 12. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 13. Children's Hospital of Fudan University, Shanghai, China. 14. Affiliated Hospital of Qingdao University, China. 15. Children's Hospital of Chongqing Medical University, Shandong, China. 16. Peking University First Hospital, Beijing, China. 17. Ningbo Women and Children's Hospital, Zhejiang, China. 18. Second Xiangya Hospital of Central South University, Hunan, China. 19. Children's Hospital of Philadelphia, Philadelphia, Pa. 20. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. Electronic address: aksentii@mail.nih.gov. 21. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Life Sciences Institute, Zhejiang University, Zhejiang, China. Electronic address: zhouq2@zju.edu.cn.
Abstract
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment. Published by Elsevier Inc.
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment. Published by Elsevier Inc.
Authors: Karyl S Barron; Ivona Aksentijevich; Natalie T Deuitch; Deborah L Stone; Patrycja Hoffmann; Ryan Videgar-Laird; Ariane Soldatos; Jenna Bergerson; Camilo Toro; Cornelia Cudrici; Michele Nehrebecky; Tina Romeo; Anne Jones; Manfred Boehm; Jennifer A Kanakry; Dimana Dimitrova; Katherine R Calvo; Hawwa Alao; Devika Kapuria; Gil Ben-Yakov; Dominique C Pichard; Londa Hathaway; Alessandra Brofferio; Elisa McRae; Natalia Sampaio Moura; Oskar Schnappauf; Sofia Rosenzweig; Theo Heller; Edward W Cowen; Daniel L Kastner; Amanda K Ombrello Journal: Front Immunol Date: 2022-01-10 Impact factor: 7.561
Authors: Gerasimos Evangelatos; Giorgos Bamias; George D Kitas; George Kollias; Petros P Sfikakis Journal: Rheumatol Int Date: 2022-05-03 Impact factor: 3.580
Authors: Ying Hong; Marina Casimir; Benjamin C Houghton; Fang Zhang; Barbara Jensen; Ebun Omoyinmi; Robert Torrance; Charalampia Papadopoulou; Michelle Cummins; Marion Roderick; Adrian J Thrasher; Paul A Brogan; Despina Eleftheriou Journal: Front Immunol Date: 2022-04-22 Impact factor: 8.786