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929 results on '"Kastner, Daniel L."'

1. 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.

Published
2024
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2. 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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3. Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome

Author

Baghdassarian, Hratch, Blackstone, Sarah A, Clay, Owen S, Philips, Rachael, Matthiasardottir, Brynja, Nehrebecky, Michele, Hua, Vivian K, McVicar, Rachael, Liu, Yang, Tucker, Suzanne M, Randazzo, Davide, Deuitch, Natalie, Rosenzweig, Sofia, Mark, Adam, Sasik, Roman, Fisch, Kathleen M, Pimpale Chavan, Pallavi, Eren, Elif, Watts, Norman R, Ma, Chi A, Gadina, Massimo, Schwartz, Daniella M, Sanyal, Anwesha, Werner, Giffin, Murdock, David R, Horita, Nobuyuki, Chowdhury, Shimul, Dimmock, David, Jepsen, Kristen, Remmers, Elaine F, Goldbach-Mansky, Raphaela, Gahl, William A, O'Shea, John J, Milner, Joshua D, Lewis, Nathan E, Chang, Johanna, Kastner, Daniel L, Torok, Kathryn, Oda, Hirotsugu, Putnam, Christopher D, and Broderick, Lori

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Biotechnology, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Janus Kinases, Nitriles, Pyrazoles, Pyrimidines, Scleroderma, Systemic, Autoimmune Diseases, Mutation, Missense, Gain of Function Mutation, Dermatologic Agents, Anti-Inflammatory Agents, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDisabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high.MethodsWe evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy.ResultsGenome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.ConclusionsGain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

Published
2023

5. Venous and arterial thrombosis in patients with VEXAS syndrome

Author

Kusne, Yael, Ghorbanzadeh, Atefeh, Dulau-Florea, Alina, Shalhoub, Ruba, Alcedo, Pedro E., Nghiem, Khanh, Ferrada, Marcela A., Hines, Alexander, Quinn, Kaitlin A., Panicker, Sumith R., Ombrello, Amanda K., Reichard, Kaaren, Darden, Ivana, Goodspeed, Wendy, Durrani, Jibran, Wilson, Lorena, Olteanu, Horatiu, Lasho, Terra, Kastner, Daniel L., Warrington, Kenneth J., Mangaonkar, Abhishek, Go, Ronald S., Braylan, Raul C., Beck, David B., Patnaik, Mrinal M., Young, Neal S., Calvo, Katherine R., Casanegra, Ana I., Grayson, Peter C., Koster, Matthew J., Wu, Colin O., Kanthi, Yogendra, Patel, Bhavisha A., Houghton, Damon E., and Groarke, Emma M.

Published
2024
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6. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

Author

Beck, David B, Basar, Mohammed A, Asmar, Anthony J, Thompson, Joyce J, Oda, Hirotsugu, Uehara, Daniela T, Saida, Ken, Pajusalu, Sander, Talvik, Inga, D’Souza, Precilla, Bodurtha, Joann, Mu, Weiyi, Barañano, Kristin W, Miyake, Noriko, Wang, Raymond, Kempers, Marlies, Tamada, Tomoko, Nishimura, Yutaka, Okada, Satoshi, Kosho, Tomoki, Dale, Ryan, Mitra, Apratim, Macnamara, Ellen, Matsumoto, Naomichi, Inazawa, Johji, Walkiewicz, Magdalena, Õunap, Katrin, Tifft, Cynthia J, Aksentijevich, Ivona, Kastner, Daniel L, Rocha, Pedro P, and Werner, Achim

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Human Genome, Rare Diseases, Pediatric, Generic health relevance, Chromatin, Genomics, Humans, Signal Transduction, Ubiquitin, Ubiquitination, Undiagnosed Diseases Network
Abstract

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Published
2021

7. Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS

Author

Wu, Zhijie, Gao, Shouguo, Gao, Qingyan, Patel, Bhavisha A., Groarke, Emma M., Feng, Xingmin, Manley, Ash Lee, Li, Haoran, Ospina Cardona, Daniela, Kajigaya, Sachiko, Alemu, Lemlem, Quinones Raffo, Diego, Ombrello, Amanda K., Ferrada, Marcela A., Grayson, Peter C., Calvo, Katherine R., Kastner, Daniel L., Beck, David B., and Young, Neal S.

Published
2023
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8. Spectrum of clonal hematopoiesis in VEXAS syndrome

Author

Gutierrez-Rodrigues, Fernanda, Kusne, Yael, Fernandez, Jenna, Lasho, Terra, Shalhoub, Ruba, Ma, Xiaoyang, Alessi, Hugh, Finke, Christy, Koster, Matthew J., Mangaonkar, Abhishek, Warrington, Kenneth J., Begna, Kebede, Xie, Zhuoer, Ombrello, Amanda K., Viswanatha, David, Ferrada, Marcela, Wilson, Lorena, Go, Ronald, Kourelis, Taxiarchis, Reichard, Kaaren, Olteanu, Horatiu, Darden, Ivana, Hironaka, Dalton, Alemu, Lemlem, Kajigaya, Sachiko, Rosenzweig, Sofia, Calado, Rodrigo T., Groarke, Emma M., Kastner, Daniel L., Calvo, Katherine R., Wu, Colin O., Grayson, Peter C., Young, Neal S., Beck, David B., Patel, Bhavisha A., and Patnaik, Mrinal M.

Published
2023
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9. HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry

Author

Gourh, Pravitt, Safran, Sarah A, Alexander, Theresa, Boyden, Steven E, Morgan, Nadia D, Shah, Ami A, Mayes, Maureen D, Doumatey, Ayo, Bentley, Amy R, Shriner, Daniel, Domsic, Robyn T, Medsger, Thomas A, Ramos, Paula S, Silver, Richard M, Steen, Virginia D, Varga, John, Hsu, Vivien, Saketkoo, Lesley Ann, Schiopu, Elena, Khanna, Dinesh, Gordon, Jessica K, Kron, Brynn, Criswell, Lindsey A, Gladue, Heather, Derk, Chris T, Bernstein, Elana J, Bridges, S Louis, Shanmugam, Victoria K, Kolstad, Kathleen D, Chung, Lorinda, Kafaja, Suzanne, Jan, Reem, Trojanowski, Marcin, Goldberg, Avram, Korman, Benjamin D, Steinbach, Peter J, Chandrasekharappa, Settara C, Mullikin, James C, Adeyemo, Adebowale, Rotimi, Charles, Wigley, Fredrick M, Kastner, Daniel L, Boin, Francesco, and Remmers, Elaine F

Subjects
Biomedical and Clinical Sciences, Immunology, Autoimmune Disease, Clinical Research, Scleroderma, Genetics, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Black or African American, Alleles, Amino Acid Sequence, Antigens, Viral, Autoantibodies, Autoantigens, Computational Biology, Datasets as Topic, Female, Genetic Predisposition to Disease, HLA Antigens, Humans, Male, Mimiviridae, Molecular Mimicry, Phycodnaviridae, Protein Structure, Secondary, Risk Assessment, Scleroderma, Systemic, Sequence Homology, Amino Acid, White People, scleroderma, HLA, autoantibodies, molecular mimicry, mimivirus
Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Published
2020

10. 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

12. 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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14. Clinical and serological features of systemic sclerosis in a multicenter African American cohort

Author

Morgan, Nadia D, Shah, Ami A, Mayes, Maureen D, Domsic, Robyn T, Medsger, Thomas A, Steen, Virginia D, Varga, John, Carns, Mary, Ramos, Paula S, Silver, Richard M, Schiopu, Elena, Khanna, Dinesh, Hsu, Vivien, Gordon, Jessica K, Gladue, Heather, Saketkoo, Lesley A, Criswell, Lindsey A, Derk, Chris T, Trojanowski, Marcin A, Shanmugam, Victoria K, Chung, Lorinda, Valenzuela, Antonia, Jan, Reem, Goldberg, Avram, Remmers, Elaine F, Kastner, Daniel L, Wigley, Fredrick M, Gourh, Pravitt, and Boin, Francesco

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Lung, Autoimmune Disease, Rare Diseases, Scleroderma, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Inflammatory and immune system, Adult, Black or African American, Chromosome Mapping, Cohort Studies, Cross-Sectional Studies, Databases, Factual, Female, Humans, Male, Prevalence, Prospective Studies, Retrospective Studies, Scleroderma, Systemic, Severity of Illness Index, Socioeconomic Factors, United States, African Americans, autoantibodies, systemic sclerosis
Abstract

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

Published
2017

16. Common genetic susceptibility loci link PFAPA syndrome, Behçet’s disease, and recurrent aphthous stomatitis

Author

The Genomic Ascertainment Cohort, Manthiram, Kalpana, Preite, Silvia, Dedeoglu, Fatma, Demir, Selcan, Ozen, Seza, Edwards, Kathryn M., Lapidus, Sivia, Katz, Alexander E., Feder, Henry M., Lawton, Maranda, Licameli, Greg R., Wright, Peter F., Le, Julie, Barron, Karyl S., Ombrello, Amanda K., Barham, Beverly, Romeo, Tina, Jones, Anne, Srinivasalu, Hemalatha, Mudd, Pamela A., DeBiasi, Roberta L., Gül, Ahmet, Marshall, Gary S., Jones, Olcay Y., Chandrasekharappa, Settara C., Stepanovskiy, Yuriy, Ferguson, Polly J., Schwartzberg, Pamela L., Remmers, Elaine F., and Kastner, Daniel L.

Published
2020

17. 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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21. Control of the innate immune response by the mevalonate pathway

Author

Akula, Murali K, Shi, Man, Jiang, Zhaozhao, Foster, Celia E, Miao, David, Li, Annie S, Zhang, Xiaoman, Gavin, Ruth M, Forde, Sorcha D, Germain, Gail, Carpenter, Susan, Rosadini, Charles V, Gritsman, Kira, Chae, Jae Jin, Hampton, Randolph, Silverman, Neal, Gravallese, Ellen M, Kagan, Jonathan C, Fitzgerald, Katherine A, Kastner, Daniel L, Golenbock, Douglas T, Bergo, Martin O, and Wang, Donghai

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Immunology, Alkyl and Aryl Transferases, Animals, Cells, Cultured, Familial Mediterranean Fever, Humans, Immunity, Innate, Inflammasomes, Interleukin-1beta, Macrophages, Mice, Inbred C57BL, Mutation, Phosphatidylinositol 3-Kinases, Phosphotransferases (Alcohol Group Acceptor), Polyisoprenyl Phosphates, Protein Processing, Post-Translational, Pyrin, Signal Transduction, Toll-Like Receptors, Biochemistry and cell biology
Abstract

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Published
2016

23. Strategic vision for improving human health at The Forefront of Genomics

Author

Green, Eric D., Gunter, Chris, Biesecker, Leslie G., Di Francesco, Valentina, Easter, Carla L., Feingold, Elise A., Felsenfeld, Adam L., Kaufman, David J., Ostrander, Elaine A., Pavan, William J., Phillippy, Adam M., Wise, Anastasia L., Dayal, Jyoti Gupta, Kish, Britny J., Mandich, Allison, Wellington, Christopher R., Wetterstrand, Kris A., Bates, Sarah A., Leja, Darryl, Vasquez, Susan, Gahl, William A., Graham, Bettie J., Kastner, Daniel L., Liu, Paul, Rodriguez, Laura Lyman, Solomon, Benjamin D., Bonham, Vence L., Brody, Lawrence C., Hutter, Carolyn M., and Manolio, Teri A.

Published
2020
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24. 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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27. Effective Sample Size: Quick Estimation of the Effect of Related Samples in Genetic Case-Control Association Analyses

Author

Yang, Yaning, Remmers, Elaine F., Ogunwole, Chukwuma B., Kastner, Daniel L., Gregersen, Peter K., and Li, Wentian

Subjects
Quantitative Biology - Quantitative Methods
Abstract

Affected relatives are essential for pedigree linkage analysis, however, they cause a violation of the independent sample assumption in case-control association studies. To avoid the correlation between samples, a common practice is to take only one affected sample per pedigree in association analysis. Although several methods exist in handling correlated samples, they are still not widely used in part because these are not easily implemented, or because they are not widely known. We advocate the effective sample size method as a simple and accessible approach for case-control association analysis with correlated samples. This method modifies the chi-square test statistic, p-value, and 95% confidence interval of the odds-ratio by replacing the apparent number of allele or genotype counts with the effective ones in the standard formula, without the need for specialized computer programs. We present a simple formula for calculating effective sample size for many types of relative pairs and relative sets. For allele frequency estimation, the effective sample size method captures the variance inflation exactly. For genotype frequency, simulations showed that effective sample size provides a satisfactory approximation. A gene which is previously identified as a type 1 diabetes susceptibility locus, the interferon-induced helicase gene (IFIH1), is shown to be significantly associated with rheumatoid arthritis when the effective sample size method is applied. This significant association is not established if only one affected sib per pedigree were used in the association analysis. Relationship between the effective sample size method and other methods -- the generalized estimation equation, variance of eigenvalues for correlation matrices, and genomic controls -- are discussed., Comment: 3 figures

Published
2006
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28. Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis

Author

Meguro, Akira, Ishihara, Mami, Petrek, Martin, Yamamoto, Ken, Takeuchi, Masaki, Mrazek, Frantisek, Kolek, Vitezslav, Benicka, Alzbeta, Yamane, Takahiro, Shibuya, Etsuko, Yoshino, Atsushi, Isomoto, Akiko, Ota, Masao, Yatsu, Keisuke, Shijubo, Noriharu, Nagai, Sonoko, Yamaguchi, Etsuro, Yamaguchi, Tetsuo, Namba, Kenichi, Kaburaki, Toshikatsu, Takase, Hiroshi, Morimoto, Shin-ichiro, Hori, Junko, Kono, Keiko, Goto, Hiroshi, Suda, Takafumi, Ikushima, Soichiro, Ando, Yasutaka, Takenaka, Shinobu, Takeuchi, Masaru, Yuasa, Takenosuke, Sugisaki, Katsunori, Ohguro, Nobuyuki, Hiraoka, Miki, Kitaichi, Nobuyoshi, Sugiyama, Yukihiko, Horita, Nobuyuki, Asukata, Yuri, Kawagoe, Tatsukata, Kimura, Ikuko, Ishido, Mizuho, Inoko, Hidetoshi, Mochizuki, Manabu, Ohno, Shigeaki, Bahram, Seiamak, Remmers, Elaine F., Kastner, Daniel L., and Mizuki, Nobuhisa

Published
2020
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29. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

Author

Nakanishi, Hiroshi, Kawashima, Yoshiyuki, Kurima, Kiyoto, Chae, Jae Jin, Ross, Astin M., Pinto-Patarroyo, Gineth, Patel, Seema K., Muskett, Julie A., Ratay, Jessica S., Chattaraj, Parna, Park, Yong Hwan, Grevich, Sriharsha, Brewer, Carmen C., Hoa, Michael, Kim, H. Jeffrey, Butman, John A., Broderick, Lori, Hoffman, Hal M., Aksentijevich, Ivona, Kastner, Daniel L., Goldbach-Mansky, Raphaela, and Griffith, Andrew J.

Published
2017

30. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis

Author

Gregersen, Peter K, Amos, Chistopher I, Lee, Annette T, Lu, Yue, Remmers, Elaine F, Kastner, Daniel L, Seldin, Michael F, Criswell, Lindsey A, Plenge, Robert M, Holers, V Michael, Mikuls, Ted R, Sokka, Tuulikki, Moreland, Larry W, Bridges, S Louis, Xie, Gang, Begovich, Ann B, and Siminovitch, Katherine A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Clinical Research, Rheumatoid Arthritis, Autoimmune Disease, Arthritis, Inflammatory and immune system, Arthritis, Rheumatoid, Genes, rel, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 x 10(-14)) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 x 10(-11)) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappaB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ.

Published
2009

31. REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.

Author

Gregersen, Peter K, Amos, Chistopher I, Lee, Annette T, Lu, Yue, Remmers, Elaine F, Kastner, Daniel L, Seldin, Michael F, Criswell, Lindsey A, Plenge, Robert M, Holers, V Michael, Mikuls, Ted R, Sokka, Tuulikki, Moreland, Larry W, Bridges, S Louis, Xie, Gang, Begovich, Ann B, and Siminovitch, Katherine A

Subjects
Humans, Arthritis, Rheumatoid, Polymorphism, Single Nucleotide, Genes, rel, Genome-Wide Association Study, Arthritis, Rheumatoid, Polymorphism, Single Nucleotide, Genes, rel, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 x 10(-14)) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 x 10(-11)) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappaB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ.

Published
2009

33. A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.

Author

Chang, Monica, Rowland, Charles M, Garcia, Veronica E, Schrodi, Steven J, Catanese, Joseph J, van der Helm-van Mil, Annette HM, Ardlie, Kristin G, Amos, Christopher I, Criswell, Lindsey A, Kastner, Daniel L, Gregersen, Peter K, Kurreeman, Fina AS, Toes, Rene EM, Huizinga, Tom WJ, Seldin, Michael F, and Begovich, Ann B

Subjects
Chromosomes, Human, Pair 9, Humans, Arthritis, Rheumatoid, Genetic Predisposition to Disease, TNF Receptor-Associated Factor 1, Nuclear Proteins, DNA, Intergenic, Genetic Markers, Rheumatoid Factor, Logistic Models, Risk Factors, Case-Control Studies, Physical Chromosome Mapping, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, European Continental Ancestry Group, North America, Netherlands, Female, Male, Genetic Variation, DNA-Binding Proteins, Transcription Factors, Arthritis, Rheumatoid, Chromosomes, Human, Pair 9, DNA, Intergenic, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb) 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

Published
2008

38. Pathogenesis

Author

Chae, Jae Jin, Kastner, Daniel L., Emmi, Lorenzo, Series editor, Prisco, Domenico, Series editor, and Gattorno, Marco, editor

Published
2015
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40. Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB–Mediated Autoinflammatory Disease with Retinal Dystrophy

Author

Huryn, Laryssa A., primary, Kozycki, Christina Torres, additional, Serpen, Jasmine Y., additional, Zein, Wadih M., additional, Ullah, Ehsan, additional, Iannaccone, Alessandro, additional, Williams, Lloyd B., additional, Sobrin, Lucia, additional, Brooks, Brian P., additional, Sen, H. Nida, additional, Hufnagel, Robert B., additional, Kastner, Daniel L., additional, and Kodati, Shilpa, additional

Published
2023
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42. Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

Author

Research UMC Utrecht, Cluster B, Immuno/reuma patientenzorg, Child Health, Infection & Immunity, Lee, Pui Y., Davidson, Brad A., Abraham, Roshini S., Alter, Blanche, Arostegui, Juan I., Bell, Katherine, Belot, Alexandre, Bergerson, Jenna R.E., Bernard, Timothy J., Brogan, Paul A., Berkun, Yackov, Deuitch, Natalie T., Dimitrova, Dimana, Georgin-Lavialle, Sophie A., Gattorno, Marco, Grimbacher, Bodo, Hashem, Hasan, Hershfield, Michael S., Ichord, Rebecca N., Izawa, Kazushi, Kanakry, Jennifer A., Khubchandani, Raju P., Klouwer, Femke C.C., Luton, Evan A., Man, Ada W., Meyts, Isabelle, Van Montfrans, Joris M., Ozen, Seza, Saarela, Janna, Santo, Gustavo C., Sharma, Aman, Soldatos, Ariane, Sparks, Rachel, Torgerson, Troy R., Uriarte, Ignacio Leandro, Youngstein, Taryn A.B., Zhou, Qing, Aksentijevich, Ivona, Kastner, Daniel L., Chambers, Eugene P., Ombrello, Amanda K., Research UMC Utrecht, Cluster B, Immuno/reuma patientenzorg, Child Health, Infection & Immunity, Lee, Pui Y., Davidson, Brad A., Abraham, Roshini S., Alter, Blanche, Arostegui, Juan I., Bell, Katherine, Belot, Alexandre, Bergerson, Jenna R.E., Bernard, Timothy J., Brogan, Paul A., Berkun, Yackov, Deuitch, Natalie T., Dimitrova, Dimana, Georgin-Lavialle, Sophie A., Gattorno, Marco, Grimbacher, Bodo, Hashem, Hasan, Hershfield, Michael S., Ichord, Rebecca N., Izawa, Kazushi, Kanakry, Jennifer A., Khubchandani, Raju P., Klouwer, Femke C.C., Luton, Evan A., Man, Ada W., Meyts, Isabelle, Van Montfrans, Joris M., Ozen, Seza, Saarela, Janna, Santo, Gustavo C., Sharma, Aman, Soldatos, Ariane, Sparks, Rachel, Torgerson, Troy R., Uriarte, Ignacio Leandro, Youngstein, Taryn A.B., Zhou, Qing, Aksentijevich, Ivona, Kastner, Daniel L., Chambers, Eugene P., and Ombrello, Amanda K.

Published
2023

43. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease

Author

Zhou, Qing, Yu, Xiaomin, Demirkaya, Erkan, Deuitch, Natalie, Stone, Deborah, Tsai, Wanxia Li, Kuehn, Hye Sun, Wang, Hongying, Yang, Dan, Park, Yong Hwan, Ombrello, Amanda K., Blake, Mary, Romeo, Tina, Remmers, Elaine F., Chae, Jae Jin, Mullikin, James C., Güzel, Ferhat, Milner, Joshua D., Boehm, Manfred, Rosenzweig, Sergio D., Gadina, Massimo, Welch, Steven B., Özen, Seza, Topaloglu, Rezan, Abinun, Mario, Kastner, Daniel L., and Aksentijevich, Ivona

Published
2016

44. Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

Author

Lee, Pui Y, Davidson, Brad A, Abraham, Roshini S, Alter, Blanche, Arostegui, Juan I, Bell, Katherine, Belot, Alexandre, Bergerson, Jenna RE, Bernard, Timothy J, Brogan, Paul A, Berkun, Yackov, Deuitch, Natalie T, Dimitrova, Dimana, Georgin-Lavialle, Sophie A, Gattorno, Marco, Grimbacher, Bodo, Hashem, Hasan, Hershfield, Michael S, Ichord, Rebecca N, Izawa, Kazushi, Kanakry, Jennifer A, Khubchandani, Raju P, Klouwer, Femke CC, Luton, Evan A, Man, Ada W, Meyts, Isabelle, Van Montfrans, Joris M, Ozen, Seza, Saarela, Janna, Santo, Gustavo C, Sharma, Aman, Soldatos, Ariane, Sparks, Rachel, Torgerson, Troy R, Uriarte, Ignacio Leandro, Youngstein, Taryn AB, Zhou, Qing, Aksentijevich, Ivona, Kastner, Daniel L, Chambers, Eugene P, Ombrello, Amanda K, and DADA2 Foundation

Subjects
Heterozygote, Phenotype, Adenosine Deaminase, Intercellular Signaling Peptides and Proteins
Abstract

IMPORTANCE: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. OBJECTIVE: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. EVIDENCE REVIEW: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. FINDINGS: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. CONCLUSIONS AND RELEVANCE: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2. ispartof: JAMA Netw Open vol:6 issue:5 pages:e2315894- ispartof: location:United States status: Published online

Published
2023

45. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Author

British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group, International Childhood Arthritis Genetics (INCHARGE) Consortium, Ombrello, Michael J., Remmers, Elaine F., Tachmazidou, Ioanna, Grom, Alexei, Foell, Dirk, Haas, Johannes-Peter, Martini, Alberto, Gattorno, Marco, Özen, Seza, Prahalad, Sampath, Zeft, Andrew S., Bohnsack, John F., Mellins, Elizabeth D., Ilowite, Norman T., Russo, Ricardo, Len, Claudio, Hilario, Maria Odete E., Oliveira, Sheila, Yeung, Rae S.M., Rosenberg, Alan, Wedderburn, Lucy R., Anton, Jordi, Schwarz, Tobias, Hinks, Anne, Bilginer, Yelda, Park, Jane, Cobb, Joanna, Satorius, Colleen L., Han, Buhm, Baskin, Elizabeth, Signa, Sara, Duerr, Richard H., Achkar, J. P., Kamboh, M. Ilyas, Kaufman, Kenneth M., Kottyan, Leah C., Pinto, Dalila, Scherer, Stephen W., Alarcón-Riquelme, Marta E., Docampo, Elisa, Estivill, Xavier, Gül, Ahmet, de Bakker, Paul I. W., Raychaudhuri, Soumya, Langefeld, Carl D., Thompson, Susan, Zeggini, Eleftheria, Thomson, Wendy, Kastner, Daniel L., and Woo, Patricia

Published
2015

46. 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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47. Case report: Novel variants in RELA associated with familial Behcet’s-like disease

Author

An, Jason W., primary, Pimpale-Chavan, Pallavi, additional, Stone, Deborah L., additional, Bandeira, Marcia, additional, Dedeoglu, Fatma, additional, Lo, Jeffrey, additional, Bohnsack, John, additional, Rosenzweig, Sofia, additional, Schnappauf, Oskar, additional, Dissanayake, Dilan, additional, Hiraki, Linda T., additional, Kastner, Daniel L., additional, Pelajo, Christina, additional, Laxer, Ronald M., additional, and Aksentijevich, Ivona, additional

Published
2023
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48. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Author

Beck, David B., primary, Bodian, Dale L., additional, Shah, Vandan, additional, Mirshahi, Uyenlinh L., additional, Kim, Jung, additional, Ding, Yi, additional, Magaziner, Samuel J., additional, Strande, Natasha T., additional, Cantor, Anna, additional, Haley, Jeremy S., additional, Cook, Adam, additional, Hill, Wesley, additional, Schwartz, Alan L., additional, Grayson, Peter C., additional, Ferrada, Marcela A., additional, Kastner, Daniel L., additional, Carey, David J., additional, and Stewart, Douglas R., additional

Published
2023
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49. Author Correction: A guiding map for inflammation

Author

Netea, Mihai G., Balkwill, Frances, Chonchol, Michel, Cominelli, Fabio, Donath, Marc Y., Giamarellos-Bourboulis, Evangelos J., Golenbock, Douglas, Gresnigt, Mark S., Heneka, Michael T., Hoffman, Hal M., Hotchkiss, Richard, Joosten, Leo A. B., Kastner, Daniel L., Korte, Martin, Latz, Eicke, Libby, Peter, Mandrup-Poulsen, Thomas, Mantovani, Alberto, Mills, Kingston H. G., Nowak, Kristen L., O’Neill, Luke A., Pickkers, Peter, van der Poll, Tom, Ridker, Paul M., Schalkwijk, Joost, Schwartz, David A., Siegmund, Britta, Steer, Clifford J., Tilg, Herbert, van der Meer, Jos W. M., van de Veerdonk, Frank L., and Dinarello, Charles A.

Published
2021
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