Publications by authors named "Jakob Matthes"

6 Publications

  • Page 1 of 1

Immunophenotyping in pemphigus reveals a T17/T17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

J Allergy Clin Immunol 2020 Nov 20. Epub 2020 Nov 20.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Background: T2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear.

Objective: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus.

Methods: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of T cell and folliclular helper (T) cell subsets was analyzed by flow cytometry. Finally, the capacity of T and T cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments.

Results: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17 T17, T17, and T17.1 cells. Notably, levels of T17 and T17 cells correlated with levels of Dsg-specific CD19CD27 memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T17 cells. Coculture experiments revealed T17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.

Conclusion: Our findings show that T17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2020.11.008DOI Listing
November 2020

Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia.

Front Neurol 2019 18;10:1332. Epub 2019 Dec 18.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

This study's aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the gene, making use of a new, cost-efficient enrichment technology for NGS-based screening. Single molecule Molecular Inversion Probes (smMIPs) were used for targeted enrichment and sequencing of all protein coding exons and exon-intron boundaries of the gene in 373 dystonia patients and six positive controls with known variants. Additionally, a rare-variant association study was performed. One patient (0.3%) was compound heterozygous and 21 others were carriers of variants of unknown significance (VUS) in the gene. Although mutations in sporadic dystonia patients are not common, exclusion of pathogenic variants is crucial to recognize a potential tumor predisposition syndrome. SmMIPs produced similar results as routinely used NGS-based approaches. Our results underline the importance of implementing in the routine genetic testing of dystonia patients and confirm the reliability of smMIPs and their usability for germline screenings in rare neurodegenerative conditions.
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http://dx.doi.org/10.3389/fneur.2019.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930228PMC
December 2019

Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy.

Cytotherapy 2019 09 25;21(9):973-986. Epub 2019 Jul 25.

Dr. von Hauner Children's Hospital University Hospital, Ludwig Maximilian University Munich, Munich, Germany. Electronic address:

Background: Medulloblastoma is the most common malignant brain tumor in childhood and adolescence. Although some patients present with distinct genetic alterations, such as mutated TP53 or MYC amplification, pediatric medulloblastoma is a tumor entity with minimal mutational load and low immunogenicity.

Methods: We identified tumor-specific mutations using next-generation sequencing of medulloblastoma DNA and RNA derived from primary tumor samples from pediatric patients. Tumor-specific mutations were confirmed using deep sequencing and in silico analyses predicted high binding affinity of the neoantigen-derived peptides to the patients' human leukocyte antigen molecules. Tumor-specific peptides were synthesized and used to induce a de novo T-cell response characterized by interferon gamma and tumor necrosis factor alpha release of CD8 cytotoxic T cells in vitro.

Results: Despite low mutational tumor burden, at least two immunogenic tumor-specific peptides were identified in each patient. T cells showed a balanced CD4/CD8 ratio and mostly effector memory phenotype. Induction of a CD8-specific T-cell response was achieved for the neoepitopes derived from Histidine Ammonia-Lyase (HAL), Neuraminidase 2 (NEU2), Proprotein Convertase Subtilisin (PCSK9), Programmed Cell Death 10 (PDCD10), Supervillin (SVIL) and tRNA Splicing Endonuclease Subunit 54 (TSEN54) variants.

Conclusion: Detection of patient-specific, tumor-derived neoantigens confirms that even in tumors with low mutational load a molecular design of targets for specific T-cell immunotherapy is possible. The identified neoantigens may guide future approaches of adoptive T-cell transfer, transgenic T-cell receptor transfer or tumor vaccination.
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http://dx.doi.org/10.1016/j.jcyt.2019.06.009DOI Listing
September 2019

Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma.

Genome Med 2019 04 30;11(1):28. Epub 2019 Apr 30.

Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, D-72076, Tübingen, Germany.

Background: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs.

Methods: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data.

Results: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations.

Conclusions: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
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http://dx.doi.org/10.1186/s13073-019-0636-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492406PMC
April 2019

Transcriptional response of Escherichia coli to ammonia and glucose fluctuations.

Microb Biotechnol 2017 07 26;10(4):858-872. Epub 2017 Apr 26.

Institute of Biochemical Engineering, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.

In large-scale production processes, metabolic control is typically achieved by limited supply of essential nutrients such as glucose or ammonia. With increasing bioreactor dimensions, microbial producers such as Escherichia coli are exposed to changing substrate availabilities due to limited mixing. In turn, cells sense and respond to these dynamic conditions leading to frequent activation of their regulatory programmes. Previously, we characterized short- and long-term strategies of cells to adapt to glucose fluctuations. Here, we focused on fluctuating ammonia supply while studying a continuously running two-compartment bioreactor system comprising a stirred tank reactor (STR) and a plug-flow reactor (PFR). The alarmone ppGpp rapidly accumulated in PFR, initiating considerable transcriptional responses after 70 s. About 400 genes were repeatedly switched on/off when E. coli returned to the STR. E. coli revealed highly diverging long-term transcriptional responses in ammonia compared to glucose fluctuations. In contrast, the induction of stringent regulation was a common feature of both short-term responses. Cellular ATP demands for coping with fluctuating ammonia supply were found to increase maintenance by 15%. The identification of genes contributing to the increased ATP demand together with the elucidation of regulatory mechanisms may help to create robust cells and processes for large-scale application.
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http://dx.doi.org/10.1111/1751-7915.12713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481515PMC
July 2017

JSBML 1.0: providing a smorgasbord of options to encode systems biology models.

Bioinformatics 2015 Oct 16;31(20):3383-6. Epub 2015 Jun 16.

University of California, San Diego, La Jolla, CA, USA, Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tübingen, Germany.

Unlabelled: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users.

Availability And Implementation: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/.

Contact: jsbml-development@googlegroups.com or andraeger@eng.ucsd.edu

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595895PMC
October 2015