Towards a large-scale human inflammation atlas at single-cell resolution
[eng] Inflammation is a physiological response essential for maintaining homeostasis, but when the immune system becomes dysregulated, it can drive a range of pathological conditions and become a key contributor to many diseases. Understanding these complex, disease-specific inflammatory mechanisms...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/218700 |
| Acceso en línea: | https://hdl.handle.net/2445/218700 http://hdl.handle.net/10803/693643 |
| Access Level: | acceso abierto |
| Palabra clave: | Immunologia RNA Inflamació Malalties immunitàries Immunology Inflammation Immunologic diseases |
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oai:diposit.ub.edu:2445/218700 |
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España |
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Towards a large-scale human inflammation atlas at single-cell resolution |
| title |
Towards a large-scale human inflammation atlas at single-cell resolution |
| spellingShingle |
Towards a large-scale human inflammation atlas at single-cell resolution Jiménez Gracia, Laura Immunologia RNA Inflamació Malalties immunitàries Immunology Inflammation Immunologic diseases |
| title_short |
Towards a large-scale human inflammation atlas at single-cell resolution |
| title_full |
Towards a large-scale human inflammation atlas at single-cell resolution |
| title_fullStr |
Towards a large-scale human inflammation atlas at single-cell resolution |
| title_full_unstemmed |
Towards a large-scale human inflammation atlas at single-cell resolution |
| title_sort |
Towards a large-scale human inflammation atlas at single-cell resolution |
| dc.creator.none.fl_str_mv |
Jiménez Gracia, Laura |
| author |
Jiménez Gracia, Laura |
| author_facet |
Jiménez Gracia, Laura |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Heyn, Holger Gut, Ivo G. Universitat de Barcelona. Facultat de Biologia |
| dc.subject.none.fl_str_mv |
Immunologia RNA Inflamació Malalties immunitàries Immunology Inflammation Immunologic diseases |
| topic |
Immunologia RNA Inflamació Malalties immunitàries Immunology Inflammation Immunologic diseases |
| description |
[eng] Inflammation is a physiological response essential for maintaining homeostasis, but when the immune system becomes dysregulated, it can drive a range of pathological conditions and become a key contributor to many diseases. Understanding these complex, disease-specific inflammatory mechanisms is crucial for developing effective treatments. Single-cell sequencing technologies offer a powerful approach to study the immune system at high resolution, providing detailed insights into cellular heterogeneity and immune dynamics. To fully exploit their potential in large-scale studies, standardized protocols for sample collection and processing, coupled with advanced computational methods for robust data analysis, are needed. Since immune-driven diseases often target specific tissues and exhibit distinct inflammatory profiles, a comprehensive approach is required. Blood, as a minimally invasive sample, offers a valuable opportunity to monitor inflammation by tracking cytokine levels and cellular activity, making it ideal for elucidating disease mechanisms and therapeutic responses. In this thesis, experimental protocols and computational approaches were developed for large-scale studies focused on analyzing human inflammatory profiles using single-cell RNA sequencing (scRNA-seq). First, we implemented FixNCut, a protocol that preserves transcriptional profiles and tissue composition by fixing samples at the time of collection, enabling subsequent tissue dissociation with minimal stress-induced artifacts. We then generated a comprehensive reference of the inflammatory spectrum in circulating immune cells using single-cell transcriptomic profiles from over 1,000 patients suffering from 20 immune-driven diseases and healthy individuals. By analyzing the immune cell composition and inflammatory molecule expression, we characterized the immune response across diseases, identifying both commonalities and disease-specific differences. Using interpretable machine learning algorithms, we captured disease-specific inflammatory genes at the cell type level that could serve as clinical biomarkers. Furthermore, we proposed a framework for classifying patients based on their blood-derived inflammatory profiles. Finally, we studied the immunomodulatory effects of albumin treatment in patients with acute decompensated cirrhosis, which resulted in immune transcriptional reprogramming that primarily affected B lymphocytes and enhanced neutrophil antimicrobial activity, boosting the patients' immune response against infections. In summary, this thesis integrates scRNA-seq experimental and computational methods to facilitate large-scale, decentralized research on immune-driven diseases with the goal of applying these approaches for disease diagnosis, monitoring progression, and assessing therapy responses in clinical settings. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
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https://hdl.handle.net/2445/218700 http://hdl.handle.net/10803/693643 |
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https://hdl.handle.net/2445/218700 http://hdl.handle.net/10803/693643 |
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Inglés |
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Inglés |
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cc by-nc-nd (c) Jiménez Gracia, Laura, 2025 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess |
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cc by-nc-nd (c) Jiménez Gracia, Laura, 2025 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
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openAccess |
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application/pdf |
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Universitat de Barcelona |
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Universitat de Barcelona |
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Tesis Doctorals - Facultat - Biologia reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869403852088803328 |
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Towards a large-scale human inflammation atlas at single-cell resolutionJiménez Gracia, LauraImmunologiaRNAInflamacióMalalties immunitàriesImmunologyInflammationImmunologic diseases[eng] Inflammation is a physiological response essential for maintaining homeostasis, but when the immune system becomes dysregulated, it can drive a range of pathological conditions and become a key contributor to many diseases. Understanding these complex, disease-specific inflammatory mechanisms is crucial for developing effective treatments. Single-cell sequencing technologies offer a powerful approach to study the immune system at high resolution, providing detailed insights into cellular heterogeneity and immune dynamics. To fully exploit their potential in large-scale studies, standardized protocols for sample collection and processing, coupled with advanced computational methods for robust data analysis, are needed. Since immune-driven diseases often target specific tissues and exhibit distinct inflammatory profiles, a comprehensive approach is required. Blood, as a minimally invasive sample, offers a valuable opportunity to monitor inflammation by tracking cytokine levels and cellular activity, making it ideal for elucidating disease mechanisms and therapeutic responses. In this thesis, experimental protocols and computational approaches were developed for large-scale studies focused on analyzing human inflammatory profiles using single-cell RNA sequencing (scRNA-seq). First, we implemented FixNCut, a protocol that preserves transcriptional profiles and tissue composition by fixing samples at the time of collection, enabling subsequent tissue dissociation with minimal stress-induced artifacts. We then generated a comprehensive reference of the inflammatory spectrum in circulating immune cells using single-cell transcriptomic profiles from over 1,000 patients suffering from 20 immune-driven diseases and healthy individuals. By analyzing the immune cell composition and inflammatory molecule expression, we characterized the immune response across diseases, identifying both commonalities and disease-specific differences. Using interpretable machine learning algorithms, we captured disease-specific inflammatory genes at the cell type level that could serve as clinical biomarkers. Furthermore, we proposed a framework for classifying patients based on their blood-derived inflammatory profiles. Finally, we studied the immunomodulatory effects of albumin treatment in patients with acute decompensated cirrhosis, which resulted in immune transcriptional reprogramming that primarily affected B lymphocytes and enhanced neutrophil antimicrobial activity, boosting the patients' immune response against infections. In summary, this thesis integrates scRNA-seq experimental and computational methods to facilitate large-scale, decentralized research on immune-driven diseases with the goal of applying these approaches for disease diagnosis, monitoring progression, and assessing therapy responses in clinical settings.[cat] La inflamació és una resposta fisiològica essencial per mantenir l’homeòstasi, però quan el sistema immunitari es desregula, pot resultar patològica i desencadenar malalties. Entendre la complexitat dels mecanismes inflamatoris de cada malaltia és clau per desenvolupar tractaments efectius. Les tecnologies de seqüenciació de cèl·lula única permeten estudiar el sistema immunitari a alta resolució, proporcionant informació sobre la heterogeneïtat cel·lular i la dinàmica de la resposta immunitària. Per maximitzar-ne el potencial, calen protocols estandarditzats per a la recollida i processament de mostres així com mètodes computacionals que garanteixin un anàlisi robust. Les malalties amb component immunitari sovint afecten teixits específics i presenten perfils inflamatoris diferents pel que cal un enfoc global. La sang permet monitoritzar la inflamació mesurant els nivells de citocines i l’activitat cel·lular, convertint-la en una mostra ideal per entendre els mecanismes de la malaltia i les respostes terapèutiques. En aquesta tesi, s’han desenvolupat protocols experimentals i eines computacionals per a l’estudi de perfils inflamatoris humans amb seqüenciació d’ARN de cèl·lula única (scRNA-seq). Per començar, hem implementat el FixNCut, un protocol que fixa les mostres en el moment d’obtenció, preservant el perfil transcripcional i la composició cel·lular i minimitzant els artefactes tècnics. També hem creat una referència exhaustiva de l’espectre inflamatori de cèl·lules immunitàries de la sang amb més de 1,000 pacients, incloent 20 malalties i individus sans. Analitzant la composició cel·lular i l’expressió de molècules inflamatòries, hem caracteritzat la resposta immunitària d’aquestes malalties. Mitjançant l’ús d’algoritmes d’aprenentatge automàtic, hem identificat gens inflamatoris específics de malaltia i tipus cel·lular que podrien servir com a biomarcadors clínics, i hem proposat una estratègia per classificar pacients segons els seus perfils inflamatoris derivats de la sang. Finalment, hem analitzat els efectes immunomoduladors del tractament amb albúmina en pacients amb cirrosi descompensada aguda, observant reprogramació transcripcional en els limfòcits B i un augment de l’activitat antimicrobiana dels neutròfils, millorant la resposta immunitària envers infeccions. Per concloure, aquesta tesi integra mètodes experimentals i computacionals de scRNA-seq per la investigació de malalties originades per la disfunció del sistema immunitari amb l’objectiu d’aplicar aquests coneixements al diagnòstic, monitoratge i respostes terapèutiques en un context clínic.Universitat de BarcelonaHeyn, HolgerGut, Ivo G.Universitat de Barcelona. Facultat de Biologia2024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/218700http://hdl.handle.net/10803/693643Tesis Doctorals - Facultat - Biologiareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc by-nc-nd (c) Jiménez Gracia, Laura, 2025http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2187002026-05-27T06:46:51Z |
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15,812455 |