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1. A human autoimmune organoid model reveals IL-7 function in coeliac disease

Author

Santos, António J. M., van Unen, Vincent, Lin, Zhongqi, Chirieleison, Steven M., Ha, Nhi, Batish, Arpit, Chan, Joshua E., Cedano, Jose, Zhang, Elisa T., Mu, Qinghui, Guh-Siesel, Alexander, Tomaske, Madeline, Colburg, Deana, Varma, Sushama, Choi, Shannon S., Christophersen, Asbjørn, Baghdasaryan, Ani, Yost, Kathryn E., Karlsson, Kasper, Ha, Andrew, Li, Jing, Dai, Hongjie, Sellers, Zachary M., Chang, Howard Y., Dunn, James C. Y., Zhang, Bing M., Mellins, Elizabeth D., Sollid, Ludvig M., Fernandez-Becker, Nielsen Q., Davis, Mark M., and Kuo, Calvin J.

Published
2024
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2. Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis

Author

Vastert, Sebastiaan J., Canny, Susan P., Canna, Scott W., Schneider, Rayfel, Mellins, Elizabeth D., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, Cron, Randy Q., editor, and Behrens, Edward M., editor

Published
2024
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3. Interleukin (IL)-1/IL-6-Inhibitor–Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses

Author

Aamir, R., Abulaban, K., Adams, A., Lapsia, C. Aguiar, Akinsete, A., Akoghlanian, S., Al Manaa, M., AlBijadi, A., Allenspach, E., Almutairi, A., Alperin, R., Amarilyo, G., Ambler, W., Amoruso, M., Angeles-Han, S., Ardoin, S., Armendariz, S., Asfaw, L., Aviran Dagan, N., Bacha, C., Balboni, I., Balevic, S., Ballinger, S., Baluta, S., Barillas-Arias, L., Basiaga, M., Baszis, K., Baxter, S., Becker, M., Begezda, A., Behrens, E., Beil, E., Benseler, S., Bermudez-Santiago, L., Bernal, W., Bigley, T., Bingham, C., Binstadt, B., Black, C., Blackmon, B., Blakley, M., Bohnsack, J., Boneparth, A., Bradfield, H., Bridges, J., Brooks, E., Brothers, M., Brunner, H., Buckley, L., Buckley, M., Bukulmez, H., Bullock, D., Canna, S., Cannon, L., Canny, S., Cartwright, V., Cassidy, E., Castro, D., Chalom, E., Chang, J., Chang, M., Chang-Hoftman, A., Chen, A., Chiraseveenuprapund, P., Ciaglia, K., Co, D., Cohen, E., Collinge, J., Conlon, H., Connor, R., Cook, K., Cooper, A., Cooper, J., Corbin, K., Correll, C., Cron, R., Curry, M., Dalrymple, A., Datyner, E., Davis, T., De Ranieri, D., Dean, J., DeCoste, C., Dedeoglu, F., DeGuzman, M., Delnay, N., DeSantis, E., Devine, R., Dhalla, M., Dhanrajani, A., Dissanayake, D., Dizon, B., Drapeau, N., Drew, J., Driest, K., Du, Q., Duncan, E., Dunnock, K., Durkee, D., Dvergsten, J., Eberhard, A., Ede, K., Edelheit, B., Edens, C., El Tal, T., Elder, M., Elzaki, Y., Fadrhonc, S., Failing, C., Fair, D., Favier, L., Feldman, B., Fennell, J., Ferguson, P., Ferguson, I., Figueroa, C., Flanagan, E., Fogel, L., Fox, E., Fox, M., Franklin, L., Fuhlbrigge, R., Fuller, J., Furey, M., Futch-West, T., Gagne, S., Gennaro, V., Gerstbacher, D., Gilbert, M., Gironella, A., Glaser, D., Goh, I., Goldsmith, D., Gorry, S., Goswami, N., Gottlieb, B., Graham, T., Grevich, S., Griffin, T., Grim, A., Grom, A., Guevara, M., Hahn, T., Halyabar, O., Hamda Natur, M., Hammelev, E., Hammond, T., Harel, L., Harris, J., Harry, O., Hausmann, J., Hay, A., Hays, K., Hayward, K., Henderson, L., Henrickson, M., Hersh, A., Hickey, K., Hiraki, L., Hiskey, M., Hobday, P., Hoffart, C., Holland, M., Hollander, M., Hong, S., Horton, D., Horwitz, M., Hsu, J., Huber, A., Huberts, A., Huggins, J., Huie, L., Hui-Yuen, J., Ibarra, M., Imlay, A., Imundo, L., Inman, C., Jackson, A., James, K., Janow, G., Jared, S., Jiang, Y., Johnson, L., Johnson, N., Jones, J., Kafisheh, D., Kahn, P., Kaidar, K., Kasinathan, S., Kaur, R., Kessler, E., Kienzle, B., Kim, S., Kimura, Y., Kingsbury, D., Kitcharoensakkul, M., Klausmeier, T., Klein, K., Klein-Gitelman, M., Knight, A., Kovalick, L., Kramer, S., Kremer, C., Kudas, O., LaFlam, T., Lang, B., Lapidus, S., Lapin, B., Lasky, A., Lawler, C., Lawson, E., Laxer, R., Lee, P., Lee, T., Lee, A., Leisinger, E., Lentini, L., Lerman, M., Levinsky, Y., Levy, D., Li, S., Lieberman, S., Lim, L., Limenis, E., Lin, C., Ling, N., Lionetti, G., Livny, R., Lloyd, M., Lo, M., Long, A., Lopez-Peña, M., Lovell, D., Luca, N., Lvovich, S., Lytch, A., Ma, M., Machado, A., MacMahon, J., Madison, J., Mannion, M., Manos, C., Mansfield, L., Marston, B., Mason, T., Matchett, D., McAllister, L., McBrearty, K., McColl, J., McCurdy, D., McDaniels, K., McDonald, J., Meidan, E., Mellins, E., Mian, Z., Miettunen, P., Miller, M., Milojevic, D., Mitacek, R., Modica, R., Mohan, S., Moore, T., Moore, K., Moorthy, L., Moreno, J., Morgan, E., Moyer, A., Murante, B., Murphy, A., Muscal, E., Mwizerwa, O., Najafi, A., Nanda, K., Nasah, N., Nassi, L., Nativ, S., Natter, M., Nearanz, K., Neely, J., Newhall, L., Nguyen, A., Nigrovic, P., Nocton, J., Nolan, B., Nowicki, K., Oakes, R., Oberle, E., Ogbonnaya-Whittesley, S., Ogbu, E., Oliver, M., Olveda, R., Onel, K., Orandi, A., Padam, J., Paller, A., Pan, N., Pandya, J., Panupattanapong, S., Toledano, A. Pappo, Parsons, A., Patel, J., Patel, P., Patrick, A., Patrizi, S., Paul, S., Perfetto, J., Perron, M., Peskin, M., Ponder, L., Pooni, R., Prahalad, S., Puplava, B., Quinlan-Waters, M., Rabinovich, C., Rafko, J., Rahimi, H., Rampone, K., Ramsey, S., Randell, R., Ray, L., Reed, A., Reid, H., Reiff, D., Richins, S., Riebschleger, M., Rife, E., Riordan, M., Riskalla, M., Robinson, A., Robinson, L., Rodgers, L., Rodriquez, M., Rogers, D., Ronis, T., Rosado, A., Rosenkranz, M., Rosenwasser, N., Rothermel, H., Rothman, D., Rothschild, E., Roth-Wojcicki, E., Rouster-Stevens, K., Rubinstein, T., Rupp, J., Ruth, N., Sabbagh, S., Sadun, R., Santiago, L., Saper, V., Sarkissian, A., Scalzi, L., Schahn, J., Schikler, K., Schlefman, A., Schmeling, H., Schmitt, E., Schneider, R., Schulert, G., Schultz, K., Schutt, C., Seper, C., Sheets, R., Shehab, A., Shenoi, S., Sherman, M., Shirley, J., Shishov, M., Siegel, D., Singer, N., Sivaraman, V., Sloan, E., Smith, C., Smith, J., Smitherman, E., Soep, J., Son, Mary B., Sosna, D., Spencer, C., Spiegel, L., Spitznagle, J., Srinivasalu, H., Stapp, H., Steigerwald, K., Stephens, A., Sterba Rakovchik, Y., Stern, S., Stevens, B., Stevenson, R., Stewart, K., Stewart, W., Stingl, C., Stoll, M., Stringer, E., Sule, S., Sullivan, J., Sundel, R., Sutter, M., Swaffar, C., Swayne, N., Syed, R., Symington, T., Syverson, G., Szymanski, A., Taber, S., Tal, R., Tambralli, A., Taneja, A., Tanner, T., Tarvin, S., Tate, L., Taxter, A., Taylor, J., Tesher, M., Thakurdeen, T., Theisen, A., Thomas, B., Thomas, L., Thomas, N., Ting, T., Todd, C., Toib, D., Torok, K., Tory, H., Toth, M., Tse, S., Tsin, C., Twachtman-Bassett, J., Twilt, M., Valcarcel, T., Valdovinos, R., Vallee, A., Van Mater, H., Vandenbergen, S., Vannoy, L., Varghese, C., Vasquez, N., Vega-Fernandez, P., Velez, J., Verbsky, J., Verstegen, R., von Scheven, E., Vora, S., Wagner-Weiner, L., Wahezi, D., Waite, H., Walker, B., Walters, H., Waterfield, M., Waters, A., Weiser, P., Weiss, P., Weiss, J., Wershba, E., Westheuser, V., White, A., Widrick, K., Williams, C., Wong, S., Woolnough, L., Wright, T., Wu, E., Yalcindag, A., Yasin, S., Yeung, R., Yomogida, K., Zeft, A., Zhang, Y., Zhao, Y., Zhu, A., Saper, Vivian E., Tian, Lu, Verstegen, Ruud H.J., Conrad, Carol K., Cidon, Michal, Hopper, Rachel K., Kuo, Christin S., Osoegawa, Kazutoyo, Baszis, Kevin, Bingham, Catherine A., Ferguson, Ian, Hahn, Timothy, Horne, Annacarin, Isupova, Eugenia A., Jones, Jordan T., Kasapcopur, Özgür, Klein-Gitelman, Marisa S., Kostik, Mikhail M., Ozen, Seza, Phadke, Omkar, Prahalad, Sampath, Randell, Rachel L., Sener, Seher, Stingl, Cory, Abdul-Aziz, Rabheh, Akoghlanian, Shoghik, Al Julandani, Dalila, Alvarez, Marcela B., Bader-Meunier, Brigitte, Balay-Dustrude, Erin E., Balboni, Imelda, Baxter, Sarah K., Berard, Roberta A., Bhattad, Sagar, Bolaria, Roxana, Boneparth, Alexis, Cassidy, Elaine A., Co, Dominic O., Collins, Kathleen P., Dancey, Paul, Dickinson, Aileen M., Edelheit, Barbara S., Espada, Graciela, Flanagan, Elaine R., Imundo, Lisa F., Jindal, Ankur K., Kim, Hyoun-Ah, Klaus, Günter, Lake, Carol, Lapin, W. Blaine, Lawson, Erica F., Marmor, Itay, Mombourquette, Joy, Ogunjimi, Benson, Olveda, Rebecca, Ombrello, Michael J., Onel, Karen, Poholek, Catherine, Ramanan, Athimalaipet V., Ravelli, Angelo, Reinhardt, Adam, Robinson, Amanda D., Rouster-Stevens, Kelly, Saad, Nadine, Schneider, Rayfel, Selmanovic, Velma, Sefic Pasic, Irmina, Shenoi, Susan, Shilo, Natalie R., Soep, Jennifer B., Sura, Angeli, Taber, Sarah F., Tesher, Melissa, Tibaldi, Jessica, Torok, Kathryn S., Tsin, Cathy Mei, Vasquez-Canizares, Natalia, Villacis Nunez, Diana S., Way, Emily E., Whitehead, Benjamin, Zemel, Lawrence S., Sharma, Surbhi, Fernández-Viña, Marcelo A., and Mellins, Elizabeth D.

Published
2024
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4. Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity

Author

Chakraborty, Saborni, Gonzalez, Joseph C, Sievers, Benjamin L, Mallajosyula, Vamsee, Chakraborty, Srijoni, Dubey, Megha, Ashraf, Usama, Cheng, Bowie Yik-Ling, Kathale, Nimish, Tran, Kim Quyen Thi, Scallan, Courtney, Sinnott, Aanika, Cassidy, Arianna, Chen, Steven T, Gelbart, Terri, Gao, Fei, Golan, Yarden, Ji, Xuhuai, Kim-Schulze, Seunghee, Prahl, Mary, Gaw, Stephanie L, Gnjatic, Sacha, Marron, Thomas U, Merad, Miriam, Arunachalam, Prabhu S, Boyd, Scott D, Davis, Mark M, Holubar, Marisa, Khosla, Chaitan, Maecker, Holden T, Maldonado, Yvonne, Mellins, Elizabeth D, Nadeau, Kari C, Pulendran, Bali, Singh, Upinder, Subramanian, Aruna, Utz, Paul J, Sherwood, Robert, Zhang, Sheng, Jagannathan, Prasanna, Tan, Gene S, and Wang, Taia T

Subjects
Biomedical and Clinical Sciences, Immunology, Infectious Diseases, Pneumonia & Influenza, Lung, Vaccine Related, Pneumonia, Prevention, Biotechnology, Immunization, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Respiratory, Good Health and Well Being, Antibodies, Neutralizing, Antibodies, Viral, Antibody Formation, COVID-19, COVID-19 Vaccines, Humans, Prospective Studies, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19.

Published
2022

5. Multicohort Analysis Identifies Monocyte Gene Signatures to Accurately Monitor Subset-Specific Changes in Human Diseases

Author

Vallania, Francesco, Zisman, Liron, Macaubas, Claudia, Hung, Shu-Chen, Rajasekaran, Narendiran, Mason, Sonia, Graf, Jonathan, Nakamura, Mary, Mellins, Elizabeth D, and Khatri, Purvesh

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Prevention, Human Genome, Biotechnology, Detection, screening and diagnosis, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Biomarkers, Cell Plasticity, Computational Biology, Disease Susceptibility, Flow Cytometry, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Homeostasis, Humans, Immunophenotyping, Monocytes, Signal Transduction, Transcriptome, Systems Immunology, Gene signatures, monocyte subsets, gene expression, flow cytometry markers, Immunology, Medical Microbiology, Biochemistry and cell biology
Abstract

Monocytes are crucial regulators of inflammation, and are characterized by three distinct subsets in humans, of which classical and non-classical are the most abundant. Different subsets carry out different functions and have been previously associated with multiple inflammatory conditions. Dissecting the contribution of different monocyte subsets to disease is currently limited by samples and cohorts, often resulting in underpowered studies and poor reproducibility. Publicly available transcriptome profiles provide an alternative source of data characterized by high statistical power and real-world heterogeneity. However, most transcriptome datasets profile bulk blood or tissue samples, requiring the use of in silico approaches to quantify changes in cell levels. Here, we integrated 853 publicly available microarray expression profiles of sorted human monocyte subsets from 45 independent studies to identify robust and parsimonious gene expression signatures, consisting of 10 genes specific to each subset. These signatures maintain their accuracy regardless of disease state in an independent cohort profiled by RNA-sequencing and are specific to their respective subset when compared to other immune cells from both myeloid and lymphoid lineages profiled across 6160 transcriptome profiles. Consequently, we show that these signatures can be used to quantify changes in monocyte subsets levels in expression profiles from patients in clinical trials. Finally, we show that proteins encoded by our signature genes can be used in cytometry-based assays to specifically sort monocyte subsets. Our results demonstrate the robustness, versatility, and utility of our computational approach and provide a framework for the discovery of new cellular markers.

Published
2021

6. mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome

Author

Huang, Zhengping, You, Xiaomeng, Chen, Liang, Du, Yan, Brodeur, Kailey, Jee, Hyuk, Wang, Qiang, Linder, Grace, Darbousset, Roxane, Cunin, Pierre, Chang, Margaret H., Wactor, Alexandra, Wauford, Brian M., Todd, Marc J. C., Wei, Kevin, Li, Ying, Levescot, Anais, Iwakura, Yoichiro, Pascual, Virginia, Baldwin, Nicole E., Quartier, Pierre, Li, Tianwang, Gianatasio, Maria T., Hasserjian, Robert P., Henderson, Lauren A., Sykes, David B., Mellins, Elizabeth D., Canna, Scott W., Charles, Julia F., Nigrovic, Peter A., and Lee, Pui Y.

Published
2022
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7. IVIG response in pediatric acuteonset neuropsychiatric syndrome correlates with reduction in proinflammatory monocytes and neuropsychiatric measures.

Author

Melamed, Isaac, Rahman, Shamma, Pein, Heather, Heffron, Melinda, Frankovich, Jennifer, Kreuwel, Huub, and Mellins, Elizabeth D.

Abstract

Introduction: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder or eating restriction along with the abrupt onset of other co-occurring symptoms (tics, behavioral and cognitive regression, etc.). PANS is thought to be a postinfectious immunopsychiatric disorder, although as with most post-infectious disorders, it is challenging to establish a causal relationship with proposed infectious triggers. Intravenous immunoglobulin (IVIG) can modulate inflammation and support the elimination of infection and has been used for treatment of many post-infectious inflammatory disorders and autoimmune conditions. The aim of the study is to explore the pro-inflammatory state in PANS before and after administration of IVIG. Methods: Children with moderate-to-severe PANS received six infusions of IVIG (Octagam 5%, Octapharma) every 3 weeks with post treatment follow-up. Blood samples and psychiatric measures were obtained at Visits 1 (pre-treatment), 7 and 8 (4 and 11 weeks after last infusion, respectively). Myeloid cell activation was assessed via flow cytometry. Results: All ten patients included in the study were male, White, with mean age 12.4 years (range 6–16). Statistically significant improvements following IVIG treatment were demonstrated in all psychometric assessments and parent questionnaires including CY-BOCS (obsessive compulsive scale), YGTSS (tic scale) and a parent PANS rating scale (for all scales p<0.001). The fraction of pro-inflammatory monocytes and dendritic cells decreased from pre-IVIG treatment levels. The proportional reductions were not compensated by increases in total white blood cells; pro-inflammatory monocytes post-IVIG were decreased as a proportion of CD14+ myeloid cells and in absolute number. Conclusions: The results of this study suggest that active PANS is associated with a pro-inflammatory state. This pro-inflammatory profile and psychometric scores improved following IVIG treatment. Future work will aim to further elucidate the roles of innate and adaptive immune responses in PANS and the regulatory mechanism(s) of IVIG in PANS treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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8. IVIG response in pediatric acuteonset neuropsychiatric syndrome correlates with reduction in pro-inflammatory monocytes and neuropsychiatric measures.

Author

Melamed, Isaac, Rahman, Shamma, Pein, Heather, Heffron, Melinda, Frankovich, Jennifer, Kreuwel, Huub, and Mellins, Elizabeth D.

Subjects
LEUCOCYTES, MYELOID cells, POST-infectious disorders, STREPTOCOCCAL diseases, INFLAMMATION
Abstract

Introduction: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder or eating restriction along with the abrupt onset of other co-occurring symptoms (tics, behavioral and cognitive regression, etc.). PANS is thought to be a postinfectious immunopsychiatric disorder, although as with most post-infectious disorders, it is challenging to establish a causal relationship with proposed infectious triggers. Intravenous immunoglobulin (IVIG) can modulate inflammation and support the elimination of infection and has been used for treatment of many post-infectious inflammatory disorders and autoimmune conditions. The aim of the study is to explore the pro-inflammatory state in PANS before and after administration of IVIG. Methods: Children with moderate-to-severe PANS received six infusions of IVIG (Octagam 5%, Octapharma) every 3 weeks with post treatment follow-up. Blood samples and psychiatric measures were obtained at Visits 1 (pre-treatment), 7 and 8 (4 and 11 weeks after last infusion, respectively). Myeloid cell activation was assessed via flow cytometry. Results: All ten patients included in the study were male, White, with mean age 12.4 years (range 6-16). Statistically significant improvements following IVIG treatment were demonstrated in all psychometric assessments and parent questionnaires including CY-BOCS (obsessive compulsive scale), YGTSS (tic scale) and a parent PANS rating scale (for all scales p<0.001). The fraction of pro-inflammatory monocytes and dendritic cells decreased from pre-IVIG treatment levels. The proportional reductions were not compensated by increases in total white blood cells; pro-inflammatory monocytes post-IVIG were decreased as a proportion of CD14+ myeloid cells and in absolute number. Conclusions: The results of this study suggest that active PANS is associated with a pro-inflammatory state. This pro-inflammatory profile and psychometric scores improved following IVIG treatment. Future work will aim to further elucidate the roles of innate and adaptive immune responses in PANS and the regulatory mechanism(s) of IVIG in PANS treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation

Author

Cheung, Peggie, Schaffert, Steven, Chang, Sarah E., Dvorak, Mai, Donato, Michele, Macaubas, Claudia, Foecke, Mariko H., Li, Tie-Mei, Zhang, Lichao, Coan, John P., Schulert, Grant S., Grom, Alexei A., Henderson, Lauren A., Nigrovic, Peter A., Elias, Joshua E., Gozani, Or, Mellins, Elizabeth D., Khatri, Purvesh, Utz, Paul J., and Kuo, Alex J.

Published
2021
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11. Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis

Author

Infection & Immunity, Immunologie/Reumatologie, Immuno/reuma onderzoek 1 (Vastert), CTI Van Loosdregt, Child Health, Vastert, Sebastiaan J., Canny, Susan P., Canna, Scott W., Schneider, Rayfel, Mellins, Elizabeth D., Infection & Immunity, Immunologie/Reumatologie, Immuno/reuma onderzoek 1 (Vastert), CTI Van Loosdregt, Child Health, Vastert, Sebastiaan J., Canny, Susan P., Canna, Scott W., Schneider, Rayfel, and Mellins, Elizabeth D.

Published
2024

14. A general platform for targeting MHC-II antigens via a single loop

Author

Du, Haotian, primary, Liu, Jingjia, additional, Jude, Kevin M., additional, Yang, Xinbo, additional, Li, Ying, additional, Bell, Braxton, additional, Yang, Hongli, additional, Kassardjian, Audrey, additional, Mobedi, Ali, additional, Parekh, Udit, additional, Sperberg, R. Andres Parra, additional, Julien, Jean-Philippe, additional, Mellins, Elizabeth D., additional, Garcia, K. Christopher, additional, and Huang, Po-Ssu, additional

Published
2024
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16. Assembly and architecture of the EBV B cell entry triggering complex.

Author

Sathiyamoorthy, Karthik, Jiang, Jiansen, Hu, Yao Xiong, Rowe, Cynthia L, Möhl, Britta S, Chen, Jia, Jiang, Wei, Mellins, Elizabeth D, Longnecker, Richard, Zhou, Z Hong, and Jardetzky, Theodore S

Subjects
B-Lymphocytes, CHO Cells, Animals, Cricetulus, Herpesvirus 4, Human, Epstein-Barr Virus Infections, Membrane Glycoproteins, Molecular Chaperones, Viral Proteins, Viral Envelope Proteins, HLA-DQ Antigens, Microscopy, Electron, Image Processing, Computer-Assisted, Cricetinae, Virus Internalization, Host-Parasite Interactions, Infectious Diseases, Rare Diseases, Hematology, Lymphoma, Cancer, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 1.1 Normal biological development and functioning, Infection, Virology, Microbiology, Immunology, Medical Microbiology
Abstract

Epstein-Barr Virus (EBV) is an enveloped double-stranded DNA virus of the gammaherpesvirinae sub-family that predominantly infects humans through epithelial cells and B cells. Three EBV glycoproteins, gH, gL and gp42, form a complex that targets EBV infection of B cells. Human leukocyte antigen (HLA) class II molecules expressed on B cells serve as the receptor for gp42, triggering membrane fusion and virus entry. The mechanistic role of gHgL in herpesvirus entry has been largely unresolved, but it is thought to regulate the activation of the virally-encoded gB protein, which acts as the primary fusogen. Here we study the assembly and function of the reconstituted B cell entry complex comprised of gHgL, gp42 and HLA class II. The structure from negative-stain electron microscopy provides a detailed snapshot of an intermediate state in EBV entry and highlights the potential for the triggering complex to bring the two membrane bilayers into proximity. Furthermore, gHgL interacts with a previously identified, functionally important hydrophobic pocket on gp42, defining the overall architecture of the complex and playing a critical role in membrane fusion activation. We propose a macroscopic model of the initiating events in EBV B cell fusion centered on the formation of the triggering complex in the context of both viral and host membranes. This model suggests how the triggering complex may bridge the two membrane bilayers, orienting critical regions of the N- and C- terminal ends of gHgL to promote the activation of gB and efficient membrane fusion.

Published
2014

20. Urine Peptidomic and Targeted Plasma Protein Analyses in the Diagnosis and Monitoring of Systemic Juvenile Idiopathic Arthritis

Author

Ling, Xuefeng B., Lau, Kenneth, Deshpande, Chetan, Park, Jane L., Milojevic, Diana, Macaubas, Claudia, Xiao, Chris, Lopez-Avila, Viorica, Kanegaye, John, Burns, Jane C., Cohen, Harvey, Schilling, James, and Mellins, Elizabeth D.

Subjects
Life Sciences, Biotechnology, Pathology, Cell Biology, Urine, Arthritis, Inflammation, Proteomics, Antibody, Biomarker, Predictor
Abstract

Systemic juvenile idiopathic arthritis is a chronic pediatric disease. The initial clinical presentation can mimic other pediatric inflammatory conditions, which often leads to significant delays in diagnosis and appropriate therapy. SJIA biomarker development is an unmet diagnostic/prognostic need to prevent disease complications.We profiled the urine peptidome to analyze a set of 102 urine samples, from patients with SJIA, Kawasaki disease (KD), febrile illnesses (FI), and healthy controls. A set of 91 plasma samples, from SJIA flare and quiescent patients, were profiled using a customized antibody array against 43 proteins known to be involved in inflammatory and protein catabolic processes.We identified a 17-urine-peptide biomarker panel that could effectively discriminate SJIA patients at active, quiescent, and remission disease states, and patients with active SJIA from confounding conditions including KD and FI. Targeted sequencing of these peptides revealed that they fall into several tight clusters from seven different proteins, suggesting disease-specific proteolytic activities. The antibody array plasma profiling identified an SJIA plasma flare signature consisting of tissue inhibitor of metalloproteinase-1 (TIMP1), interleukin (IL)-18, regulated upon activation, normal T cell expressed and secreted (RANTES), P-Selectin, MMP9, and L-Selectin.The urine peptidomic and plasma protein analyses have the potential to improve SJIA care and suggest that SJIA urine peptide biomarkers may be an outcome of inflammation-driven effects on catabolic pathways operating at multiple sites.

Published
2010

22. Evaluation of C4 Gene Copy Number in Pediatric Acute Neuropsychiatric Syndrome

Author

Kalinowski, Agnieszka, primary, Tian, Lu, additional, Pattni, Reenal, additional, Ollila, Hanna, additional, Khan, Maroof, additional, Manko, Cindy, additional, Silverman, Melissa, additional, Ma, Meiqian, additional, Columbo, Laurie, additional, Farhadian, Bahare, additional, Swedo, Susan, additional, Murphy, Tanya, additional, Johnson, Mats, additional, Fernell, Elisabeth, additional, Gillberg, Christopher, additional, Thienemann, Margo, additional, Mellins, Elizabeth D, additional, Levinson, Douglas F, additional, Urban, Alexander E, additional, and Frankovich, Jennifer, additional

Published
2023
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25. Tmem178 Negatively Regulates IL‐1β Production Through Inhibition of the NLRP3 Inflammasome.

Author

Khanna, Kunjan, Yan, Hui, Mehra, Muneshwar, Rohatgi, Nidhi, Mbalaviele, Gabriel, Mellins, Elizabeth D., and Faccio, Roberta

Subjects
TREATMENT of arthritis, BIOMARKERS, INTERLEUKINS, BIOLOGICAL models, INFLAMMATION, ANIMAL experimentation, CELLULAR signal transduction, MITOCHONDRIA, CALCIUM, REACTIVE oxygen species, MICE, CHEMICAL inhibitors
Abstract

Objective: Inflammasomes modulate the release of bioactive interleukin (IL)‐1β. Excessive IL‐1β levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL‐1β regulation in these disorders. Methods: To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Transmembrane protein 178 (Tmem178), a negative regulator of calcium levels in macrophages, and measured IL‐1β and caspase‐1 activation in wild‐type (WT) and Tmem178−/− macrophages after calcium chelators, silencing of Stim1, a component of store‐operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking the Stromal Interaction Molecule 1 (Stim1) binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin−/−/Tmem178−/− mice infected with lymphocytic choriomeningitis virus (LCMV) in which inflammasome or IL‐1β signaling was pharmacologically inhibited. Human TMEM178 and IL1B transcripts were analyzed in data sets of whole blood and peripheral blood monocytes from healthy controls and patients with active sJIA. Results: TMEM178 levels are reduced in whole blood and monocytes from patients with sJIA while IL1B levels are increased. Accordingly, Tmem178−/− macrophages produce elevated IL‐1β compared with WT cells. The elevated intracellular calcium levels after SOCE activation in Tmem178−/− macrophages induce mitochondrial damage, release mtROS, and ultimately promote NLRP3 inflammasome activation. In vivo, inhibition of inflammasome or IL‐1β neutralization prolongs Tmem178−/− mouse survival in LCMV‐induced CSS. Conclusion: Down‐regulation of TMEM178 levels may represent a marker of disease activity and help identify patients who could benefit from inflammasome targeting. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma

Author

Movassagh, Hesam, primary, Prunicki, Mary, additional, Kaushik, Abhinav, additional, Zhou, Xiaoying, additional, Dunham, Diane, additional, Smith, Eric M., additional, He, Ziyuan, additional, Aleman Muench, German R., additional, Shi, Minyi, additional, Weimer, Annika K., additional, Cao, Shu, additional, Andorf, Sandra, additional, Feizi, Amir, additional, Snyder, Michael P., additional, Soroosh, Pejman, additional, Mellins, Elizabeth D., additional, and Nadeau, Kari C., additional

Published
2023
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30. 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

34. Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma

Author

Nadeau, Kari, primary, Movassagh, Hesam, additional, Prunicki, Mary, additional, Kaushik, Abhinav, additional, Zhou, Xiaoying, additional, Dunham, Diane, additional, Smith, Eric, additional, He, Ziyuan, additional, Muench, German R. Aleman, additional, Shi, Minyi, additional, Weimer, Annika K., additional, Cao, Shu, additional, Andorf, Sandra, additional, Feizi, Amir, additional, Snyder, Michael, additional, Soroosh, Pejman, additional, and Mellins, Elizabeth D., additional

Published
2022
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36. Inflammatory bowel disease in children with systemic juvenile idiopathic arthritis

Author

Maller, Justine, Fox, Emily, Park, K. T., Paul, Sarah Sertial, Baszis, Kevin, Borocco, Charlotte, Prahalad, Sampath, Quartier, Pierre, Reinhardt, Adam, Schonenberg-Meinema, Dieneke, Shipman-Duensing, Lauren, Terreri, Maria Teresa, Simard, Julia, Lavi, Idit, Chalom, Elizabeth, Hsu, Joyce, Zisman, Devy, Mellins, Elizabeth D., Abramson, L., Anderson, E., Andrew, M., Battle, N., Becker, M., Benham, H., Beukelman, T., Birmingham, J., Blier, P., Brown, A., Brunner, H., Cabrera, A., Canter, D., Carlton, D., Caruso, B., Ceracchio, L., Chang, J., Charpentier, P., Clark, K., Dean, J., Dedeoglu, F., Feldman, B., Ferguson, P., Fox, M., Francis, K., Gervasini, M., Goldsmith, D., Gorton, G., Gottlieb, B., Graham, T., Griffin, T., Grosbein, H., Graduate School, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, and Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
0301 basic medicine, medicine.medical_specialty, Immunology, Arthritis, Cytokine inhibitors, Inflammatory bowel disease, digestive system, Article, Etanercept, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Systemic juvenile idiopathic arthritis, Internal medicine, Humans, Immunology and Allergy, Medicine, Pediatric rheumatology, Registries, Family history, Child, 030203 arthritis & rheumatology, business.industry, Macrophage Activation Syndrome, Incidence (epidemiology), Inflammatory Bowel Diseases, medicine.disease, Arthritis, Juvenile, digestive system diseases, Canakinumab, 030104 developmental biology, Macrophage activation syndrome, Cohort, Autoinflammation, business, medicine.drug
Abstract

ObjectiveThe incidence of inflammatory bowel disease (IBD) in juvenile idiopathic arthritis (JIA) is higher than in the general pediatric population. However, reports of IBD in the systemic JIA (sJIA) subtype are limited. We sought to characterize sJIA patients diagnosed with IBD and to identify potential contributing risk factors.MethodsUsing an internationally distributed survey, we identified 16 patients with sJIA who were subsequently diagnosed with IBD (sJIA-IBD cohort). Five hundred twenty-two sJIA patients without IBD were identified from the CARRA Legacy Registry and served as the sJIA-only cohort for comparison. Differences in demographic, clinical characteristics, and therapy were assessed using chi-square test, Fisher exact test,t-test, and univariate and multivariate logistic regression, as appropriate.ResultsOf the patients with sJIA-IBD, 75% had a persistent sJIA course and 25% had a history of macrophage activation syndrome. sJIA-IBD subjects were older at sJIA diagnosis, more often non-White, had a higher rate of IBD family history, and were more frequently treated with etanercept or canakinumab compared to sJIA-only subjects. Sixty-nine percent of sJIA-IBD patients successfully discontinued sJIA medications following IBD diagnosis, and sJIA symptoms resolved in 9 of 12 patients treated with tumor necrosis factor-α (TNF-α) inhibitors.ConclusionIBD in the setting of sJIA is a rare occurrence. The favorable response of sJIA symptoms to therapeutic TNF-α inhibition suggests that the sJIA-IBD cohort may represent a mechanistically distinct sJIA subgroup. Our study highlights the importance of maintaining a high level of suspicion for IBD when gastrointestinal involvement occurs in patients with sJIA and the likely broad benefit of TNF-α inhibition in those cases.

Published
2021

39. Serum proteome analysis of systemic JIA and related lung disease identifies distinct inflammatory programs and biomarkers

Author

Chen, Guangbo, Deutsch, Gail H., Schulert, Grant, Zheng, Hong, Jang, SoRi, Trapnell, Bruce, Lee, Pui, Macaubas, Claudia, Ho, Katherine, Schneider, Corinne, Saper, Vivian E., de Jesus, Adriana Almeida, Krasnow, Mark, Grom, Alexei, Goldbach-Mansky, Raphaela, Khatri, Purvesh, Mellins, Elizabeth D, and Canna, Scott W.

Subjects
Lung Diseases, Proteome, Macrophage Activation Syndrome, Matrix Metalloproteinase 7, Humans, Article, Arthritis, Juvenile, Biomarkers
Abstract

Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD.We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated.Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD.

Published
2022

42. Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis

Author

Chen, Guangbo, primary, Deutsch, Gail H., additional, Schulert, Grant S., additional, Zheng, Hong, additional, Jang, SoRi, additional, Trapnell, Bruce, additional, Lee, Pui Y., additional, Macaubas, Claudia, additional, Ho, Katherine, additional, Schneider, Corinne, additional, Saper, Vivian E., additional, de Jesus, Adriana Almeida, additional, Krasnow, Mark A., additional, Grom, Alexei, additional, Goldbach‐Mansky, Raphaela, additional, Khatri, Purvesh, additional, Mellins, Elizabeth D., additional, and Canna, Scott W., additional

Published
2022
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49. Regulation of the BCR signalosome by the class II peptide editor, H2-M, affects the development and repertoire of innate-like B cells

Author

Ghosh, Debopam, primary, Pham, Tho D., additional, Nanaware, Padma P., additional, Sengupta, Deepanwita, additional, Adler, Lital N., additional, Li, Caiyun G., additional, He, Xiao, additional, O'Mara, Mary E., additional, Kantor, Aaron B., additional, Nguyen, Khoa D., additional, Yang, Yang, additional, Eisenlohr, Laurence C., additional, Jensen, Peter E., additional, Herzenberg, Leonore A., additional, Stern, Lawrence J., additional, Boyd, Scott D., additional, Ghosn, Eliver E.B., additional, and Mellins, Elizabeth D., additional

Published
2022
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50. DRB1*0401-Restricted Human T Cell Clone Specific for the Major Proinsulin73-90 Epitope Expresses a Down-Regulatory T Helper 2 Phenotype

Author

Durinovic-Belló, Ivana, Rosinger, Silke, Olson, Jennifer A., Congia, Mauro, Ahmad, Regina C., Rickert, Mathias, Hampl, Johannes, Kalbacher, Hubert, Drijfhout, Jan W., Mellins, Elizabeth D., Al Dahouk, Sascha, Kamradt, Thomas, Maeurer, Markus J., Nhan, Carol, Roep, Bart O., Boehm, Bernhard O., Polychronakos, Constantin, Nepom, Gerald T., Karges, Wolfram, McDevitt, Hugh O., and Sønderstrup, Grete

Published
2006
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