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48 results on '"Hoffmann, Patrycja"'

1. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency

Author

Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Rieser, Eva, Veli, Önay, Kaya, Öykü, Rauch, Charles, Nakabo, Shuichiro, Kuehn, Hye Sun, Swart, Mariël, Wang, Yanli, Çelik, Nisa Ilgim, Molitor, Anne, Ziaee, Vahid, Movahedi, Nasim, Shahrooei, Mohammad, Parvaneh, Nima, Alipour-olyei, Nasrin, Carapito, Raphael, Xu, Qin, Preite, Silvia, Beck, David B., Chae, Jae Jin, Nehrebecky, Michele, Ombrello, Amanda K., Hoffmann, Patrycja, Romeo, Tina, Deuitch, Natalie T., Matthíasardóttir, Brynja, Mullikin, James, Komarow, Hirsh, Stoddard, Jennifer, Niemela, Julie, Dobbs, Kerry, Sweeney, Colin L., Anderton, Holly, Lawlor, Kate E., Yoshitomi, Hiroyuki, Yang, Dan, Boehm, Manfred, Davis, Jeremy, Mudd, Pamela, Randazzo, Davide, Tsai, Wanxia Li, Gadina, Massimo, Kaplan, Mariana J., Toguchida, Junya, Mayer, Christian T., Rosenzweig, Sergio D., Notarangelo, Luigi D., Iwai, Kazuhiro, Silke, John, Schwartzberg, Pamela L., Boisson, Bertrand, Casanova, Jean-Laurent, Bahram, Seiamak, Rao, Anand Prahalad, Peltzer, Nieves, Walczak, Henning, Lalaoui, Najoua, Aksentijevich, Ivona, and Kastner, Daniel L.

Published
2024
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2. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease

Author

Lalaoui, Najoua, Boyden, Steven E, Oda, Hirotsugu, Wood, Geryl M, Stone, Deborah L, Chau, Diep, Liu, Lin, Stoffels, Monique, Kratina, Tobias, Lawlor, Kate E, Zaal, Kristien JM, Hoffmann, Patrycja M, Etemadi, Nima, Shield-Artin, Kristy, Biben, Christine, Tsai, Wanxia Li, Blake, Mary D, Kuehn, Hye Sun, Yang, Dan, Anderton, Holly, Silke, Natasha, Wachsmuth, Laurens, Zheng, Lixin, Moura, Natalia Sampaio, Beck, David B, Gutierrez-Cruz, Gustavo, Ombrello, Amanda K, Pinto-Patarroyo, Gineth P, Kueh, Andrew J, Herold, Marco J, Hall, Cathrine, Wang, Hongying, Chae, Jae Jin, Dmitrieva, Natalia I, McKenzie, Mark, Light, Amanda, Barham, Beverly K, Jones, Anne, Romeo, Tina M, Zhou, Qing, Aksentijevich, Ivona, Mullikin, James C, Gross, Andrew J, Shum, Anthony K, Hawkins, Edwin D, Masters, Seth L, Lenardo, Michael J, Boehm, Manfred, Rosenzweig, Sergio D, Pasparakis, Manolis, Voss, Anne K, Gadina, Massimo, Kastner, Daniel L, and Silke, John

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Biodefense, Prevention, Rare Diseases, Vaccine Related, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Caspase 3, Caspase 8, Female, Hereditary Autoinflammatory Diseases, Humans, MAP Kinase Kinase Kinases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, General Science & Technology
Abstract

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Published
2020

3. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Author

Ferrada, Marcela A., Savic, Sinisa, Cardona, Daniela Ospina, Collins, Jason C., Alessi, Hugh, Gutierrez-Rodrigues, Fernanda, Kumar, Dinesh Babu Uthaya, Wilson, Lorena, Goodspeed, Wendy, Topilow, James S., Paik, Julie J., Poulter, James A., Kermani, Tanaz A., Koster, Matthew J., Warrington, Kenneth J., Cargo, Catherine, Tattersall, Rachel S., Duncan, Christopher J.A., Cantor, Anna, Hoffmann, Patrycja, Payne, Elspeth M., Bonnekoh, Hanna, Krause, Karoline, Cowen, Edward W., Calvo, Katherine R., Patel, Bhavisha A., Ombrello, Amanda K., Kastner, Daniel L., Young, Neal S., Werner, Achim, Grayson, Peter C., and Beck, David B.

Published
2022
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4. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1

Author

Obiorah, Ifeyinwa Emmanuela, Patel, Bhavisha A., Groarke, Emma M., Wang, Weixin, Trick, Megan, Ombrello, Amanda K., Ferrada, Marcela A., Wu, Zhijie, Gutierrez-Rodrigues, Fernanda, Lotter, Jennifer, Wilson, Lorena, Hoffmann, Patrycja, Cardona, Daniela Ospina, Patel, Nisha, Dulau-Florea, Alina, Kastner, Daniel L., Grayson, Peter C., Beck, David B., Young, Neal S., and Calvo, Katherine R.

Published
2021
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6. Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Author

Park, Yong Hwan, Remmers, Elaine F., Lee, Wonyong, Ombrello, Amanda K., Chung, Lawton K., Shilei, Zhao, Stone, Deborah L., Ivanov, Maya I., Loeven, Nicole A., Barron, Karyl S., Hoffmann, Patrycja, Nehrebecky, Michele, Akkaya-Ulum, Yeliz Z., Sag, Erdal, Balci-Peynircioglu, Banu, Aksentijevich, Ivona, Gül, Ahmet, Rotimi, Charles N., Chen, Hua, Bliska, James B., Ozen, Seza, Kastner, Daniel L., Shriner, Daniel, and Chae, Jae Jin

Published
2020
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7. Biallelic human SHARPINloss of function induces autoinflammation and immunodeficiency

Author

Oda, Hirotsugu, Manthiram, Kalpana, Chavan, Pallavi Pimpale, Rieser, Eva, Veli, Önay, Kaya, Öykü, Rauch, Charles, Nakabo, Shuichiro, Kuehn, Hye Sun, Swart, Mariël, Wang, Yanli, Çelik, Nisa Ilgim, Molitor, Anne, Ziaee, Vahid, Movahedi, Nasim, Shahrooei, Mohammad, Parvaneh, Nima, Alipour-olyei, Nasrin, Carapito, Raphael, Xu, Qin, Preite, Silvia, Beck, David B., Chae, Jae Jin, Nehrebecky, Michele, Ombrello, Amanda K., Hoffmann, Patrycja, Romeo, Tina, Deuitch, Natalie T., Matthíasardóttir, Brynja, Mullikin, James, Komarow, Hirsh, Stoddard, Jennifer, Niemela, Julie, Dobbs, Kerry, Sweeney, Colin L., Anderton, Holly, Lawlor, Kate E., Yoshitomi, Hiroyuki, Yang, Dan, Boehm, Manfred, Davis, Jeremy, Mudd, Pamela, Randazzo, Davide, Tsai, Wanxia Li, Gadina, Massimo, Kaplan, Mariana J., Toguchida, Junya, Mayer, Christian T., Rosenzweig, Sergio D., Notarangelo, Luigi D., Iwai, Kazuhiro, Silke, John, Schwartzberg, Pamela L., Boisson, Bertrand, Casanova, Jean-Laurent, Bahram, Seiamak, Rao, Anand Prahalad, Peltzer, Nieves, Walczak, Henning, Lalaoui, Najoua, Aksentijevich, Ivona, and Kastner, Daniel L.

Abstract

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpinleads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Published
2024
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8. A unified metric of human immune health

Author

Sparks, Rachel, Rachmaninoff, Nicholas, Lau, William W., Hirsch, Dylan C., Bansal, Neha, Martins, Andrew J., Chen, Jinguo, Liu, Candace C., Cheung, Foo, Failla, Laura E., Biancotto, Angelique, Fantoni, Giovanna, Sellers, Brian A., Chawla, Daniel G., Howe, Katherine N., Mostaghimi, Darius, Farmer, Rohit, Kotliarov, Yuri, Calvo, Katherine R., Palmer, Cindy, Daub, Janine, Foruraghi, Ladan, Kreuzburg, Samantha, Treat, Jennifer D., Urban, Amanda K., Jones, Anne, Romeo, Tina, Deuitch, Natalie T., Moura, Natalia Sampaio, Weinstein, Barbara, Moir, Susan, Ferrucci, Luigi, Barron, Karyl S., Aksentijevich, Ivona, Kleinstein, Steven H., Townsley, Danielle M., Young, Neal S., Frischmeyer-Guerrerio, Pamela A., Uzel, Gulbu, Pinto-Patarroyo, Gineth Paola, Cudrici, Cornelia D., Hoffmann, Patrycja, Stone, Deborah L., Ombrello, Amanda K., Freeman, Alexandra F., Zerbe, Christa S., Kastner, Daniel L., Holland, Steven M., and Tsang, John S.

Abstract

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Published
2024
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11. TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2)

Author

Deuitch, Natalie T., primary, Yang, Dan, additional, Lee, Pui Y., additional, Yu, Xiaomin, additional, Moura, Natalia Sampaio, additional, Schnappauf, Oskar, additional, Ombrello, Amanda K., additional, Stone, Deborah, additional, Kuehn, Hye Sun, additional, Rosenzweig, Sergio D., additional, Hoffmann, Patrycja, additional, Cudrici, Cornelia, additional, Levy, Deborah M., additional, Kessler, Elizabeth, additional, Soep, Jennifer B., additional, Hay, Arielle D., additional, Dalrymple, Austin, additional, Zhang, Yu, additional, Sun, Li, additional, Zhang, Qiuye, additional, Tang, Xuemei, additional, Wu, Yuan, additional, Rao, Koneti, additional, Li, Haibo, additional, Luo, Hong, additional, Zhang, Yao, additional, Burnham, Jon M., additional, Boehm, Manfred, additional, Barron, Karyl, additional, Kastner, Daniel L., additional, Aksentijevich, Ivona, additional, and Zhou, Qing, additional

Published
2022
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12. Brief Report: Deficiency of Complement 1r Subcomponent in Early‐Onset Systemic Lupus Erythematosus: The Role of Disease‐Modifying Alleles in a Monogenic Disease

Author

Demirkaya, Erkan, Zhou, Qing, Smith, Carolyne K., Ombrello, Michael J., Deuitch, Natalie, Tsai, Wanxia L., Hoffmann, Patrycja, Remmers, Elaine F., Takeuchi, Masaki, Park, Yong Hwan, Chae, JaeJin, Barut, Kenan, Simsek, Dogan, Adrovic, Amra, Sahin, Sezgin, Caliskan, Salim, Chandrasekharappa, Settara C., Hasni, Sarfaraz A., Ombrello, Amanda K., Gadina, Massimo, Kastner, Daniel L., Kaplan, Mariana J., Kasapcopur, Ozgur, and Aksentijevich, Ivona

Published
2017
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13. The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

Author

Barron, Karyl S., primary, Aksentijevich, Ivona, additional, Deuitch, Natalie T., additional, Stone, Deborah L., additional, Hoffmann, Patrycja, additional, Videgar-Laird, Ryan, additional, Soldatos, Ariane, additional, Bergerson, Jenna, additional, Toro, Camilo, additional, Cudrici, Cornelia, additional, Nehrebecky, Michele, additional, Romeo, Tina, additional, Jones, Anne, additional, Boehm, Manfred, additional, Kanakry, Jennifer A., additional, Dimitrova, Dimana, additional, Calvo, Katherine R., additional, Alao, Hawwa, additional, Kapuria, Devika, additional, Ben-Yakov, Gil, additional, Pichard, Dominique C., additional, Hathaway, Londa, additional, Brofferio, Alessandra, additional, McRae, Elisa, additional, Moura, Natalia Sampaio, additional, Schnappauf, Oskar, additional, Rosenzweig, Sofia, additional, Heller, Theo, additional, Cowen, Edward W., additional, Kastner, Daniel L., additional, and Ombrello, Amanda K., additional

Published
2022
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14. Single-cell profiling of T lymphocytes in deficiency of adenosine deaminase 2

Author

Wu, Zhijie, primary, Gao, Shouguo, additional, Watanabe, Naoki, additional, Batchu, Sai, additional, Kajigaya, Sachiko, additional, Diamond, Carrie, additional, Alemu, Lemlem, additional, Raffo, Diego Quinones, additional, Feng, Xingmin, additional, Hoffmann, Patrycja, additional, Stone, Deborah, additional, Ombrello, Amanda, additional, and Young, Neal S, additional

Published
2021
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15. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS

Author

Ferrada, Marcela A., primary, Sikora, Keith A., additional, Luo, Yiming, additional, Wells, Kristina V., additional, Patel, Bhavisha, additional, Groarke, Emma M., additional, Ospina Cardona, Daniela, additional, Rominger, Emily, additional, Hoffmann, Patrycja, additional, Le, Mimi T., additional, Deng, Zuoming, additional, Quinn, Kaitlin A., additional, Rose, Emily, additional, Tsai, Wanxia L., additional, Wigerblad, Gustaf, additional, Goodspeed, Wendy, additional, Jones, Anne, additional, Wilson, Lorena, additional, Schnappauf, Oskar, additional, Laird, Ryan S., additional, Kim, Jeff, additional, Allen, Clint, additional, Sirajuddin, Arlene, additional, Chen, Marcus, additional, Gadina, Massimo, additional, Calvo, Katherine R., additional, Kaplan, Mariana J., additional, Colbert, Robert A., additional, Aksentijevich, Ivona, additional, Young, Neal S., additional, Savic, Sinisa, additional, Kastner, Daniel L., additional, Ombrello, Amanda K., additional, Beck, David B., additional, and Grayson, Peter C., additional

Published
2021
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19. Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes

Author

Watanabe, Naoki, primary, Gao, Shouguo, additional, Wu, Zhijie, additional, Batchu, Sai, additional, Kajigaya, Sachiko, additional, Diamond, Carrie, additional, Alemu, Lemlem, additional, Raffo, Diego Quinones, additional, Hoffmann, Patrycja, additional, Stone, Deborah, additional, Ombrello, Amanda K, additional, and Young, Neal S, additional

Published
2021
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20. Next generation sequencing panel screening of 320 patients with clinically unclassified systemic autoinflammatory diseases

Author

Schnappauf, Oskar, primary, Wang, Hongying, additional, Deuitch, Natalie, additional, Moura, Natalia Sampaio, additional, Rosenzweig, Sofia, additional, Cardona, Daniela Ospina, additional, Hoffmann, Patrycja, additional, Stone, Deborah, additional, Ombrello, Amanda, additional, Kastner, Daniel, additional, and Aksentijevich, Ivona, additional

Published
2021
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21. Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2

Author

Zhou, Qing, Yang, Dan, Ombrello, Amanda K., Zavialov, Andrey V., Toro, Camilo, Zavialov, Anton V., Stone, Deborah L., Chae, Jae Jin, Rosenzweig, Sergio D., Bishop, Kevin, Barron, Karyl S., Kuehn, Hye Sun, Hoffmann, Patrycja, Negro, Alejandra, Tsai, Wanxia L., Cowen, Edward W., Pei, Wuhong, Milner, Joshua D., Silvin, Christopher, Heller, Theo, Chin, David T., Patronas, Nicholas J., Barber, John S., Lee, Chyi-Chia R., Wood, Geryl M., Ling, Alexander, Kelly, Susan J., Kleiner, David E., Mullikin, James C., Ganson, Nancy J., Kong, Heidi H., Hambleton, Sophie, Candotti, Fabio, Quezado, Martha M., Calvo, Katherine R., Alao, Hawwa, Barham, Beverly K., Jones, Anne, Meschia, James F., Worrall, Bradford B., Kasner, Scott E., Rich, Stephen S., Goldbach-Mansky, Raphaela, Abinun, Mario, Chalom, Elizabeth, Gotte, Alisa C., Punaro, Marilynn, Pascual, Virginia, Verbsky, James W., Torgerson, Troy R., Singer, Nora G., Gershon, Timothy R., Ozen, Seza, Karadag, Omer, Fleisher, Thomas A., Remmers, Elaine F., Burgess, Shawn M., Moir, Susan L., Gadina, Massimo, Sood, Raman, Hershfield, Michael S., Boehm, Manfred, Kastner, Daniel L., and Aksentijevich, Ivona

Published
2014
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22. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features

Author

Schwartz, Daniella Muallem, primary, Kitakule, Moses M, additional, Dizon, Brian LP, additional, Gutierrez-Huerta, Cristhian, additional, Blackstone, Sarah A, additional, Burma, Aarohan M, additional, Son, Aran, additional, Deuitch, Natalie, additional, Rosenzweig, Sofia, additional, Komarow, Hirsh, additional, Stone, Deborah L, additional, Jones, Anne, additional, Nehrebecky, Michele, additional, Hoffmann, Patrycja, additional, Romeo, Tina, additional, de Jesus, Adriana Almeida, additional, Alehashemi, Sara, additional, Garg, Megha, additional, Torreggiani, Sofia, additional, Montealegre Sanchez, Gina A, additional, Honer, Katelin, additional, Souto Adeva, Gema, additional, Barron, Karyl S, additional, Aksentijevich, Ivona, additional, Ombrello, Amanda K, additional, Goldbach-Mansky, Raphaela, additional, Kastner, Daniel L, additional, Milner, Joshua D, additional, and Frischmeyer-Guerrerio, Pamela, additional

Published
2021
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23. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Author

Beck, David B., primary, Ferrada, Marcela A., additional, Sikora, Keith A., additional, Ombrello, Amanda K., additional, Collins, Jason C., additional, Pei, Wuhong, additional, Balanda, Nicholas, additional, Ross, Daron L., additional, Ospina Cardona, Daniela, additional, Wu, Zhijie, additional, Patel, Bhavisha, additional, Manthiram, Kalpana, additional, Groarke, Emma M., additional, Gutierrez-Rodrigues, Fernanda, additional, Hoffmann, Patrycja, additional, Rosenzweig, Sofia, additional, Nakabo, Shuichiro, additional, Dillon, Laura W., additional, Hourigan, Christopher S., additional, Tsai, Wanxia L., additional, Gupta, Sarthak, additional, Carmona-Rivera, Carmelo, additional, Asmar, Anthony J., additional, Xu, Lisha, additional, Oda, Hirotsugu, additional, Goodspeed, Wendy, additional, Barron, Karyl S., additional, Nehrebecky, Michele, additional, Jones, Anne, additional, Laird, Ryan S., additional, Deuitch, Natalie, additional, Rowczenio, Dorota, additional, Rominger, Emily, additional, Wells, Kristina V., additional, Lee, Chyi-Chia R., additional, Wang, Weixin, additional, Trick, Megan, additional, Mullikin, James, additional, Wigerblad, Gustaf, additional, Brooks, Stephen, additional, Dell’Orso, Stefania, additional, Deng, Zuoming, additional, Chae, Jae J., additional, Dulau-Florea, Alina, additional, Malicdan, May C.V., additional, Novacic, Danica, additional, Colbert, Robert A., additional, Kaplan, Mariana J., additional, Gadina, Massimo, additional, Savic, Sinisa, additional, Lachmann, Helen J., additional, Abu-Asab, Mones, additional, Solomon, Benjamin D., additional, Retterer, Kyle, additional, Gahl, William A., additional, Burgess, Shawn M., additional, Aksentijevich, Ivona, additional, Young, Neal S., additional, Calvo, Katherine R., additional, Werner, Achim, additional, Kastner, Daniel L., additional, and Grayson, Peter C., additional

Published
2020
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24. Single‐cell profiling of T lymphocytes in deficiency of adenosine deaminase 2.

Author

Wu, Zhijie, Gao, Shouguo, Watanabe, Naoki, Batchu, Sai, Kajigaya, Sachiko, Diamond, Carrie, Alemu, Lemlem, Raffo, Diego Quinones, Feng, Xingmin, Hoffmann, Patrycja, Stone, Deborah, Ombrello, Amanda, and Young, Neal S.

Subjects
ADENOSINE deaminase, T cells, CELL communication, RNA sequencing, GENE regulatory networks
Abstract

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by autosomal‐recessive loss‐of‐function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy, and inflammation are dominant clinical features of this disease; the spectrum of manifestations includes immunodeficiency and lymphoproliferation as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. Aberrant monocyte differentiation to macrophages and neutrophils are important in the pathogenesis of DADA2, but little is known about T lymphocytes in this disease. We performed combined single‐cell RNA sequencing and single‐cell TCR sequencing in order to profile T cell repertoires in 10 patients with DADA2. Although there were no significant alterations of T cell subsets, we observed activation of both CD8+ and CD4+ T cells. There was no clonal expansion of T cells: most TCRs were expressed at basal levels in patients and healthy donors. TCR usage was private to individual patients and not disease specific, indicating as unlikely a common pathogenic background or predisposition to a common pathogen. We recognized activation of IFN pathways as a signature of T cells and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients showed distinct cell–cell interactions with monocytes, as compared with healthy donors, and many of these ligand–receptor interactions likely drove up‐regulation of STAT1 in both T cells and other immune cells in patients. Our analysis reveals previously undercharacterized cell characteristics in DADA2. [ABSTRACT FROM AUTHOR]

Published
2022
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25. Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance

Author

Schnappauf, Oskar, primary, Zhou, Qing, additional, Moura, Natalia Sampaio, additional, Ombrello, Amanda K., additional, Michael, Drew G., additional, Deuitch, Natalie, additional, Barron, Karyl, additional, Stone, Deborah L., additional, Hoffmann, Patrycja, additional, Hershfield, Michael, additional, Applegate, Carolyn, additional, Bjornsson, Hans T., additional, Beck, David B., additional, Witmer, P. Dane, additional, Sobreira, Nara, additional, Wohler, Elizabeth, additional, Chiorini, John A., additional, Center, The American Genome, additional, Dalgard, Clifton L., additional, Center, NIH Intramural Sequencing, additional, Kastner, Daniel L., additional, and Aksentijevich, Ivona, additional

Published
2020
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26. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease

Author

Lalaoui, Najoua, primary, Boyden, Steven E., additional, Oda, Hirotsugu, additional, Wood, Geryl M., additional, Stone, Deborah L., additional, Chau, Diep, additional, Liu, Lin, additional, Stoffels, Monique, additional, Kratina, Tobias, additional, Lawlor, Kate E., additional, Zaal, Kristien J. M., additional, Hoffmann, Patrycja M., additional, Etemadi, Nima, additional, Shield-Artin, Kristy, additional, Biben, Christine, additional, Tsai, Wanxia Li, additional, Blake, Mary D., additional, Kuehn, Hye Sun, additional, Yang, Dan, additional, Anderton, Holly, additional, Silke, Natasha, additional, Wachsmuth, Laurens, additional, Zheng, Lixin, additional, Moura, Natalia Sampaio, additional, Beck, David B., additional, Gutierrez-Cruz, Gustavo, additional, Ombrello, Amanda K., additional, Pinto-Patarroyo, Gineth P., additional, Kueh, Andrew J., additional, Herold, Marco J., additional, Hall, Cathrine, additional, Wang, Hongying, additional, Chae, Jae Jin, additional, Dmitrieva, Natalia I., additional, McKenzie, Mark, additional, Light, Amanda, additional, Barham, Beverly K., additional, Jones, Anne, additional, Romeo, Tina M., additional, Zhou, Qing, additional, Aksentijevich, Ivona, additional, Mullikin, James C., additional, Gross, Andrew J., additional, Shum, Anthony K., additional, Hawkins, Edwin D., additional, Masters, Seth L., additional, Lenardo, Michael J., additional, Boehm, Manfred, additional, Rosenzweig, Sergio D., additional, Pasparakis, Manolis, additional, Voss, Anne K., additional, Gadina, Massimo, additional, Kastner, Daniel L., additional, and Silke, John, additional

Published
2019
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27. Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20

Author

Schwartz, Daniella Muallem, primary, Blackstone, Sarah A, additional, Sampaio-Moura, Natalia, additional, Rosenzweig, Sofia, additional, Burma, Aarohan M, additional, Stone, Deborah, additional, Hoffmann, Patrycja, additional, Jones, Anne, additional, Romeo, Tina, additional, Barron, Karyl S, additional, Waldman, Meryl A, additional, Aksentijevich, Ivona, additional, Kastner, Daniel L, additional, Milner, Joshua D, additional, and Ombrello, Amanda K, additional

Published
2019
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28. Treatment Strategies for Deficiency of Adenosine Deaminase 2

Author

Ombrello, Amanda K., primary, Qin, Jing, additional, Hoffmann, Patrycja M., additional, Kumar, Parag, additional, Stone, Deborah, additional, Jones, Anne, additional, Romeo, Tina, additional, Barham, Beverly, additional, Pinto-Patarroyo, Gineth, additional, Toro, Camilo, additional, Soldatos, Ariane, additional, Zhou, Qing, additional, Deuitch, Natalie, additional, Aksentijevich, Ivona, additional, Sheldon, Sherry L., additional, Kelly, Susan, additional, Man, Ada, additional, Barron, Karyl, additional, Hershfield, Michael, additional, Flegel, Willy A., additional, and Kastner, Daniel L., additional

Published
2019
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29. Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC

Author

Oda, Hirotsugu, primary, Beck, David B., additional, Kuehn, Hye Sun, additional, Sampaio Moura, Natalia, additional, Hoffmann, Patrycja, additional, Ibarra, Maria, additional, Stoddard, Jennifer, additional, Tsai, Wanxia Li, additional, Gutierrez-Cruz, Gustavo, additional, Gadina, Massimo, additional, Rosenzweig, Sergio D., additional, Kastner, Daniel L., additional, Notarangelo, Luigi D., additional, and Aksentijevich, Ivona, additional

Published
2019
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30. Sequence‐Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2.

Author

Schnappauf, Oskar, Sampaio Moura, Natalia, Aksentijevich, Ivona, Stoffels, Monique, Ombrello, Amanda K., Hoffmann, Patrycja, Barron, Karyl, Remmers, Elaine F., Hershfield, Michael, Kelly, Susan J., Cuthbertson, David, Carette, Simon, Chung, Sharon A., Forbess, Lindsy, Khalidi, Nader A., Koening, Curry L., Langford, Carol A., McAlear, Carol A., Monach, Paul A., and Moreland, Larry

Subjects
MICROSCOPIC polyangiitis, SEQUENCE analysis, GENETICS, MEDICAL screening, GRANULOMATOSIS with polyangiitis, HYDROLASES, POLYARTERITIS nodosa
Abstract

Objective: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease‐causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA). Methods: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA‐2 enzyme activity was assessed in selected serum samples. Results: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA‐2 enzyme activity. ADA‐2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA‐2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2. Conclusion: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA‐2 testing should strongly be considered in patients with hepatitis B virus–negative idiopathic PAN. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Deficiency of Complement 1r subcomponent in early-onset SLE: Role for disease-modifying alleles in a monogenic disease

Author

Demirkaya, Erkan, Zhou, Qing, Smith, Carolyne K., Ombrello, Michael J., Deuitch, Natalie, Tsai, Wanxia L., Hoffmann, Patrycja, Remmers, Elaine F., Takeuchi, Masaki, Park, Yong Hwan, Chae, JaeJin, Barut, Kenan, Simsek, Dogan, Adrovic, Amra, Sahin, Sezgin, Caliskan, Salim, Chandrasekharappa, Settara C., Hasni, Sarfaraz A, Ombrello, Amanda K., Gadina, Massimo, Kastner, Daniel L., Kaplan, Mariana J., Kasapcopur, Ozgur, and Aksentijevich, Ivona

Subjects
Adult, Male, Adolescent, Genotype, Turkey, Complement C1r, Neutrophils, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Severity of Illness Index, Article, Consanguinity, Phenotype, Child, Preschool, Interferon Type I, Leukocytes, Mononuclear, Humans, Lupus Erythematosus, Systemic, Exome, Female, Genetic Predisposition to Disease, Age of Onset, Child, Alleles
Abstract

To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease.We performed whole-exome sequencing and single-nucleotide polymorphism array genotyping in family members with and without SLE. Protein and gene expression, cytokine profile, neutrophil extracellular trap (NET) formation, and presence of low-density granulocytes were evaluated in patient primary cells and serum samples.We identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with SLE and in an asymptomatic 9-year-old girl. Complement levels were low in sera from patients with truncated C1r protein. Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The type I IFN transcriptional signature in the patients' blood correlated with disease expressivity, whereas the neutrophil signature in peripheral blood mononuclear cells was likely associated with disease severity. The female patient with SLE with the most severe phenotype presented with a stronger neutrophil signature, defined by enhanced NET formation and the presence of low-density granulocytes. Analysis of exome data for modifying alleles suggested enrichment of common SLE-associated variants in the more severely affected patients. Lupus-associated HLA alleles or HLA haplotypes were not shared among the 4 affected subjects.Our findings revealed a novel high-penetrance mutation in C1R as the cause of monogenic SLE. Disease expressivity in this family appears to be influenced by additional common and rare genetic variants.

Published
2017

32. Deficiency Of Complement 1R Subcomponent In Early-Onset Systemic Lupus Erythematosus: The Role Of Disease-Modifying Alleles In A Monogenic Disease

Author

Demirkaya, Erkan, Zhou, Qing, Smith, Carolyne K., Ombrello, Michael J., Deuitch, Natalie, Tsai, Wanxia L., Hoffmann, Patrycja, Remmers, Elaine F., Takeuchi, Masaki, Park, Yong Hwan, Chae, JaeJin, Barut, Kenan, Simsek, Dogan, Adrovic, Amra, Sahin, Sezgin, Caliskan, Salim, Chandrasekharappa, Settara C., Hasni, Sarfaraz A., Ombrello, Amanda K., and Gadina, Massimo

Subjects
immune system diseases, skin and connective tissue diseases
Abstract

Objective. To identify a genetic cause of early-onset systemic lupus erythematosus (SLE) in a large consanguineous family from Turkey and to study the mechanisms of the disease.

Published
2017

33. Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome

Author

Mistry, Pragnesh, primary, Carmona-Rivera, Carmelo, additional, Ombrello, Amanda K, additional, Hoffmann, Patrycja, additional, Seto, Nickie L, additional, Jones, Anne, additional, Stone, Deborah L, additional, Naz, Faiza, additional, Carlucci, Philip, additional, Dell’Orso, Stefania, additional, Gutierrez-Cruz, Gustavo, additional, Sun, Hong-Wei, additional, Kastner, Daniel L, additional, Aksentijevich, Ivona, additional, and Kaplan, Mariana J, additional

Published
2018
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34. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease

Author

Aeschlimann, Florence A, primary, Batu, Ezgi D, additional, Canna, Scott W, additional, Go, Ellen, additional, Gül, Ahmet, additional, Hoffmann, Patrycja, additional, Leavis, Helen L, additional, Ozen, Seza, additional, Schwartz, Daniella M, additional, Stone, Deborah L, additional, van Royen-Kerkof, Annet, additional, Kastner, Daniel L, additional, Aksentijevich, Ivona, additional, and Laxer, Ronald M, additional

Published
2018
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35. Cryopyrin-associated Periodic Syndrome Caused by a Myeloid-Restricted Somatic NLRP3 Mutation

Author

Zhou, Qing, Aksentijevich, Ivona, Wood, Geryl M., Walts, Avram D., Hoffmann, Patrycja, Remmers, Elaine F., Kastner, Daniel L., and Ombrello, Amanda K.

Subjects
B-Lymphocytes, T-Lymphocytes, Mouth Mucosa, Sequence Analysis, DNA, Fibroblasts, Middle Aged, Article, Cryopyrin-Associated Periodic Syndromes, Monocytes, Mutation, NLR Family, Pyrin Domain-Containing 3 Protein, Humans, Exome, Female, Myeloid Cells, Carrier Proteins, Granulocytes
Abstract

To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional Sanger DNA sequencing.We performed whole-exome sequencing and targeted deep sequencing using DNA from the patient's whole blood to identify a possible NLRP3 somatic mutation. We then screened for this mutation in subcloned NLRP3 amplicons from fibroblasts, buccal cells, granulocytes, negatively selected monocytes, and T and B lymphocytes and further confirmed the somatic mutation by targeted sequencing of exon 3.We identified a previously reported CAPS-associated mutation, p.Tyr570Cys, with a mutant allele frequency of 15% based on exome data. Targeted sequencing and subcloning of NLRP3 amplicons confirmed the presence of the somatic mutation in whole blood at a ratio similar to the exome data. The mutant allele frequency was in the range of 13.3-16.8% in monocytes and 15.2-18% in granulocytes. Notably, this mutation was either absent or present at a very low frequency in B and T lymphocytes, in buccal cells, and in the patient's cultured fibroblasts.Our findings indicate the possibility of myeloid-restricted somatic mosaicism in the pathogenesis of CAPS, underscoring the emerging role of massively parallel sequencing in clinical diagnosis.

Published
2015

36. Connecting Two Pathways through Ca2+ Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation

Author

Chae, Jae J., Park, Yong H., Park, Chung, Hwang, Il-Young, Hoffmann, Patrycja, Kehrl, John H., Aksentijevich, Ivona, and Kastner, Daniel L.

Subjects
Lipopolysaccharides, Inflammasomes, Phospholipase C gamma, Interleukin-1beta, Immunologic Deficiency Syndromes, Calcium Channel Blockers, Endoplasmic Reticulum, Article, Immune System Diseases, Case-Control Studies, Mutation, NLR Family, Pyrin Domain-Containing 3 Protein, Leukocytes, Mononuclear, Humans, Calcium, Calcium Signaling, Carrier Proteins, Signal Transduction
Abstract

We previously reported that p.Ser707Tyr, a novel variant in phospholipase Cγ2 (PLCγ2), is the cause of a dominantly inherited autoinflammatory disease, autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID). The hypermorphic mutation enhances PLCγ2 activity and causes an increase in intracellular Ca2+ release from endoplasmic reticulum stores. Because increased intracellular Ca2+ signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID.Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and 2 patients with APLAID. Inflammasome activation was analyzed by Western blotting. Intracellular Ca2+ levels were measured with a FLIPR Calcium 4 assay kit.Cells from the patients had elevated basal levels of intracellular Ca2+, and the intracellular Ca2+ flux triggered by extracellular CaCl2 was substantially enhanced. Patient PBMCs secreted interleukin-1β in response to lipopolysaccharide priming alone, and this effect was attenuated by treatment with a PLC inhibitor, intracellular Ca2+ blockers, or an adenylate cyclase activator.Our findings suggest that the inflammation in patients with APLAID is partially driven by activation of the NLRP3 inflammasome. These data link 2 seemingly distinct molecular pathways and provide new insights into the pathogenesis of APLAID and autoinflammation.

Published
2015

37. Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2

Author

Silvin, Christopher, Zhou, Qing, Stone, Deborah L., Wood, Geryl M., Mullikin, James C., Patronas, Nicholas J., Heller, Theo, Barber, John S., Ombrello, Amanda K., Negro, Alejandra, Yang, Dan, Zavialov, Anton V., Hoffmann, Patrycja, Pei, Wuhong, Barron, Karyl S., Ling, Alexander, Milner, Joshua D., Rosenzweig, Sergio D., Kong, Heidi H., Chin, David T., Kleiner, David E., Tsai, Wanxia L., Lee, Chyi-Chia R., Hambleton, Sophie, Kuehn, Hye Sun, Toro, Camilo, Zavialov, Andrey V., Cowen, Edward W., Chae, Jae Jin, Bishop, Kevin, Ganson, Nancy J., and Kelly, Susan J.

Subjects
cardiovascular diseases, nervous system diseases
Abstract

We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood.

Published
2014
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41. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Author

Zhou, Qing, primary, Wang, Hongying, additional, Schwartz, Daniella M, additional, Stoffels, Monique, additional, Park, Yong Hwan, additional, Zhang, Yuan, additional, Yang, Dan, additional, Demirkaya, Erkan, additional, Takeuchi, Masaki, additional, Tsai, Wanxia Li, additional, Lyons, Jonathan J, additional, Yu, Xiaomin, additional, Ouyang, Claudia, additional, Chen, Celeste, additional, Chin, David T, additional, Zaal, Kristien, additional, Chandrasekharappa, Settara C, additional, P Hanson, Eric, additional, Yu, Zhen, additional, Mullikin, James C, additional, Hasni, Sarfaraz A, additional, Wertz, Ingrid E, additional, Ombrello, Amanda K, additional, Stone, Deborah L, additional, Hoffmann, Patrycja, additional, Jones, Anne, additional, Barham, Beverly K, additional, Leavis, Helen L, additional, van Royen-Kerkof, Annet, additional, Sibley, Cailin, additional, Batu, Ezgi D, additional, Gül, Ahmet, additional, Siegel, Richard M, additional, Boehm, Manfred, additional, Milner, Joshua D, additional, Ozen, Seza, additional, Gadina, Massimo, additional, Chae, JaeJin, additional, Laxer, Ronald M, additional, Kastner, Daniel L, additional, and Aksentijevich, Ivona, additional

Published
2015
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42. Brief Report: Anakinra Use During Pregnancy in Patients With Cryopyrin-Associated Periodic Syndromes

Author

Chang, Zenas, primary, Spong, Catherine Y., additional, Jesus, Adriana A., additional, Davis, Michael A., additional, Plass, Nicole, additional, Stone, Deborah L., additional, Chapelle, Dawn, additional, Hoffmann, Patrycja, additional, Kastner, Daniel L., additional, Barron, Karyl, additional, Goldbach-Mansky, Raphaela T., additional, and Stratton, Pamela, additional

Published
2014
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43. Brief Report: Connecting Two Pathways Through Ca2+ Signaling: NLRP3 Inflammasome Activation Induced by a Hypermorphic PLCG2 Mutation.

Author

Chae, Jae Jin, Park, Yong Hwan, Park, Chung, Hwang, Il‐Young, Hoffmann, Patrycja, Kehrl, John H., Aksentijevich, Ivona, and Kastner, Daniel L.

Subjects
GENETICS of autoimmune diseases, CALCIUM antagonists, ACADEMIC medical centers, CALCIUM, CELLULAR signal transduction, GENETIC mutation, RESEARCH funding, WESTERN immunoblotting, DATA analysis software, THERAPEUTICS
Abstract

Objective We previously reported that p.Ser707Tyr, a novel variant in phospholipase Cγ2 (PLCγ2), is the cause of a dominantly inherited autoinflammatory disease, autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID). The hypermorphic mutation enhances PLCγ2 activity and causes an increase in intracellular Ca2+ release from endoplasmic reticulum stores. Because increased intracellular Ca2+ signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID. Methods Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and 2 patients with APLAID. Inflammasome activation was analyzed by Western blotting. Intracellular Ca2+ levels were measured with a FLIPR Calcium 4 assay kit. Results Cells from the patients had elevated basal levels of intracellular Ca2+, and the intracellular Ca2+ flux triggered by extracellular CaCl2 was substantially enhanced. Patient PBMCs secreted interleukin-1β in response to lipopolysaccharide priming alone, and this effect was attenuated by treatment with a PLC inhibitor, intracellular Ca2+ blockers, or an adenylate cyclase activator. Conclusion Our findings suggest that the inflammation in patients with APLAID is partially driven by activation of the NLRP3 inflammasome. These data link 2 seemingly distinct molecular pathways and provide new insights into the pathogenesis of APLAID and autoinflammation. [ABSTRACT FROM AUTHOR]

Published
2015
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44. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Author

Zhou, Qing, Wang, Hongying, Schwartz, Daniella M, Stoffels, Monique, Park, Yong Hwan, Zhang, Yuan, Yang, Dan, Demirkaya, Erkan, Takeuchi, Masaki, Tsai, Wanxia Li, Lyons, Jonathan J, Yu, Xiaomin, Ouyang, Claudia, Chen, Celeste, Chin, David T, Zaal, Kristien, Chandrasekharappa, Settara C, P Hanson, Eric, Yu, Zhen, Mullikin, James C, Hasni, Sarfaraz A, Wertz, Ingrid E, Ombrello, Amanda K, Stone, Deborah L, Hoffmann, Patrycja, Jones, Anne, Barham, Beverly K, Leavis, Helen L, van Royen-Kerkof, Annet, Sibley, Cailin, Batu, Ezgi D, Gül, Ahmet, Siegel, Richard M, Boehm, Manfred, Milner, Joshua D, Ozen, Seza, Gadina, Massimo, Chae, JaeJin, Laxer, Ronald M, Kastner, Daniel L, and Aksentijevich, Ivona

Abstract

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB–mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB–dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

Published
2016
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46. Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne.

Author

Lee W, Stone DL, Hoffmann P, Rosenzweig S, Tsai WL, Gadina M, Romeo T, Lee CR, Randazzo D, Pimpale Chavan P, Manthiram K, Canna S, Park YH, Ombrello AK, Aksentijevich I, Kastner DL, and Chae JJ

Subjects
Humans, Animals, Mice, Janus Kinase Inhibitors therapeutic use, Janus Kinase Inhibitors pharmacology, Mice, Knockout, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Feedback, Physiological, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Pyrin genetics, Mutation, Phosphoproteins metabolism, Phosphoproteins genetics, Gene Knock-In Techniques, Interleukin-18 metabolism, THP-1 Cells, Pyoderma Gangrenosum genetics, Arthritis, Infectious, Acne Vulgaris immunology, Inflammasomes metabolism, Inflammasomes immunology, Disease Models, Animal, Interferon-gamma metabolism
Abstract

Objectives: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1 ., Methods: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients., Results: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement., Conclusion: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition., Competing Interests: Competing interests: SC has received consulting fees from Apollo Therapeutics and honorary speaker fees from Sobi and PracticePoint CME., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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47. Multiomics integration of 22 immune-mediated monogenic diseases reveals an emergent axis of human immune health.

Author

Sparks R, Rachmaninoff N, Hirsch DC, Bansal N, Lau WW, Martins AJ, Chen J, Liu CC, Cheung F, Failla LE, Biancotto A, Fantoni G, Sellers BA, Chawla DG, Howe KN, Mostaghimi D, Farmer R, Kotliarov Y, Calvo KR, Palmer C, Daub J, Foruraghi L, Kreuzburg S, Treat J, Urban AK, Jones A, Romeo T, Deuitch NT, Moura NS, Weinstein B, Moir S, Ferrucci L, Barron KS, Aksentijevich I, Kleinstein SH, Townsley DM, Young NS, Frischmeyer-Guerrerio PA, Uzel G, Pinto-Patarroyo GP, Cudrici CD, Hoffmann P, Stone DL, Ombrello AK, Freeman AF, Zerbe CS, Kastner DL, Holland SM, and Tsang JS

Abstract

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health., Competing Interests: Declaration of Interests The authors declare no competing interests.

Published
2023
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48. Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation.

Author

Chae JJ, Park YH, Park C, Hwang IY, Hoffmann P, Kehrl JH, Aksentijevich I, and Kastner DL

Subjects
Calcium metabolism, Calcium Channel Blockers pharmacology, Case-Control Studies, Endoplasmic Reticulum metabolism, Humans, Immune System Diseases genetics, Immune System Diseases pathology, Immune System Diseases physiopathology, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes pathology, Interleukin-1beta metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Lipopolysaccharides pharmacology, NLR Family, Pyrin Domain-Containing 3 Protein, Calcium Signaling physiology, Carrier Proteins physiology, Immunologic Deficiency Syndromes physiopathology, Inflammasomes physiology, Mutation genetics, Phospholipase C gamma genetics, Signal Transduction physiology
Abstract

Objective: We previously reported that p.Ser707Tyr, a novel variant in phospholipase Cγ2 (PLCγ2), is the cause of a dominantly inherited autoinflammatory disease, autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID). The hypermorphic mutation enhances PLCγ2 activity and causes an increase in intracellular Ca2+ release from endoplasmic reticulum stores. Because increased intracellular Ca2+ signaling has been associated with NLRP3 inflammasome activation, we studied the role of the NLRP3 inflammasome in the pathogenesis of APLAID., Methods: Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy control subjects and 2 patients with APLAID. Inflammasome activation was analyzed by Western blotting. Intracellular Ca2+ levels were measured with a FLIPR Calcium 4 assay kit., Results: Cells from the patients had elevated basal levels of intracellular Ca2+, and the intracellular Ca2+ flux triggered by extracellular CaCl2 was substantially enhanced. Patient PBMCs secreted interleukin-1β in response to lipopolysaccharide priming alone, and this effect was attenuated by treatment with a PLC inhibitor, intracellular Ca2+ blockers, or an adenylate cyclase activator., Conclusion: Our findings suggest that the inflammation in patients with APLAID is partially driven by activation of the NLRP3 inflammasome. These data link 2 seemingly distinct molecular pathways and provide new insights into the pathogenesis of APLAID and autoinflammation.

Published
2015
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