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1. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

Author

Ahuja, Sunil K, Manoharan, Muthu Saravanan, Lee, Grace C, McKinnon, Lyle R, Meunier, Justin A, Steri, Maristella, Harper, Nathan, Fiorillo, Edoardo, Smith, Alisha M, Restrepo, Marcos I, Branum, Anne P, Bottomley, Matthew J, Orrù, Valeria, Jimenez, Fabio, Carrillo, Andrew, Pandranki, Lavanya, Winter, Caitlyn A, Winter, Lauryn A, Gaitan, Alvaro A, Moreira, Alvaro G, Walter, Elizabeth A, Silvestri, Guido, King, Christopher L, Zheng, Yong-Tang, Zheng, Hong-Yi, Kimani, Joshua, Blake Ball, T, Plummer, Francis A, Fowke, Keith R, Harden, Paul N, Wood, Kathryn J, Ferris, Martin T, Lund, Jennifer M, Heise, Mark T, Garrett, Nigel, Canady, Kristen R, Abdool Karim, Salim S, Little, Susan J, Gianella, Sara, Smith, Davey M, Letendre, Scott, Richman, Douglas D, Cucca, Francesco, Trinh, Hanh, Sanchez-Reilly, Sandra, Hecht, Joan M, Cadena Zuluaga, Jose A, Anzueto, Antonio, Pugh, Jacqueline A, Agan, Brian K, Root-Bernstein, Robert, Clark, Robert A, Okulicz, Jason F, and He, Weijing

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Biodefense, Infectious Diseases, Aging, Vaccine Related, Prevention, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Infection, Good Health and Well Being, Female, Humans, Longevity, COVID-19, Inflammation, Outcome Assessment, Health Care, South Texas Veterans Health Care System COVID-19 team
Abstract

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Published
2023

3. Immunologic resilience and COVID-19 survival advantage.

Author

Lee, Grace C, Restrepo, Marcos I, Harper, Nathan, Manoharan, Muthu Saravanan, Smith, Alisha M, Meunier, Justin A, Sanchez-Reilly, Sandra, Ehsan, Aamir, Branum, Anne P, Winter, Caitlyn, Winter, Lauryn, Jimenez, Fabio, Pandranki, Lavanya, Carrillo, Andrew, Perez, Graciela L, Anzueto, Antonio, Trinh, Hanh, Lee, Monica, Hecht, Joan M, Martinez-Vargas, Celida, Sehgal, Raj T, Cadena, Jose, Walter, Elizabeth A, Oakman, Kimberly, Benavides, Raymond, Pugh, Jacqueline A, South Texas Veterans Health Care System COVID-19 Team, Letendre, Scott, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Cucca, Francesco, Moreira, Alvaro G, Zhang, Nu, Leadbetter, Elizabeth, Agan, Brian K, Richman, Douglas D, He, Weijing, Clark, Robert A, Okulicz, Jason F, and Ahuja, Sunil K

Subjects
South Texas Veterans Health Care System COVID-19 Team, AIDS, Aging, COVID-19, HIV, SARS-CoV-2, biomarkers, immune, inflammation, influenza, Infectious Diseases, Biodefense, Lung, Prevention, Emerging Infectious Diseases, Vaccine Related, Clinical Research, Pneumonia & Influenza, Pneumonia, 2.4 Surveillance and distribution, 2.1 Biological and endogenous factors, Infection, Allergy, Immunology
Abstract

BackgroundThe risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR).ObjectiveWe sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality.MethodsIR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes.ResultsIHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females.ConclusionsPreservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Published
2021

4. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Author

Huffman, Jennifer E., Nicholas, Jayna, Hahn, Julie, Heath, Adam S., Raffield, Laura M., Yanek, Lisa R., Brody, Jennifer A., Thibord, Florian, Almasy, Laura, Bartz, Traci M., Bielak, Lawrence F., Bowler, Russell P., Carrasquilla, Germán D., Chasman, Daniel I., Chen, Ming-Huei, Emmert, David B., Ghanbari, Mohsen, Haessler, Jeffrey, Hottenga, Jouke-Jan, Kleber, Marcus E., Le, Ngoc-Quynh, Lee, Jiwon, Lewis, Joshua P., Li-Gao, Ruifang, Luan, Jian'an, Malmberg, Anni, Mangino, Massimo, Marioni, Riccardo E., Martinez-Perez, Angel, Pankratz, Nathan, Polasek, Ozren, Richmond, Anne, Rodriguez, Benjamin A. T., Rotter, Jerome I., Steri, Maristella, Suchon, Pierre, Trompet, Stella, Weiss, Stefan, Zare, Marjan, Auer, Paul, Cho, Michael H., Christofidou, Paraskevi, Davies, Gail, de Geus, Eco, Deleuze, Jean-François, Delgado, Graciela E., Ekunwe, Lynette, Faraday, Nauder, Gögele, Martin, Greinacher, Andreas, Gao, He, Howard, Tom, Joshi, Peter K., Kilpeläinen, Tuomas O., Lahti, Jari, Linneberg, Allan, Naitza, Silvia, Noordam, Raymond, Paüls-Vergés, Ferran, Rich, Stephen S., Rosendaal, Frits R., Rudan, Igor, Ryan, Kathleen A., Souto, Juan Carlos, van Rooij, Frank J. A., Wang, Heming, Zhao, Wei, Becker, Lewis C., Beswick, Andrew, Brown, Michael R., Cade, Brian E., Campbell, Harry, Cho, Kelly, Crapo, James D., Curran, Joanne E., de Maat, Moniek P. M., Doyle, Margaret, Elliott, Paul, Floyd, James S., Fuchsberger, Christian, Grarup, Niels, Guo, Xiuqing, Harris, Sarah E., Hou, Lifang, Kolcic, Ivana, Kooperberg, Charles, Menni, Cristina, Nauck, Matthias, O'Connell, Jeffrey R., Orrù, Valeria, Psaty, Bruce M., Räikkönen, Katri, Smith, Jennifer A., Soria, Jose Manuel, Stott, David J., van Hylckama Vlieg, Astrid, Watkins, Hugh, Willemsen, Gonneke, Wilson, Peter W. F., Ben-Shlomo, Yoav, Blangero, John, Boomsma, Dorret, Cox, Simon R., Dehghan, Abbas, Eriksson, Johan G., Fiorillo, Edoardo, Fornage, Myriam, Hansen, Torben, Hayward, Caroline, Ikram, M. Arfan, Jukema, J. Wouter, Kardia, Sharon L. R., Lange, Leslie A., März, Winfried, Mathias, Rasika A., Mitchell, Braxton D., Mook-Kanamori, Dennis O., Morange, Pierre-Emmanuel, Pedersen, Oluf, Pramstaller, Peter P., Redline, Susan, Reiner, Alexander, Ridker, Paul M., Silverman, Edwin K., Spector, Tim D., Völker, Uwe, Wareham, Nicholas J., Wilson, James F., Yao, Jie, Trégouët, David-Alexandre, Johnson, Andrew D., Wolberg, Alisa S., de Vries, Paul S., Sabater-Lleal, Maria, Morrison, Alanna C., and Smith, Nicholas L.

Published
2024
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6. Genetic diversity fuels gene discovery for tobacco and alcohol use

Author

Saunders, Gretchen R. B., Wang, Xingyan, Chen, Fang, Jang, Seon-Kyeong, Liu, Mengzhen, Wang, Chen, Gao, Shuang, Jiang, Yu, Khunsriraksakul, Chachrit, Otto, Jacqueline M., Addison, Clifton, Akiyama, Masato, Albert, Christine M., Aliev, Fazil, Alonso, Alvaro, Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Barr, R. Graham, Bartz, Traci M., Becker, Diane M., Bielak, Lawrence F., Benjamin, Emelia J., Bis, Joshua C., Bjornsdottir, Gyda, Blangero, John, Bleecker, Eugene R., Boardman, Jason D., Boerwinkle, Eric, Boomsma, Dorret I., Boorgula, Meher Preethi, Bowden, Donald W., Brody, Jennifer A., Cade, Brian E., Chasman, Daniel I., Chavan, Sameer, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Iona, Cho, Michael H., Choquet, Hélène, Cole, John W., Cornelis, Marilyn C., Cucca, Francesco, Curran, Joanne E., de Andrade, Mariza, Dick, Danielle M., Docherty, Anna R., Duggirala, Ravindranath, Eaton, Charles B., Ehringer, Marissa A., Esko, Tõnu, Faul, Jessica D., Silva, Lilian Fernandes, Fiorillo, Edoardo, Fornage, Myriam, Freedman, Barry I., Gabrielsen, Maiken E., Garrett, Melanie E., Gharib, Sina A., Gieger, Christian, Gillespie, Nathan, Glahn, David C., Gordon, Scott D., Gu, Charles C., Gu, Dongfeng, Gudbjartsson, Daniel F., Guo, Xiuqing, Haessler, Jeffrey, Hall, Michael E., Haller, Toomas, Harris, Kathleen Mullan, He, Jiang, Herd, Pamela, Hewitt, John K., Hickie, Ian, Hidalgo, Bertha, Hokanson, John E., Hopfer, Christian, Hottenga, JoukeJan, Hou, Lifang, Huang, Hongyan, Hung, Yi-Jen, Hunter, David J., Hveem, Kristian, Hwang, Shih-Jen, Hwu, Chii-Min, Iacono, William, Irvin, Marguerite R., Jee, Yon Ho, Johnson, Eric O., Joo, Yoonjung Y., Jorgenson, Eric, Justice, Anne E., Kamatani, Yoichiro, Kaplan, Robert C., Kaprio, Jaakko, Kardia, Sharon L. R., Keller, Matthew C., Kelly, Tanika N., Kooperberg, Charles, Korhonen, Tellervo, Kraft, Peter, Krauter, Kenneth, Kuusisto, Johanna, Laakso, Markku, Lasky-Su, Jessica, Lee, Wen-Jane, Lee, James J., Levy, Daniel, Li, Liming, Li, Kevin, Li, Yuqing, Lin, Kuang, Lind, Penelope A., Liu, Chunyu, Lloyd-Jones, Donald M., Lutz, Sharon M., Ma, Jiantao, Mägi, Reedik, Manichaikul, Ani, Martin, Nicholas G., Mathur, Ravi, Matoba, Nana, McArdle, Patrick F., McGue, Matt, McQueen, Matthew B., Medland, Sarah E., Metspalu, Andres, Meyers, Deborah A., Millwood, Iona Y., Mitchell, Braxton D., Mohlke, Karen L., Moll, Matthew, Montasser, May E., Morrison, Alanna C., Mulas, Antonella, Nielsen, Jonas B., North, Kari E., Oelsner, Elizabeth C., Okada, Yukinori, Orrù, Valeria, Palmer, Nicholette D., Palviainen, Teemu, Pandit, Anita, Park, S. Lani, Peters, Ulrike, Peters, Annette, Peyser, Patricia A., Polderman, Tinca J. C., Rafaels, Nicholas, Redline, Susan, Reed, Robert M., Reiner, Alex P., Rice, John P., Rich, Stephen S., Richmond, Nicole E., Roan, Carol, Rotter, Jerome I., Rueschman, Michael N., Runarsdottir, Valgerdur, Saccone, Nancy L., Schwartz, David A., Shadyab, Aladdin H., Shi, Jingchunzi, Shringarpure, Suyash S., Sicinski, Kamil, Skogholt, Anne Heidi, Smith, Jennifer A., Smith, Nicholas L., Sotoodehnia, Nona, Stallings, Michael C., Stefansson, Hreinn, Stefansson, Kari, Stitzel, Jerry A., Sun, Xiao, Syed, Moin, Tal-Singer, Ruth, Taylor, Amy E., Taylor, Kent D., Telen, Marilyn J., Thai, Khanh K., Tiwari, Hemant, Turman, Constance, Tyrfingsson, Thorarinn, Wall, Tamara L., Walters, Robin G., Weir, David R., Weiss, Scott T., White, Wendy B., Whitfield, John B., Wiggins, Kerri L., Willemsen, Gonneke, Willer, Cristen J., Winsvold, Bendik S., Xu, Huichun, Yanek, Lisa R., Yin, Jie, Young, Kristin L., Young, Kendra A., Yu, Bing, Zhao, Wei, Zhou, Wei, Zöllner, Sebastian, Zuccolo, Luisa, Batini, Chiara, Bergen, Andrew W., Bierut, Laura J., David, Sean P., Gagliano Taliun, Sarah A., Hancock, Dana B., Jiang, Bibo, Munafò, Marcus R., Thorgeirsson, Thorgeir E., Liu, Dajiang J., and Vrieze, Scott

Published
2022
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8. The longitudinal dynamics and natural history of clonal haematopoiesis

Author

Fabre, Margarete A., de Almeida, José Guilherme, Fiorillo, Edoardo, Mitchell, Emily, Damaskou, Aristi, Rak, Justyna, Orrù, Valeria, Marongiu, Michele, Chapman, Michael Spencer, Vijayabaskar, M. S., Baxter, Joanna, Hardy, Claire, Abascal, Federico, Williams, Nicholas, Nangalia, Jyoti, Martincorena, Iñigo, Campbell, Peter J., McKinney, Eoin F., Cucca, Francesco, Gerstung, Moritz, and Vassiliou, George S.

Published
2022
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9. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Liu, Mengzhen, Jiang, Yu, Wedow, Robbee, Li, Yue, Brazel, David M, Chen, Fang, Datta, Gargi, Davila-Velderrain, Jose, McGuire, Daniel, Tian, Chao, Zhan, Xiaowei, Choquet, Hélène, Docherty, Anna R, Faul, Jessica D, Foerster, Johanna R, Fritsche, Lars G, Gabrielsen, Maiken Elvestad, Gordon, Scott D, Haessler, Jeffrey, Hottenga, Jouke-Jan, Huang, Hongyan, Jang, Seon-Kyeong, Jansen, Philip R, Ling, Yueh, Mägi, Reedik, Matoba, Nana, McMahon, George, Mulas, Antonella, Orrù, Valeria, Palviainen, Teemu, Pandit, Anita, Reginsson, Gunnar W, Skogholt, Anne Heidi, Smith, Jennifer A, Taylor, Amy E, Turman, Constance, Willemsen, Gonneke, Young, Hannah, Young, Kendra A, Zajac, Gregory JM, Zhao, Wei, Zhou, Wei, Bjornsdottir, Gyda, Boardman, Jason D, Boehnke, Michael, Boomsma, Dorret I, Chen, Chu, Cucca, Francesco, Davies, Gareth E, Eaton, Charles B, Ehringer, Marissa A, Esko, Tõnu, Fiorillo, Edoardo, Gillespie, Nathan A, Gudbjartsson, Daniel F, Haller, Toomas, Harris, Kathleen Mullan, Heath, Andrew C, Hewitt, John K, Hickie, Ian B, Hokanson, John E, Hopfer, Christian J, Hunter, David J, Iacono, William G, Johnson, Eric O, Kamatani, Yoichiro, Kardia, Sharon LR, Keller, Matthew C, Kellis, Manolis, Kooperberg, Charles, Kraft, Peter, Krauter, Kenneth S, Laakso, Markku, Lind, Penelope A, Loukola, Anu, Lutz, Sharon M, Madden, Pamela AF, Martin, Nicholas G, McGue, Matt, McQueen, Matthew B, Medland, Sarah E, Metspalu, Andres, Mohlke, Karen L, Nielsen, Jonas B, Okada, Yukinori, Peters, Ulrike, Polderman, Tinca JC, Posthuma, Danielle, Reiner, Alexander P, Rice, John P, Rimm, Eric, Rose, Richard J, Runarsdottir, Valgerdur, Stallings, Michael C, Stančáková, Alena, Stefansson, Hreinn, Thai, Khanh K, Tindle, Hilary A, Tyrfingsson, Thorarinn, and Wall, Tamara L

Subjects
Substance Misuse, Human Genome, Brain Disorders, Tobacco, Tobacco Smoke and Health, Genetics, Alcoholism, Alcohol Use and Health, Prevention, Aetiology, 2.1 Biological and endogenous factors, Stroke, Cancer, Cardiovascular, Good Health and Well Being, Alcohol Drinking, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Risk, Smoking, Tobacco Use Disorder, 23andMe Research Team, HUNT All-In Psychiatry, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Published
2019

11. Transcriptome organization of white blood cells through gene co-expression network analysis in a large RNA-seq dataset

Author

Forabosco, Paola, primary, Pala, Mauro, additional, Crobu, Francesca, additional, Diana, Maria Antonietta, additional, Marongiu, Mara, additional, Cusano, Roberto, additional, Angius, Andrea, additional, Steri, Maristella, additional, Orrù, Valeria, additional, Schlessinger, David, additional, Fiorillo, Edoardo, additional, Devoto, Marcella, additional, and Cucca, Francesco, additional

Published
2024
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12. Immunologic resilience and COVID-19 survival advantage

Author

Abdalla, Mohamed I., Adams, Sandra G., Agnew, Joseph, Ali, Saleem, Barker, Jennifer, Birdwell, Angela, Bradford, Stephen, Briggs, Heather, Marin Corral, Judith, Dacus, Jennifer J., Danaher, Patrick J., DePaul, Scott A., Dickerson, Jill, Doanne, Jollynn, Elbel, Samantha, Escamilla, Corina, Farrar, Robert, Feldman, David, Flynn, Julianne, Ford, Delvina, Foy, Joanna D., Freeman, Megan, Galley, Samantha, Garza, Maritza, Gilman, Sherraine, Gomez, Jennifer, Goyal, Varun K., Grassmuck, Sally, Hanson, Joshua, Harris, Brande, Hastings, Gabrielyd, Haywood, Audrey, Hinojosa, Cecilia, Ho, Tony T., Hopkins, Teri, Jewell, Pamela, Johnson, Thomas B., Kotogiannes, Vasiliki, Lawler, Austin C., Lester, Chadwick S., Levine, Stephanie M., Lewis, Haidee V., Louder, Angel, Mainor, Charmaine, Maldonado, Rachel, Martinez, Yvette, McElligott, Neil, Medlin, Laura, Mireles, Myra, Morneau, Kathleen, Munro, Samuel B., Nambiar, Anoop, Nassery, Daniel, Nathanson, Robert, O’Rorke, Jane, Padgett, Cheryl, Pascual-Guardia, Sergi, Patterson, Marisa, Perez, Rogelio, Phillips, Robert E., Polk, Patrick B., Pomager, Michael A., Preston, Kristy J., Proud, Kevin C., Rangel, Michelle, Ratcliffe, Temple A., Reichelderfer, Renee L., Renz, Evan M., Ross, Jeanette, Rudd, Teresa, Sanchez, Maria E., Sanders, Tammy, Schindler, Kevin C., Schmit, David, Solorzano, Claudio, Soni, Nilam, Tam, Win S., Tovar, Edward J., Tyler, Anna R., Vasquez, Anjuli, Veloso, Maria C., Venticinque, Steven G., Villalpando, Jorge A., Villanueva, Melissa, Villegas, Lauren, Wallace, Andrew, Wang, Emily, Williamson, Andreia, Trammell Velasquez, Sadie A., Yunes, Andrea, Zentner, Katharine H., Lee, Grace C., Restrepo, Marcos I., Harper, Nathan, Manoharan, Muthu Saravanan, Smith, Alisha M., Meunier, Justin A., Sanchez-Reilly, Sandra, Ehsan, Aamir, Branum, Anne P., Winter, Caitlyn, Winter, Lauryn, Jimenez, Fabio, Pandranki, Lavanya, Carrillo, Andrew, Perez, Graciela L., Anzueto, Antonio, Trinh, Hanh, Lee, Monica, Hecht, Joan M., Martinez-Vargas, Celida, Sehgal, Raj T., Cadena, Jose, Walter, Elizabeth A., Oakman, Kimberly, Benavides, Raymond, Pugh, Jacqueline A., Letendre, Scott, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Cucca, Francesco, Moreira, Alvaro G., Zhang, Nu, Leadbetter, Elizabeth, Agan, Brian K., Richman, Douglas D., He, Weijing, Clark, Robert A., Okulicz, Jason F., and Ahuja, Sunil K.

Published
2021
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14. Implications of disease-modifying therapies for multiple sclerosis on immune cells and response to COVID-19 vaccination.

Author

Orrù, Valeria, Serra, Valentina, Marongiu, Michele, Lai, Sandra, Lodde, Valeria, Zoledziewska, Magdalena, Steri, Maristella, Loizedda, Annalisa, Lobina, Monia, Piras, Maria Grazia, Virdis, Francesca, Delogu, Giuseppe, Marini, Maria Giuseppina, Mingoia, Maura, Floris, Matteo, Masala, Marco, Castelli, M. Paola, Mostallino, Rafaela, Frau, Jessica, and Lorefice, Lorena

Subjects
COVID-19 vaccines, VACCINE effectiveness, BOOSTER vaccines, COVID-19 pandemic, DIMETHYL fumarate, NATALIZUMAB, FINGOLIMOD
Abstract

Introduction: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete. Methods: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization. Results and Discussion: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Author

Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Marongiu, Michele, Serra, Valentina, Olla, Stefania, Sole, Gabriella, Lai, Sandra, Dei, Mariano, Mulas, Antonella, Virdis, Francesca, Piras, Maria Grazia, Lobina, Monia, Marongiu, Mara, Pitzalis, Maristella, Deidda, Francesca, Loizedda, Annalisa, Onano, Stefano, Zoledziewska, Magdalena, Sawcer, Stephen, Devoto, Marcella, Gorospe, Myriam, Abecasis, Gonçalo R., Floris, Matteo, Pala, Mauro, Schlessinger, David, Fiorillo, Edoardo, and Cucca, Francesco

Published
2020
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17. Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Author

Huffman, Jennifer E, Nicolas, Jayna, Hahn, Julie, Heath, Adam S, Raffield, Laura M, Yanek, Lisa R, Brody, Jennifer A, Thibord, Florian, Almasy, Laura, Bartz, Traci M, Bielak, Lawrence F., Bowler, Russell P, Carrasquilla, Germán D, Chasman, Daniel I, Chen, Ming-Huei, Emmert, David B, Ghanbari, Mohsen, Haessle, Jeffery, Hottenga, Jouke-Jan, Kleber, Marcus E, Le, Ngoc-Quynh, Lee, Jiwon, Lewis, Joshua P, Li-Gao, Ruifang, Luan, Jian’an, Malmberg, Anni, Mangino, Massimo, Marioni, Riccardo E, Martinez-Perez, Angel, Pankratz, Nathan, Polasek, Ozren, Richmond, Anne, Rodriguez, Benjamin AT, Rotter, Jerome I, Steri, Maristella, Suchon, Pierre, Trompet, Stella, Weiss, Stefan, Zare, Marjan, Auer, Paul, Cho, Michael H, Christofidou, Paraskevi, Davies, Gail, de Geus, Eco, Deleuze, Jean-François, Delgado, Graciela E, Ekunwe, Lynette, Faraday, Nauder, Gögele, Martin, Greinacher, Andreas, He, Gao, Howard, Tom, Joshi, Peter K, Kilpeläinen, Tuomas O, Lahti, Jari, Linneberg, Allan, Naitza, Silvia, Noordam, Raymond, Paüls-Vergés, Ferran, Rich, Stephen S, Rosendaal, Frits R, Rudan, Igor, Ryan, Kathleen A, Souto, Juan Carlos, van Rooij, Frank JA, Wang, Heming, Zhao, Wei, Becker, Lewis C, Beswick, Andrew, Brown, Michael R, Cade, Brian E, Campbell, Harry, Cho, Kelly, Crapo, James D, Curran, Joanne E, de Maat, Moniek PM, Doyle, Margaret, Elliott, Paul, Floyd, James S, Fuchsberger, Christian, Grarup, Niels, Guo, Xiuqing, Harris, Sarah E, Hou, Lifang, Kolcic, Ivana, Kooperberg, Charles, Menni, Cristina, Nauck, Matthias, O’Connell, Jeffrey R, Orrù, Valeria, Psaty, Bruce M, Räikkönen, Katri, Smith, Jennifer A, Soria, Jose Manuel, Stott, David J, van Hylckama Vlieg, Astrid, Watkins, Hugh, Willemsen, Gonneke, Wilson, Peter, Ben-Shlomo, Yoav, Blangero, John, Boomsma, Dorret, Cox, Simon R, Dehghan, Abbas, Eriksson, Johan G, Fiorillo, Edoardo, Fornage, Myriam, Hansen, Torben, Hayward, Caroline, Ikram, M. Arfan, Jukema, J Wouter, Kardia, Sharon LR, Lange, Leslie A, März, Winfried, Mathias, Rasika A, Mitchell, Braxton D, Mook-Kanamori, Dennis O, Morange, Pierre-Emmanuel, Pedersen, Oluf, Pramstaller, Peter P, Redline, Susan, Reiner, Alexander, Ridker, Paul M, Silverman, Edwin K, Spector, Tim D, Völker, Uwe, Wareham, Nick, Wilson, James F, Yao, Jie, Trégouët, David-Alexandre, Johnson, Andrew D, Wolberg, Alisa S, de Vries, Paul S, Sabater-Lleal, Maria, Morrison, Alanna C, and Smith, Nicholas L

Subjects
Article
Abstract

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel). Sufficient power achieved to identify signal driven by African population variant. Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

Published
2023

19. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, Zoledziewska, Magdalena, Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Abstract

Few genome-wide association studies (GWAS) analyzing genetic regulation of morphological traits of white blood cells have been reported. We carried out a GWAS of 12 morphological traits in 869 individuals from the general population of Sardinia, Italy. These traits, included measures of cell volume, conductivity and light scatter in four white-cell populations (eosinophils, lymphocytes, monocytes, neutrophils). This analysis yielded seven statistically significant signals, four of which were novel (four novel, PRG2, P2RX3, two of CDK6). Five signals were replicated in the independent INTERVAL cohort of 11 822 individuals. The most interesting signal with large effect size on eosinophil scatter (P-value = 8.33 x 10-32, beta = -1.651, se = 0.1351) falls within the innate immunity cluster on chromosome 11, and is located in the PRG2 gene. Computational analyses revealed that a rare, Sardinian-specific PRG2:p.Ser148Pro mutation modifies PRG2 amino acid contacts and protein dynamics in a manner that could possibly explain the changes observed in eosinophil morphology. Our discoveries shed light on genetics of morphological traits. For the first time, we describe such large effect size on eosinophils morphology that is relatively frequent in Sardinian population.

Published
2023

22. Author Correction: Complex genetic signatures in immune cells underlie autoimmunity and inform therapy

Author

Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Marongiu, Michele, Serra, Valentina, Olla, Stefania, Sole, Gabriella, Lai, Sandra, Dei, Mariano, Mulas, Antonella, Virdis, Francesca, Piras, Maria Grazia, Lobina, Monia, Marongiu, Mara, Pitzalis, Maristella, Deidda, Francesca, Loizedda, Annalisa, Onano, Stefano, Zoledziewska, Magdalena, Sawcer, Stephen, Devoto, Marcella, Gorospe, Myriam, Abecasis, Gonçalo R., Floris, Matteo, Pala, Mauro, Schlessinger, David, Fiorillo, Edoardo, and Cucca, Francesco

Published
2020
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23. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Marongiu, Michele, primary, Pérez-Mejías, Gonzalo, additional, Orrù, Valeria, additional, Steri, Maristella, additional, Sidore, Carlo, additional, Díaz-Quintana, Antonio, additional, Mulas, Antonella, additional, Busonero, Fabio, additional, Maschio, Andrea, additional, Walter, Klaudia, additional, Tardaguila, Manuel, additional, Akbari, Parsa, additional, Soranzo, Nicole, additional, Fiorillo, Edoardo, additional, Gorospe, Myriam, additional, Schlessinger, David, additional, Díaz-Moreno, Irene, additional, Cucca, Francesco, additional, and Zoledziewska, Magdalena, additional

Published
2022
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24. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology.

Author

Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Published
2023
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26. Effect of Different Disease-Modifying Therapies on Humoral Response to BNT162b2 Vaccine in Sardinian Multiple Sclerosis Patients

Author

Pitzalis, Maristella, primary, Idda, Maria Laura, additional, Lodde, Valeria, additional, Loizedda, Annalisa, additional, Lobina, Monia, additional, Zoledziewska, Magdalena, additional, Virdis, Francesca, additional, Delogu, Giuseppe, additional, Pirinu, Federica, additional, Marini, Maria Giuseppina, additional, Mingoia, Maura, additional, Frau, Jessica, additional, Lorefice, Lorena, additional, Fronza, Marzia, additional, Carmagnini, Daniele, additional, Carta, Elisa, additional, Orrù, Valeria, additional, Uzzau, Sergio, additional, Solla, Paolo, additional, Loi, Federica, additional, Devoto, Marcella, additional, Steri, Maristella, additional, Fiorillo, Edoardo, additional, Floris, Matteo, additional, Zarbo, Ignazio Roberto, additional, Cocco, Eleonora, additional, and Cucca, Francesco, additional

Published
2021
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27. Quantifying the Detrimental Effects of Multiple Freeze/Thaw Cycles on Primary Human Lymphocyte Survival and Function.

Author

Serra, Valentina, Fiorillo, Edoardo, Cucca, Francesco, and Orrù, Valeria

Subjects
B cells, MONONUCLEAR leukocytes, CRYOPRESERVATION of cells, LYMPHOCYTE subsets, FROZEN semen, LYMPHOCYTES, THAWING, CELL death
Abstract

The use of cryopreserved peripheral blood mononuclear cells is common in biological research. It is widely accepted that primary cells are rendered unusable by several freezing cycles, although this practice might be very helpful when the biological material is valuable and its re-collection is impractical. To determine the extent to which primary cells undergoing repeated freezing cycles are comparable to one another and to fresh samples, we evaluated overall lymphocyte viability, their proliferation and cytokine production capabilities, as well as the levels of 27 cell subtypes in ten human peripheral blood mononuclear cells frozen for five years and repeatedly thawed. As expected, we observed a progressive increase in cell death percentages on three rounds of thawing, but the frequency of the main lymphocyte subsets was stable across the three thawings. Nevertheless, we observed a significant reduction of B cell frequency in frozen samples compared to fresh ones. On repeated thawings and subsequent conventional stimulation, lymphocyte proliferation significantly decreased, and IL-10, IL-6, GM-CSF, IFN-gamma, and IL-8 showed a trend to lower values. [ABSTRACT FROM AUTHOR]

Published
2023
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30. The longitudinal dynamics and natural history of clonal haematopoiesis

Author

Fabre, Margarete A., primary, Almeida, José Guilherme de, additional, Fiorillo, Edoardo, additional, Mitchell, Emily, additional, Damaskou, Aristi, additional, Rak, Justyna, additional, Orrù, Valeria, additional, Marongiu, Michele, additional, Vijayabaskar, MS, additional, Baxter, Joanna, additional, Hardy, Claire, additional, Abascal, Federico, additional, Chapman, Michael Spencer, additional, Williams, Nicholas, additional, Nangalia, Jyoti, additional, Martincorena, Iñigo, additional, Campbell, Peter J., additional, McKinney, Eoin F., additional, Cucca, Francesco, additional, Gerstung, Moritz, additional, and Vassiliou., George S., additional

Published
2021
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31. CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential

Author

De Simone, Gabriele, Mazza, Emilia M.C., Cassotta, Antonino, Davydov, Alexey N., Kuka, Mirela, Zanon, Veronica, De Paoli, Federica, Scamardella, Eloise, Metsger, Maria, Roberto, Alessandra, Pilipow, Karolina, Colombo, Federico S., Tagliafico, Enrico, Gattinoni, Luca, Mavilio, Domenico, Peano, Clelia, Price, David A., Singh, Satya P., Farber, Joshua M., Serra, Valentina, Cucca, Francesco, Ferrari, Francesco, Orrù, Valeria, Iannacone, Matteo, Chudakov, Dmitriy M., Sallusto, Federica, and Lugli, Enrico

Subjects
chemical and pharmacologic phenomena, hemic and immune systems
Abstract

n mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide–HLA class I Ags. Moreover, CXCR3+ TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3+ TN cells were transcriptionally equivalent to murine CXCR3+ TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8+ T cells., The Journal of Immunology, 203 (12), ISSN:0022-1767, ISSN:1048-3233, ISSN:1047-7381, ISSN:1550-6606

Published
2019

33. Autoimmunity is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension

Author

Jones, Rowena, primary, De Bie, Eckart, additional, Groves, Emily, additional, Zalewska, Kasia I., additional, Swietlik, Emilia M., additional, Treacy, Carmen, additional, Martin, Jennifer, additional, Polwarth, Gary, additional, Guo, Jingxu, additional, Baxendale, Helen, additional, Coleman, Stephen, additional, Savinykh, Natalia, additional, Coghlan, John Gerry, additional, Corris, Paul, additional, Howard, Luke S., additional, Johnson, Martin, additional, Church, Colin, additional, Kiely, David G., additional, Lawrie, Allan, additional, Lordan, James, additional, Ross, Robert Mackenzie, additional, Zaba, Joanna Pepke, additional, Wilkins, Martin R., additional, Wort, S.John, additional, Fiorillo, Edoardo, additional, Orrù, Valeria, additional, Cucca, Francesco, additional, Rhodes, Chris, additional, Gräf, Stefan, additional, Morrell, Nicholas W., additional, McKinney, Eoin, additional, Wallace, Chris, additional, Toshner, Mark, additional, and Consortium, The UK National PAH Cohort Study, additional

Published
2021
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34. A Sardinian founder mutation in glycoprotein Ib platelet subunit beta ( GP1BB ) that impacts thrombocytopenia

Author

Busonero, Fabio, primary, Steri, Maristella, additional, Orrù, Valeria, additional, Sole, Gabriella, additional, Olla, Stefania, additional, Marongiu, Michele, additional, Maschio, Andrea, additional, Sidore, Carlo, additional, Lai, Sandra, additional, Mulas, Antonella, additional, Zoledziewska, Magdalena, additional, Floris, Matteo, additional, Pala, Mauro, additional, Forabosco, Paola, additional, Asunis, Isadora, additional, Pitzalis, Maristella, additional, Deidda, Francesca, additional, Masala, Marco, additional, Caria, Cristian Antonio, additional, Barella, Susanna, additional, Abecasis, Goncalo R., additional, Schlessinger, David, additional, Sanna, Serena, additional, Fiorillo, Edoardo, additional, and Cucca, Francesco, additional

Published
2020
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35. PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity

Author

Sidore, Carlo, primary, Orrù, Valeria, additional, Cocco, Eleonora, additional, Steri, Maristella, additional, Inshaw, Jamie RJ, additional, Pitzalis, Maristella, additional, Mulas, Antonella, additional, McGurnaghan, Stuart, additional, Frau, Jessica, additional, Porcu, Eleonora, additional, Busonero, Fabio, additional, Dei, Mariano, additional, Lai, Sandra, additional, Sole, Gabriella, additional, Virdis, Francesca, additional, Serra, Valentina, additional, Poddie, Fausto, additional, Delitala, Alessandro, additional, Marongiu, Michele, additional, Deidda, Francesca, additional, Pala, Mauro, additional, Floris, Matteo, additional, Masala, Marco, additional, Onengut-Gumuscu, Suna, additional, Robertson, Catherine C, additional, Leoni, Lidia, additional, Frongia, Annapaola, additional, Ricciardi, Maria Rossella, additional, Chessa, Margherita, additional, Olla, Nazario, additional, Lovicu, Mario, additional, Loizedda, Annalisa, additional, Maschio, Andrea, additional, Mereu, Luisa, additional, Ferrigno, Paola, additional, Curreli, Nicolo, additional, Balaci, Lenuta, additional, Loi, Francesco, additional, Ferreli, Liana AP, additional, Pilia, Maria Grazia, additional, Pani, Antonello, additional, Marrosu, Maria Giovanna, additional, Abecasis, Goncalo R, additional, Rich, Stephen S, additional, Colhoun, Helen, additional, Todd, John A, additional, Schlessinger, David, additional, Fiorillo, Edoardo, additional, Cucca, Francesco, additional, and Zoledziewska, Magdalena, additional

Published
2020
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36. Evolutionarily Selected Overexpression of the Cytokine BAFF Enhances Mucosal Immune Response Against P. falciparum

Author

Lodde, Valeria, primary, Floris, Matteo, additional, Beerman, Isabel, additional, Munk, Rachel, additional, Guha, Rajan, additional, Steri, Maristella, additional, Orrù, Valeria, additional, Abdelmohsen, Kotb, additional, Crompton, Peter D., additional, Gorospe, Myriam, additional, Idda, Maria Laura, additional, and Cucca, Francesco, additional

Published
2020
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37. A Sardinian founder mutation in GP1BB that impacts thrombocytopenia

Author

Busonero, Fabio, primary, Steri, Maristella, additional, Orrù, Valeria, additional, Sole, Gabriella, additional, Olla, Stefania, additional, Marongiu, Michele, additional, Sidore, Carlo, additional, Lai, Sandra, additional, Mulas, Antonella, additional, Maschio, Andrea, additional, Zoledziewska, Magdalena, additional, Floris, Matteo, additional, Pala, Mauro, additional, Forabosco, Paola, additional, Asunis, Isadora, additional, Pitzalis, Maristella, additional, Deidda, Francesca, additional, Masala, Marco, additional, Caria, Cristian Antonio, additional, Barella, Susanna, additional, Abecasis, Goncalo R., additional, Schlessinger, David, additional, Sanna, Serena, additional, Fiorillo, Edoardo, additional, and Cucca, Francesco, additional

Published
2020
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41. PRF1 mutation alters immune system activation, inflammation, and risk of autoimmunity.

Author

Sidore, Carlo, Orrù, Valeria, Cocco, Eleonora, Steri, Maristella, Inshaw, Jamie RJ, Pitzalis, Maristella, Mulas, Antonella, McGurnaghan, Stuart, Frau, Jessica, Porcu, Eleonora, Busonero, Fabio, Dei, Mariano, Lai, Sandra, Sole, Gabriella, Virdis, Francesca, Serra, Valentina, Poddie, Fausto, Delitala, Alessandro, Marongiu, Michele, and Deidda, Francesca

Subjects
*IMMUNE system, *TYPE 1 diabetes, *CYTOKINE release syndrome, *AUTOIMMUNITY, *INTERLEUKIN receptors, *HEMOPHAGOCYTIC lymphohistiocytosis
Abstract

Background: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines—cytokine storm. Objective: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). Methods: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. Results: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10−4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10−5, OR = 0.82. Conclusion: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2021
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42. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression

Author

Ferreira, Ricardo C., primary, Castro Dopico, Xaquin, additional, Oliveira, João J., additional, Rainbow, Daniel B., additional, Yang, Jennie H., additional, Trzupek, Dominik, additional, Todd, Sarah A., additional, McNeill, Mhairi, additional, Steri, Maristella, additional, Orrù, Valeria, additional, Fiorillo, Edoardo, additional, Crouch, Daniel J. M., additional, Pekalski, Marcin L., additional, Cucca, Francesco, additional, Tree, Tim I., additional, Vyse, Tim J., additional, Wicker, Linda S., additional, and Todd, John A., additional

Published
2019
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43. The Longitudinal Dynamics and Natural History of Clonal Hematopoiesis

Author

Fabre, Margarete A, Guillherme de Almeida, Jose, Fiorillo, Edoardo, Mitchell, Emily, Damaskou, Aristi, Rak, Justyna, Orru, Valeria, Marongiu, Michele, Vijayabaskar, MS, Baxter, Joanna E, Hardy, Claire, Abascal, Federico, Spencer Chapman, Michael, Williams, Nicholas, Nangalia, Jyoti, Martincorena, Inigo, Campbell, Peter J, Mckinney, Eoin F, Cucca, Francesco, Gerstung, Moritz, and Vassiliou, George S

Published
2021
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44. Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia

Author

Frongia Paola, Maioli Mario, Pacifico Adolfo, Pala Gavino, Nucaro Annalisa, Lampis Rosanna, Contu Daniela, Corongiu Daniela, Secci Maria, Rolesu Marcella, Cuccu Stefania, Tranquilli Stefania, Mancosu Cristina, Lai Marina, Melis Maria, Schirru Lucia, Fadda Elisabetta, Solla Elisabetta, Costa Gianna, Orrù Valeria, Motzo Costantino, Moi Loredana, Murru Daniela, Zoledziewska Magdalena, Deidda Elisabetta, Murru Raffaele, Zavattari Patrizia, Pitzalis Maristella, Chessa Margherita, Ricciardi Rossella, Lostia Stanislao, Marinaro Anna, Milia Anna, Landis Novella, Zedda Maria, Whalen Michael B, Santoni Federico, Marrosu Maria, Devoto Marcella, and Cucca Francesco

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. Methods To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. Results In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). Conclusion This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.

Published
2008
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45. Cooperative translational control of polymorphic BAFF by NF90 and miR-15a

Author

Idda, M Laura, primary, Lodde, Valeria, additional, McClusky, Waverly G, additional, Martindale, Jennifer L, additional, Yang, Xiaoling, additional, Munk, Rachel, additional, Steri, Maristella, additional, Orrù, Valeria, additional, Mulas, Antonella, additional, Cucca, Francesco, additional, Abdelmohsen, Kotb, additional, and Gorospe, Myriam, additional

Published
2018
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46. CD8+HLADR+ Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function

Author

Lukas Yani, Stella, primary, Keller, Michael, additional, Melzer, Franz Leonard, additional, Weinberger, Birgit, additional, Pangrazzi, Luca, additional, Sopper, Sieghart, additional, Trieb, Klemens, additional, Lobina, Monia, additional, Orrù, Valeria, additional, Fiorillo, Edoardo, additional, Cucca, Francesco, additional, and Grubeck-Loebenstein, Beatrix, additional

Published
2018
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47. CD8+CD28−CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?

Author

Fenoglio, Daniela, primary, Dentone, Chiara, additional, Signori, Alessio, additional, Di Biagio, Antonio, additional, Parodi, Alessia, additional, Kalli, Francesca, additional, Nasi, Giorgia, additional, Curto, Monica, additional, Cenderello, Giovanni, additional, De Leo, Pasqualina, additional, Bartolacci, Valentina, additional, Orofino, Giancarlo, additional, Nicolini, Laura Ambra, additional, Taramasso, Lucia, additional, Fiorillo, Edoardo, additional, Orrù, Valeria, additional, Traverso, Paolo, additional, Bruzzone, Bianca, additional, Ivaldi, Federico, additional, Mantia, Eugenio, additional, Guerra, Michele, additional, Negrini, Simone, additional, Giacomini, Mauro, additional, Bhagani, Sanjay, additional, and Filaci, Gilberto, additional

Published
2018
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49. Overexpression of the Cytokine BAFF and Autoimmunity Risk

Author

Steri, Maristella, primary, Orrù, Valeria, additional, Idda, M. Laura, additional, Pitzalis, Maristella, additional, Pala, Mauro, additional, Zara, Ilenia, additional, Sidore, Carlo, additional, Faà, Valeria, additional, Floris, Matteo, additional, Deiana, Manila, additional, Asunis, Isadora, additional, Porcu, Eleonora, additional, Mulas, Antonella, additional, Piras, Maria G., additional, Lobina, Monia, additional, Lai, Sandra, additional, Marongiu, Mara, additional, Serra, Valentina, additional, Marongiu, Michele, additional, Sole, Gabriella, additional, Busonero, Fabio, additional, Maschio, Andrea, additional, Cusano, Roberto, additional, Cuccuru, Gianmauro, additional, Deidda, Francesca, additional, Poddie, Fausto, additional, Farina, Gabriele, additional, Dei, Mariano, additional, Virdis, Francesca, additional, Olla, Stefania, additional, Satta, Maria A., additional, Pani, Mario, additional, Delitala, Alessandro, additional, Cocco, Eleonora, additional, Frau, Jessica, additional, Coghe, Giancarlo, additional, Lorefice, Lorena, additional, Fenu, Giuseppe, additional, Ferrigno, Paola, additional, Ban, Maria, additional, Barizzone, Nadia, additional, Leone, Maurizio, additional, Guerini, Franca R., additional, Piga, Matteo, additional, Firinu, Davide, additional, Kockum, Ingrid, additional, Lima Bomfim, Izaura, additional, Olsson, Tomas, additional, Alfredsson, Lars, additional, Suarez, Ana, additional, Carreira, Patricia E., additional, Castillo-Palma, Maria J., additional, Marcus, Joseph H., additional, Congia, Mauro, additional, Angius, Andrea, additional, Melis, Maurizio, additional, Gonzalez, Antonio, additional, Alarcón Riquelme, Marta E., additional, da Silva, Berta M., additional, Marchini, Maurizio, additional, Danieli, Maria G., additional, Del Giacco, Stefano, additional, Mathieu, Alessandro, additional, Pani, Antonello, additional, Montgomery, Stephen B., additional, Rosati, Giulio, additional, Hillert, Jan, additional, Sawcer, Stephen, additional, D’Alfonso, Sandra, additional, Todd, John A., additional, Novembre, John, additional, Abecasis, Gonçalo R., additional, Whalen, Michael B., additional, Marrosu, Maria G., additional, Meloni, Alessandra, additional, Sanna, Serena, additional, Gorospe, Myriam, additional, Schlessinger, David, additional, Fiorillo, Edoardo, additional, Zoledziewska, Magdalena, additional, and Cucca, Francesco, additional

Published
2017
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50. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression.

Author

Ferreira, Ricardo C., Castro Dopico, Xaquin, Oliveira, João J., Rainbow, Daniel B., Yang, Jennie H., Trzupek, Dominik, Todd, Sarah A., McNeill, Mhairi, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Crouch, Daniel J. M., Pekalski, Marcin L., Cucca, Francesco, Tree, Tim I., Vyse, Tim J., Wicker, Linda S., and Todd, John A.

Subjects
SUPPRESSOR cells, SYSTEMIC lupus erythematosus, TYPE I interferons, T cells, IMMUNOLOGIC diseases
Abstract

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders. [ABSTRACT FROM AUTHOR]

Published
2019
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