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1. Complex immune network and regional consistency in the human gastric mucosa revealed by high-resolution spectral cytometry

Author

Ángel De Prado, Paloma Cal-Sabater, Aida Fiz-López, Sandra Izquierdo, Daniel Corrales, Francisco Pérez-Cózar, Juan H-Vázquez, Elisa Arribas-Rodríguez, Cándido Perez-Segurado, Álvaro Martín Muñoz, José A. Garrote, Eduardo Arranz, Concepción Marañón, Sara Cuesta-Sancho, Luis Fernández-Salazar, and David Bernardo

Subjects
Spectral cytometry, Stomach, Human, Immunome, Gastric, H. pylori, Medicine, Science
Abstract

Abstract The immune cellular landscape from the gastric mucosa remains largely unknown despite its relevance in several inflammatory conditions. Human gastric biopsies were obtained from the antrum, body and incisura from 10 individuals to obtain lamina propria mononuclear cells that were further characterized by spectral cytometry. Phenotypic hierarchical analyses identified a total of 52 different immune cell subsets within the human gastric mucosa revealing that T-cells (> 60%) and NK cells (> 20%) were the main populations. Within T-cells, CD4+ and CD8+ were equally represented with both subsets displaying mainly a memory and effector phenotype. NK cells, on the contrary, were largely of the early phenotype. No regional differences were observed for any subsets among the 3 locations. Following unsupervised analysis, a total of 82 clusters were found. Again, no differences were observed amongst locations although a great degree of inter-individual variability was found, largely influenced by the presence of H. pylori infection and dyspepsia. We have unraveled the human gastric immune cellular subset composition and a unique interindividual immune fingerprint with no inter-regional variations.

Published
2024
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2. Unbiased immunome characterisation correlates with COVID-19 mRNA vaccine failure in immunocompromised adults

Author

Juan H-Vázquez, Paloma Cal-Sabater, Elisa Arribas-Rodríguez, Aida Fiz-López, Candido Perez-Segurado, Álvaro Martín-Muñoz, Ángel De Prado, Marina Perez Mazzali, Carolina G. de Castro, Alejandro G. del Hierro, Ignacio de la Fuente Graciani, Sonia Pérez González, Sara Gutiérrez, Pablo Tellería, Cristina Novoa, Silvia Rojo Rello, Antonio Garcia-Blesa, Rosa Sedano, Ana María Martínez García, Sonsoles Garcinuño Pérez, Marta Domínguez-Gil, Cristina Hernán García, Ma Mercedes Guerra, Eduardo Muñoz-Sánchez, Cristina Barragan-Pérez, Soraya Diez Morales, Oriana Casazza Donnarumma, Daniel Ramos Pollo, Natalia Santamarta Solla, Paula Ma Álvarez Manzanares, Sara Bravo, Cristina García Alonso, Luis Alberto Avendaño Fernández, Jenifer Gay Alonso, José A. Garrote, Eduardo Arranz, José María Eiros, Fernando Rescalvo Santiago, Carolina Quevedo Villegas, Eduardo Tamayo, Antonio Orduña, Carlos Dueñas, María Jesús Peñarrubia, Sara Cuesta-Sancho, María Montoya, and David Bernardo

Subjects
computational cytometry, vaccine failure, COVID-19, immunome, immunocompromised adult, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionCoronavirus disease 2019 (COVID-19) affects the population unequally, with a greater impact on older and immunosuppressed people.MethodsHence, we performed a prospective experimental cohort study to characterise the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in immune-compromised patients (older adults and oncohaematologic patients), compared with healthy counterparts, based on deep characterisation of the circulating immune cell subsets.Results and discussionWhile acquired humoral and cellular memory did not predict subsequent infection 18 months after full vaccination, spectral and computational cytometry revealed several subsets within the CD8+ T-cells, B-cells, natural killer (NK) cells, monocytes and TEMRA Tγδ cells that were differentially expressed in individuals who were subsequently infected and not infected not just following immunisation, but also prior to vaccination. Of note, we found up to seven clusters within the TEMRA Tγδ cell population, with some of them being expanded and others decreased in subsequently infected individuals. Moreover, some of these cellular clusters were also related to COVID-19-induced hospitalisation in oncohaematologic patients. Therefore, we have identified a cellular signature that even before vaccination is related to COVID-19 vulnerability as opposed to the acquisition of cellular and/or humoral memory following vaccination with SARS-CoV-2 messenger RNA (mRNA) vaccines.

Published
2024
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3. Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function

Author

Elisa Arribas-Rodríguez, Ángel De Prado, Beatriz de Andrés, Benito Velayos, Jesús Barrio, Alejandro Romero, Francisco Javier García-Alonso, Álvaro Martín-Muñoz, José A. Garrote, Eduardo Arranz, Luis Fernández-Salazar, and David Bernardo

Subjects
Tofacitinib, Intestine, Ulcerative colitis, Dendritic cells, Macrophages, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC. Methods: Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells. Results: Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC. Conclussion: Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.

Published
2025
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4. Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

Author

Albert Morales, Silvia Rojo Rello, Helena Cristóbal, Aida Fiz-López, Elisa Arribas, Montserrat Marí, Anna Tutusaus, Paloma de la Cal-Sabater, Gerry A.F. Nicolaes, José T. Ortiz-Pérez, David Bernardo, and Pablo García de Frutos

Subjects
COVID-19, AXL, MERTK, GAS6, viral infection, immune response, Biology (General), QH301-705.5
Abstract

Background: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. Methods: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. Results: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. Conclusions: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.

Published
2021
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5. Unbiased spectral cytometry immunome characterization predicts COVID-19 mRNA vaccine failure in older adults and patients with lymphoid malignancies

Author

Juan H-Vazquez, Paloma Cal-Sabater, Elisa Arribas-Rodríguez, Aida Fiz-López, Candido Perez-Segurado, Álvaro Martín-Muñoz, Ángel De Prado, Ignacio de la Fuente Graciani, Sonia Pérez González, Sara Gutiérrez, Pablo Tellería, Cristina Novoa, Silvia Rojo Rello, Antonio Garcia-Blesa, Rosa Sedano, Ana María Martínez García, Sonsoles Garcinuño Pérez, Marta Domínguez-Gil, Cristina Hernán García, Mª Mercedes Guerra, Eduardo Muñoz-Sánchez, Cristina Barragan-Pérez, Soraya Diez Morales, Oriana Casazza Donnarumma, Daniel Ramos Pollo, Natalia Santamarta Solla, Paula Mª Álvarez Manzanares, Sara Bravo, Cristina García Alonso, Ángel Tesedo Nieto, Elisabet Carmen López Moreno, María Esther Cabrera Sanz, Sara Borge Olmedo, Miguel de Paula Ortiz, Alberto Castellanos Asenjo, Jenifer Gay Alonso, José A. Garrote, Eduardo Arranz, José María Eiros, Fernando Rescalvo Santiago, Carolina Quevedo Villegas, Eduardo Tamayo, Antonio Orduña, Carlos Dueñas, María Jesús Peñarrubia, Sara Cuesta-Sancho, María Montoya, and David Bernardo

Abstract

COVID-19 affects the population unequally with a higher impact on aged and immunosuppressed people. Hence, we assessed the effect of SARS-CoV-2 vaccination in immune compromised patients (older adults and oncohematologic patients), compared with healthy counterparts. While the acquired humoral and cellular memory did not predict subsequent infection 18 months after full immunization, spectral and computational cytometry revealed several subsets within the CD8+T-cells, B-cells, NK cells, monocytes and CD45RA+CCR7-Tγδ cells differentially expressed in further infected and non-infected individuals not just following immunization, but also prior to that. Of note, up to 7 subsets were found within the CD45RA+CCR7-Tγδ population with some of them being expanded and other decreased in subsequently infected individuals. Moreover, some of these subsets also predicted COVID-induced hospitalization in oncohematologic patients. Therefore, we hereby have identified several cellular subsets that, even before vaccination, strongly related to COVID-19 vulnerability as opposed to the acquisition of cellular and/or humoral memory following vaccination with SARS-CoV- 2 mRNA vaccines.SUMMARYAn in depth and unbiased spectral cytometry characterization of the immune system before and after COVID-19 vaccination can predict not just subsequent PCR-confirmed infection, but also COVID-induced hospitalization in immune compromised patients.

Published
2023
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6. Mapping the human genetic architecture of COVID-19: an update

Author

Massimo GIRARDIS, Andrea Antinori, Eunate Arana-Arri, Stefania Mantovani, Nadia Harerimana, Carlota Dobaño Lazaro, Elisa Arribas Rodríguez, Maria Teresa La Rovere, Albert Tenesa, Arianna Gabrieli, Elizabeth Atkinson, Chiara Fallerini, David Bernardo, Kai Kisand, Jahad Alghamdi, Alex Soriano, Vorasuk Shotelersuk, Aida Fiz López, Carlo Rivolta, Andrea Ganna, Elena Bargagli, Francesca Fava, and Maurizio Bussotti

Subjects
Vaccination, Disease susceptibility, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Evolutionary biology, Public health, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pandemic, medicine, Genome-wide association study, Biology, Genetic architecture
Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic continues to pose a major public health threat especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity we formed the COVID19 Host Genetics Initiative. Here we present GWAS meta-analysis of up to 125,584 cases and over 2.5 million controls across 60 studies from 25 countries, adding 11 new genome-wide significant loci compared to those previously identified. Genes in novel loci include SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.

Published
2021
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7. Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge

Author

Carlos M. González-Casimiro, Elisa Arribas-Rodríguez, Aida Fiz-López, Javier Casas, Sara Gutiérrez, Pablo Tellería, Cristina Novoa, Silvia Rojo-Rello, Eduardo Tamayo, Antonio Orduña, Carlos Dueñas, David Bernardo, German Perdomo, European Commission, Junta de Castilla y León, Fundación 'la Caixa', Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), and CSIC-UVA - Instituto de Biología y Genética Molecular (IBGM)

Subjects
Male, insulin-degrading enzyme, COVID-19, post-COVID-19, peripheral blood mononuclear cell, monocytes, glucose, insulin, macrophage inflammatory protein-1, Insulysin, Monocytes, Catalysis, Inorganic Chemistry, COVID-19 Testing, Humans, Insulin, Lymphocytes, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, SARS-CoV-2, Macrophage inflammatory protein-1, Organic Chemistry, General Medicine, Peripheral blood mononuclear cell, Hospitals, Computer Science Applications, Zinc, Glucose, Leukocytes, Mononuclear, Female, Insulin-degrading enzyme
Abstract

Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4−), and, to a lower extent, in B-cells from healthy controls. Notably, IDE’s surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE’s surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4− T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4− T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients., This work was funded by the European Commission–NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global) and Junta de Castilla y León (Proyectos COVID 07.04.467B04.74011.0) to D.B. The project leading to these results had received funding from the “La Caixa” Foundation under agreement LCF/PR/PR18/51130007 to G.P. and grant PID2019-110496RB-C22 funded by MCIN/AEI/10.13039/501100011033 to G.P. This research was funded by the Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Junta de León and the European Social Fund (ORDER EDU/574/2018).

Published
2022
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8. Evaluation of Cytokines as Robust Diagnostic Biomarkers for COVID-19 Detection

Author

Álvaro Tamayo-Velasco, Paloma Cal-Sabater, María Heredia-Rodríguez, Marta Martín-Fernández, Pedro Martínez-Paz, José María Eiros, Eduardo Tamayo, Ignacio de la Fuente, José Pablo Miramontes-González, Rocío Aller, Hugo Gonzalo-Benito, Carlos Dueñas, Aida Fiz-López, Francisco Javier Álvarez, Esther Gómez-Sánchez, David Bernardo, María Jesús Peñarrubia-Ponce, Elisa Arribas-Rodríguez, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Junta de Castilla y León, CSIC-UVA - Instituto de Biología y Genética Molecular (IBGM), Tamayo-Velasco, Álvaro, Álvarez, Francisco Javier, Fuente, Ignacio de la, Martín-Fernández, Marta, Eirós, José M., Martínez-Paz, Pedro, Miramontes González, José Pablo, Fiz-López, Aida, Arribas, Elisa, Cal-Sabater, Paloma de la, Dueñas-Gutiérrez, Carlos, Heredia-Rodríguez, María, Bernardo, David, Gómez-Sánchez, Esther, Tamayo-Velasco, Álvaro [0000-0001-6202-5420], Álvarez, Francisco Javier [0000-0002-7566-5678], Fuente, Ignacio de la [0000-0001-5381-820X], Martín-Fernández, Marta [0000-0003-2714-8120], Eirós, José M. [0000-0002-5357-6340], Martínez-Paz, Pedro [0000-0002-5772-8153], Miramontes González, José Pablo [0000-0002-2247-9679], Fiz-López, Aida [0000-0003-2052-7996], Arribas, Elisa [0000-0002-4470-075X], Cal-Sabater, Paloma de la [0000-0003-0267-794X], Dueñas-Gutiérrez, Carlos [0000-0002-8943-1231], Heredia-Rodríguez, María [0000-0003-3691-0252], Bernardo, David [0000-0002-2843-6696], and Gómez-Sánchez, Esther [0000-0002-9457-1394]

Subjects
0301 basic medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Medicine (miscellaneous), IP-10, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Antigen, law, Internal medicine, Diagnosis, Validation, medicine, Diagnostic biomarker, Polymerase chain reaction, business.industry, Diagnóstico, COVID-19, Plasma levels, COVID-19 (Enfermedad), 030104 developmental biology, Biomarcadores, 030220 oncology & carcinogenesis, Cohort, Medicine, Biomarker (medicine), biomarker, business, Biomarkers
Abstract

Antigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962, 95%CI (0.933–0.992), p &lt, 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573, 95%CI (8.127–80.469), 0.001) and AUROC (AUC: 0.900, 95%CI (0.846–0.954), 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.

Published
2021

9. Human intestinal dendritic cell and macrophage subsets in coeliac disease

Author

Eduardo, Arranz, Ángel, De Prado, Aida, Fiz-López, Elisa, Arribas, José A, Garrote, and David, Bernardo

Subjects
Intestines, Celiac Disease, Macrophages, Immune Tolerance, Animals, Humans, Dendritic Cells, Immunity, Innate
Abstract

Dendritic cells (DC) and macrophages (Mϕ) constitute the most abundant antigen presenting cells in the human intestinal mucosa. In resting conditions, they are essential to maintain the mechanisms of immune tolerance toward food antigens and commensals, at the time that they keep the capacity to initiate and maintain antigen-specific pro-inflammatory immune responses toward invading pathogens. Nevertheless, this delicate equilibrium between immunity and tolerance is not perfect, like in coeliac disease (CD), where DC and Mϕ drive the development of antigen-specific immune responses toward dietary gluten peptides. In this review, we provide therefore a comprehensive discussion about CD pathogenesis, the human intestinal immune system and the biology of intestinal DC and Mϕ both in resting conditions and in CD. Last, but not least, we discuss about all the remaining issues pending to be studied regarding DC and Mϕ contribution toward CD pathogenesis. This may allow the identification of unique and specific factors which may be useful in the clinical practice, as well as identify new therapeutic targets in order to reestablish the loss intestinal homeostasis in CD.

Published
2021

10. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Published
2022
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11. Human intestinal dendritic cell and macrophage subsets in coeliac disease

Author

Aida Fiz-López, José Antonio Garrote, Eduardo Arranz, Elisa Arribas, Ángel De Prado, and David Bernardo

Subjects
0303 health sciences, 03 medical and health sciences, Immune system, Antigen, Intestinal mucosa, Mucosal immunology, 030302 biochemistry & molecular biology, Immunology, Macrophage, Dendritic cell, Biology, Antigen-presenting cell, Immune tolerance
Abstract

Dendritic cells (DC) and macrophages (Mϕ) constitute the most abundant antigen presenting cells in the human intestinal mucosa. In resting conditions, they are essential to maintain the mechanisms of immune tolerance toward food antigens and commensals, at the time that they keep the capacity to initiate and maintain antigen-specific pro-inflammatory immune responses toward invading pathogens. Nevertheless, this delicate equilibrium between immunity and tolerance is not perfect, like in coeliac disease (CD), where DC and Mϕ drive the development of antigen-specific immune responses toward dietary gluten peptides. In this review, we provide therefore a comprehensive discussion about CD pathogenesis, the human intestinal immune system and the biology of intestinal DC and Mϕ both in resting conditions and in CD. Last, but not least, we discuss about all the remaining issues pending to be studied regarding DC and Mϕ contribution toward CD pathogenesis. This may allow the identification of unique and specific factors which may be useful in the clinical practice, as well as identify new therapeutic targets in order to reestablish the loss intestinal homeostasis in CD.

Published
2021
Full Text
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