Institut für Medizintechnik und Medizininformatik
Dauerhafte URI für die Sammlunghttps://irf.fhnw.ch/handle/11654/23
Listen
34 Ergebnisse
Ergebnisse nach Hochschule und Institut
Publikation Discovering fundamental principles of antibody repertoires by large-scale systems and network analysis(ETH, 2017) Miho, Enkelejda05 - Forschungs- oder ArbeitsberichtPublikation Computational deconvolution of the dengue immune response complexity with identification of novel broadly neutralizing antibodies(21.09.2022) Natali, Eriberto Noel; Horst, Alexander; Meier, Patrick; Greiff, Victor; Nuvolone, Mario; Babrak, Lmar Marie; Djordjevic, Kristina; Fink, Katja; Traggiai, Elisabetta; Miho, EnkelejdaDengue virus poses a serious threat to global health as the causative agent of the dengue fever. Currently, there is no approved therapeutic, and broadly neutralizing antibodies recognizing all four serotypes may be an effective treatment. High-throughput immune repertoire sequencing and bioinformatic analysis enable in-depth understanding of the immune response in dengue infection. Here, we use these technologies and apply machine learning to identify rare and underrepresented broadly neutralizing antibody sequences through investigation of antibody response in dengue. We observed challenging the immune system with dengue elicits the following signatures on the antibody repertoire: (i) an increase of the diversity in the CDR3 regions and the germline genes; (ii) a change in the architecture by eliciting power-law network distributions and enrichment in polar amino acids of the CDR3; (iii) an increase in the expression of transcription factors of the JNK/Fos pathways and ribosomal proteins. Moreover, our work demonstrates the applicability of computational methods and machine learning to high-throughput antibody repertoire sequencing datasets for neutralizing antibody candidate identification. Further investigation with antibody expression and functional assays is planned to validate the obtained results.06 - PräsentationPublikation Computational strategies for dissecting the high-dimensional complexity of adaptive immune repertoires(Frontiers Research Foundation, 2018) Miho, Enkelejda; Yermanos, Alexander; Weber, Cédric R.; Berger, Christoph T.; Reddy, Sai T.; Greiff, VictorThe adaptive immune system recognizes antigens via an immense array of antigen binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Synthetic standards combined with error and bias correction improve the accuracy and quantitative resolution of antibody repertoire sequencing in human naïve and memory B cells(Frontiers Research Foundation, 20.06.2018) Friedensohn, Simon; Lindner, John M.; Cornacchione, Vanessa; Iazeolla, Mariavittoria; Miho, Enkelejda; Zingg, Andreas; Meng, Simon; Traggiai, Elisabetta; Reddy, Sai T.High-throughput sequencing of immunoglobulin (Ig) repertoires (Ig-seq) is a powerful method for quantitatively interrogating B cell receptor sequence diversity. When applied to human repertoires, Ig-seq provides insight into fundamental immunological questions, and can be implemented in diagnostic and drug discovery projects. However, a major challenge in Ig-seq is ensuring accuracy, as library preparation protocols and sequencing platforms can introduce substantial errors and bias that compromise immunological interpretation. Here, we have established an approach for performing highly accurate human Ig-seq by combining synthetic standards with a comprehensive error and bias correction pipeline. First, we designed a set of 85 synthetic antibody heavy-chain standards (in vitro transcribed RNA) to assess correction workflow fidelity. Next, we adapted a library preparation protocol that incorporates unique molecular identifiers (UIDs) for error and bias correction which, when applied to the synthetic standards, resulted in highly accurate data. Finally, we performed Ig-seq on purified human circulating B cell subsets (naïve and memory), combined with a cellular replicate sampling strategy. This strategy enabled robust and reliable estimation of key repertoire features such as clonotype diversity, germline segment, and isotype subclass usage, and somatic hypermutation. We anticipate that our standards and error and bias correction pipeline will become a valuable tool for researchers to validate and improve accuracy in human Ig-seq studies, thus leading to potentially new insights and applications in human antibody repertoire profiling.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Large-scale network analysis reveals the sequence space architecture of antibody repertoires(Nature, 01.12.2019) Miho, Enkelejda; Roškar, Rok; Greiff, Victor; Reddy, Sai T.The architecture of mouse and human antibody repertoires is defined by the sequence similarity networks of the clones that compose them. The major principles that define the architecture of antibody repertoires have remained largely unknown. Here, we establish a high-performance computing platform to construct large-scale networks from comprehensive human and murine antibody repertoire sequencing datasets (>100,000 unique sequences). Leveraging a network-based statistical framework, we identify three fundamental principles of antibody repertoire architecture: reproducibility, robustness and redundancy. Antibody repertoire networks are highly reproducible across individuals despite high antibody sequence dissimilarity. The architecture of antibody repertoires is robust to the removal of up to 50–90% of randomly selected clones, but fragile to the removal of public clones shared among individuals. Finally, repertoire architecture is intrinsically redundant. Our analysis provides guidelines for the large-scale network analysis of immune repertoires and may be used in the future to define disease-associated and synthetic repertoires.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Maturation of the human B-cell receptor repertoire with age(Cold Spring Harbor Laboratory, 20.12.2019) Ghraichy, Marie; Galson, Jacob D.; Kovaltsuk, Aleksandr; Niederhäusern, Valentin von; Schmid, Jana Pachlopnik; Recher, Mike; Jauch, Annaïse J; Miho, Enkelejda; Kelly, Dominic F.; Deane, Charlotte M.; Trück, JohannesB cells play a central role in adaptive immune processes, mainly through the production of antibodies. The maturation of the B-cell system with age is poorly studied. We extensively investigated age-related alterations of naïve and antigen-experienced B-cell receptor (BCR) repertoires. The most significant changes were observed in the first 10 years of life, and were characterized by altered immunoglobulin gene usage and an increased frequency of mutated antibodies structurally diverging from their germline precursors. Older age was associated with an increased usage of downstream constant region genes and fewer antibodies with self-reactive properties. As mutations accumulated with age, the frequency of germline-encoded self-reactive antibodies decreased, indicating a possible beneficial role of self-reactive B-cells in the developing immune system. Our results suggest a continuous process of change through childhood across a broad range of parameters characterizing BCR repertoires and stress the importance of using well-selected, age-appropriate controls in BCR studies01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Comparison of methods for phylogenetic B-cell lineage inference using time-resolved antibody repertoire simulations (AbSim)(Oxford University Press, 31.08.2017) Yermanos, Alexander; Greiff, Victor; Krautler, Nike Julia; Menzel, Ulrike; Dounas, Andreas; Miho, Enkelejda; Oxenius, Annette; Stadler, Tanja; Reddy, Sai T.; Kelso, JanetMotivation: The evolution of antibody repertoires represents a hallmark feature of adaptive B-cell immunity. Recent advancements in high-throughput sequencing have dramatically increased the resolution to which we can measure the molecular diversity of antibody repertoires, thereby offering for the first time the possibility to capture the antigen-driven evolution of B cells. However, there does not exist a repertoire simulation framework yet that enables the comparison of com monly utilized phylogenetic methods with regard to their accuracy in inferring antibody evolution.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Learning the high-dimensional immunogenomic features that predict public and private antibody repertoires(American Association of Immunologists, 15.10.2017) Greiff, Victor; Weber, Cédric R.; Palme, Johannes; Bodenhofer, Ulrich; Miho, Enkelejda; Menzel, Ulrike; Reddy, Sai T.Recent studies have revealed that immune repertoires contain a substantial fraction of public clones, which may be defined as Ab or TCR clonal sequences shared across individuals. It has remained unclear whether public clones possess predictable sequence features that differentiate them from private clones, which are believed to be generated largely stochastically. This knowledge gap represents a lack of insight into the shaping of immune repertoire diversity. Leveraging a machine learning approach capable of capturing the high-dimensional compositional information of each clonal sequence (defined by CDR3), we detected predictive public clone and private clone–specific immunogenomic differences concentrated in CDR3’s N1–D–N2 region, which allowed the prediction of public and private status with 80% accuracy in humans and mice. Our results unexpectedly demonstrate that public, as well as private, clones possess predictable high-dimensional immunogenomic features. Our support vector machine model could be trained effectively on large published datasets (3 million clonal sequences) and was sufficiently robust for public clone prediction across individuals and studies prepared with different library preparation and high-throughput sequencing protocols. In summary, we have uncovered the existence of high-dimensional immunogenomic rules that shape immune repertoire diversity in a predictable fashion. Our approach may pave the way for the construction of a comprehensive atlas of public mouse and human immune repertoires with potential applications in rational vaccine design and immunotherapeutics.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Synthetic standards combined with error and bias correction improve the accuracy and quantitative resolution of antibody repertoire sequencing in human naïve and memory B cells(Frontiers Research Foundation, 20.06.2018) Friedensohn, Simon; Lindner, John M.; Cornacchione, Vanessa; Iazeolla, Mariavittoria; Miho, Enkelejda; Zingg, Andreas; Meng, Simon; Traggiai, Elisabetta; Reddy, Sai T.High-throughput sequencing of immunoglobulin (Ig) repertoires (Ig-seq) is a powerful method for quantitatively interrogating B cell receptor sequence diversity. When applied to human repertoires, Ig-seq provides insight into fundamental immunological questions, and can be implemented in diagnostic and drug discovery projects. However, a major challenge in Ig-seq is ensuring accuracy, as library preparation protocols and sequencing platforms can introduce substantial errors and bias that compromise immunological interpretation. Here, we have established an approach for performing highly accurate human Ig-seq by combining synthetic standards with a comprehensive error and bias correction pipeline. First, we designed a set of 85 synthetic antibody heavy-chain standards (in vitro transcribed RNA) to assess correction workflow fidelity. Next, we adapted a library preparation protocol that incorporates unique molecular identifiers (UIDs) for error and bias correction which, when applied to the synthetic standards, resulted in highly accurate data. Finally, we performed Ig-seq on purified human circulating B cell subsets (naïve and memory), combined with a cellular replicate sampling strategy. This strategy enabled robust and reliable estimation of key repertoire features such as clonotype diversity, germline segment, and isotype subclass usage, and somatic hypermutation. We anticipate that our standards and error and bias correction pipeline will become a valuable tool for researchers to validate and improve accuracy in human Ig-seq studies, thus leading to potentially new insights and applications in human antibody repertoire profiling.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation High-throughput sequencing of human immunoglobulin variable regions with subtype identification(Public Library of Science, 03.11.2014) Schanz, Merle; Liechti, Thomas; Zagordi, Osvaldo; Miho, Enkelejda; Reddy, Sai T.; Günthard, Huldrych F.; Trkola, Alexandra; Huber, Michael; Lu, ShanThe humoral immune response plays a critical role in controlling infection, and the rapid adaptation to a broad range of pathogens depends on a highly diverse antibody repertoire. The advent of high-throughput sequencing technologies in the past decade has enabled insights into this immense diversity. However, not only the variable, but also the constant region of antibodies determines their in vivo activity. Antibody isotypes differ in effector functions and are thought to play a defining role in elicitation of immune responses, both in natural infection and in vaccination. We have developed an Illumina MiSeq high-throughput sequencing protocol that allows determination of the human IgG subtype alongside sequencing full-length antibody variable heavy chain regions. We thereby took advantage of the Illumina procedure containing two additional short reads as identifiers. By performing paired-end sequencing of the variable regions and customizing one of the identifier sequences to distinguish IgG subtypes, IgG transcripts with linked information of variable regions and IgG subtype can be retrieved. We applied our new method to the analysis of the IgG variable region repertoire from PBMC of an HIV-1 infected individual confirmed to have serum antibody reactivity to the Membrane Proximal External Region (MPER) of gp41. We found that IgG3 subtype frequencies in the memory B cell compartment increased after halted treatment and coincided with increased plasma antibody reactivity against the MPER domain. The sequencing strategy we developed is not restricted to analysis of IgG. It can be adopted for any Ig subtyping and beyond that for any research question where phasing of distant regions on the same amplicon is needed.01A - Beitrag in wissenschaftlicher Zeitschrift