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in category immunology

1,107 results found. For more information, click each entry to expand.

1: Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans
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Posted to bioRxiv 05 Jan 2018

Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans
27,636 downloads immunology

Carsten Trevor Charlesworth, Priyanka S Deshpande, Daniel P Dever, Beruh Dejene, Natalia Gomez-Ospina, Sruthi Mantri, Mara Pavel-Dinu, Joab Camarena, Kenneth I Weinberg, Matthew H Porteus

The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. The most widely used homologs of the Cas9 protein are derived from the bacteria Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). Based on the fact that these two bacterial species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureus homolog of Cas9) and SpCas9 (S. pyogenes homolog of Cas9). To determine the presence of anti-Cas9 antibodies, we probed for the two homologs using human serum and were able to detect antibodies against both, with 79% of donors staining against SaCas9 and 65% of donors staining against SpCas9. Upon investigating the presence of antigen-specific T-cells against the two homologs in human peripheral blood, we found anti-SaCas9 T-cells in 46% of donors. Upon isolating, expanding, and conducting antigen re-stimulation experiments on several of these donors anti-SaCas9 T-cells, we observed a SaCas9-specific response confirming that these T-cells were antigen-specific. We were unable to detect antigen-specific T-cells against SpCas9, although the sensitivity of the assay precludes us from concluding that such T-cells do not exist. Together, this data demonstrates that there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.

2: Dengue Virus Antibodies Enhance Zika Virus Infection
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Posted to bioRxiv 25 Apr 2016

Dengue Virus Antibodies Enhance Zika Virus Infection
9,058 downloads immunology

Lauren M Paul, Eric R Carlin, Meagan M Jenkins, Amanda L Tan, Carolyn M Barcellona, Cindo O Nicholson, Lydie Trautmann, Scott F Michael, Sharon Isern

Background For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases endemic in the same regions. Recent reports of severe disease associated with ZIKV, including Guillain-Barre syndrome and severe fetal abnormalities, have greatly heightened awareness. Given its recent history of rapid spread in immune naive populations, it is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent Aedes mosquito vectors are found. Globally, dengue virus (DENV) is the most common mosquito-transmitted human flavivirus and is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through a mechanism known as antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. However, response to DENV antibodies has not yet been investigated. Methodology / Principal Findings We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. Conclusions / Significance Our results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

3: Single-cell Map of Diverse Immune Phenotypes Driven by the Tumor Microenvironment
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Posted to bioRxiv 25 Nov 2017

Single-cell Map of Diverse Immune Phenotypes Driven by the Tumor Microenvironment
8,244 downloads immunology

Elham Azizi, Ambrose J Carr, George Plitas, Andrew E. Cornish, Catherine Konopacki, Sandhya Prabhakaran, Juozas Nainys, Kenmin Wu, Vaidotas Kiseliovas, Manu Setty, Kristy Choi, Rachel M. Fromme, Phuong Dao, Peter T. McKenney, Ruby C. Wasti, Krishna Kadaveru, Linas Mazutis, Alexander Y. Rudensky, Dana Pe'er

Knowledge of immune cell phenotypes in the tumor microenvironment is essential for understanding mechanisms of cancer progression and immunotherapy response. We created an immune map of breast cancer using single-cell RNA-seq data from 45,000 immune cells from eight breast carcinomas, as well as matched normal breast tissue, blood, and lymph node. We developed a preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, to address computational challenges inherent to single-cell data. Despite significant similarity between normal and tumor tissue-resident immune cells, we observed continuous tumor-specific phenotypic expansions driven by environmental cues. Analysis of paired single-cell RNA and T cell receptor (TCR) sequencing data from 27,000 additional T cells revealed the combinatorial impact of TCR utilization on phenotypic diversity. Our results support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer, with important implications for characterizing tumor-infiltrating immune cells.

4: Tumor-infiltrating immune repertoires captured by single-cell barcoding in emulsion
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Posted to bioRxiv 05 May 2017

Tumor-infiltrating immune repertoires captured by single-cell barcoding in emulsion
5,901 downloads immunology

Adrian W Briggs, Stephen J Goldfless, Sonia Timberlake, Brian J Belmont, Christopher R Clouser, David Koppstein, Devin Sok, Jason Vander A Heiden, Manu V Tamminen, Steven H Kleinstein, Dennis R Burton, George M Church, Francois Vigneault

Tumor-infiltrating lymphocytes (TILs) are critical to anti-cancer immune responses, but their diverse phenotypes and functions remain poorly understood and challenging to study. We therefore developed a single-cell barcoding technology for deep characterization of TILs without the need for cell-sorting or culture. Our emulsion-based method captures full-length, natively paired B-cell and T-cell receptor (BCR and TCR) sequences from lymphocytes among millions of input cells. We validated the method with 3 million B-cells from healthy human blood and 350,000 B-cells from an HIV elite controller, before processing 400,000 cells from an unsorted dissociated ovarian adenocarcinoma and recovering paired BCRs and TCRs from over 11,000 TILs. We then extended the barcoding method to detect DNA-labeled antibodies, allowing ultra-high throughput, simultaneous protein detection and RNA sequencing from single cells.

5: Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
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Posted to bioRxiv 03 Aug 2018

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function
4,862 downloads immunology

Eric Shifrut, Julia Carnevale, Victoria Tobin, Theodore L. Roth, Jonathan M Woo, Christina Bui, P. Jonathan Li, Morgan Diolaiti, Alan Ashworth, Alexander Marson

Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, sgRNA lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells. Genome-wide loss-of-function screens identified essential T cell receptor signaling components and genes that negatively tune proliferation following stimulation. Targeted ablation of individual candidate genes validated hits and identified perturbations that enhanced cancer cell killing. SLICE coupled with single-cell RNA-Seq revealed signature stimulation-response gene programs altered by key genetic perturbations. SLICE genome-wide screening was also adaptable to identify mediators of immunosuppression, revealing genes controlling response to adenosine signaling. The SLICE platform enables unbiased discovery and characterization of functional gene targets in primary cells.

6: Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation
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Posted to bioRxiv 22 Nov 2017

Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation
3,855 downloads immunology

Ricardo J Miragaia, Tomás Gomes, Agnieszka Chomka, Laura Jardine, Angela Riedel, Ahmed N Hegazy, Ida Lindeman, Guy Emerton, Thomas Krausgruber, Jacqueline Shields, Muzlifah Haniffa, Fiona Powrie, Sarah A Teichmann

Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells, the development and phenotype of which remains largely unexplored. Here, we used single-cell RNA-seq to characterise CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, the respective draining lymph nodes and spleen. From this data, we modelled a continuous lymphoid-to-NLT trajectory for Treg, and reconstructed the mechanisms of cell migration and NLT adaption. This revealed a shared transcriptional programme of NLT priming in both skin and colon-associated lymph nodes, followed by tissue-specific adaptation. Predicted migration kinetics were validated using a melanoma-induction model, emphasizing the relevance of key regulators and receptors, including Batf, Rora, Ccr8, Samsn1. Finally, we profiled human blood and NLT Treg and Tmem cells, identifying cross-mammalian conserved tissue signatures. In summary, we have identified molecular signals mediating NLT Treg recruitment and tissue adaptation through the combined use of computational prediction and in vivo validation.

7: Reference-based annotation of single-cell transcriptomes identifies a profibrotic macrophage niche after tissue injury
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Posted to bioRxiv 19 Mar 2018

Reference-based annotation of single-cell transcriptomes identifies a profibrotic macrophage niche after tissue injury
3,518 downloads immunology

Dvir Aran, Agnieszka P. Looney, Leqian Liu, Valerie Fong, Austin Hsu, Paul J. Wolters, Adam Abate, Atul J. Butte, Mallar Bhattacharya

Myeloid cells localize to peripheral tissues in a wide range of pathologic contexts. However, appreciation of distinct myeloid subtypes has been limited by the signal averaging inherent to bulk sequencing approaches. Here we applied single-cell RNA sequencing (scRNA-seq) to map cellular heterogeneity in lung fibrosis induced by bleomycin injury in mice. We first developed a computational framework that enables unbiased, granular cell-type annotation of scRNA-seq. This approach identified a macrophage subpopulation that was specific to injured lung and notable for high expression of Cx3cr1+ and MHCII genes. We found that these macrophages, which bear a gene expression profile consistent with monocytic origin, progressively acquire alveolar macrophage identity and localize to sites of fibroblast accumulation. Probing their functional role, in vitro studies showed a trophic effect of these cells on fibroblast activation, and ablation of Cx3cr1-expressing cells suppressed fibrosis in vivo. We also found by gene set analysis and immunofluorescence that markers of these macrophages were upregulated in samples from patients with lung fibrosis compared with healthy controls. Taken together, our results uncover a specific pathologic subgroup of macrophages with markers that could enable their therapeutic targeting for fibrosis.

8: The 10,000 Immunomes Project: A resource for human immunology
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Posted to bioRxiv 25 Aug 2017

The 10,000 Immunomes Project: A resource for human immunology
3,499 downloads immunology

Kelly A. Zalocusky, Matthew J. Kan, Zicheng Hu, Patrick Dunn, Elizabeth Thomson, Jeffrey Wiser, Sanchita Bhattacharya, Atul J. Butte

New immunological assays now enable rich measurements of human immune function, but difficulty attaining enough measurements across sufficiently large and diverse cohorts has hindered describing normal human immune physiology on a large scale. Here we present the 10,000 Immunomes Project (10KIP), a diverse human immunology reference derived from over 44,000 individuals across 242 studies from ImmPort, a publicly available resource of raw immunology study data and protocols. We carefully curated datasets, aggregating subjects from healthy/control arms and harmonizing data across studies. We demonstrate 10KIP's utility by describing variations in serum cytokines and leukocytes by age, race, and sex; defining a baseline cell-cytokine network; and using 10KIP as a common control to describe immunologic changes in pregnancy. Subject-level data is available for interactive visualization and download at http://10kImmunomes.org/. We believe 10KIP can serve as a common control cohort and will accelerate hypothesis generation by clinical and basic immunologists across diverse populations.

9: Profiling immunoglobulin repertoires across multiple human tissues by RNA Sequencing
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Posted to bioRxiv 22 Nov 2016

Profiling immunoglobulin repertoires across multiple human tissues by RNA Sequencing
2,962 downloads immunology

Serghei Mangul, Igor Mandric, Harry Taegyun Yang, Nicolas Strauli, Dennis Montoya, Jeremy Rotman, Will Van Der Wey, Jiem R. Ronas, Benjamin Statz, Alex Zelikovsky, Roberto Spreafico, Sagiv Shifman, Noah Zaitlen, Maura Rossetti, K. Mark Ansel, Eleazar Eskin

Assay-based approaches provide a detailed view of the adaptive immune system by profiling T and B cell receptor repertoires. However, these methods come at a high cost and lack the scale of standard RNA sequencing (RNA-seq). Here we report the development of ImReP, a novel computational method for rapid and accurate profiling of the adaptive immune repertoire from regular RNA-Seq data. We applied it to 8,555 samples across 544 individuals from 53 tissues from the Genotype-Tissue Expression (GTEx v6) project. ImReP is able to efficiently extract TCR- and BCR- derived reads from the RNA-Seq data and accurately assemble the complementarity determining regions 3 (CDR3s), the most variable regions of B- and T-cell receptors determining their antigen specificity. Using ImReP, we have created the systematic atlas of immunological sequences for B- and T-cell repertoires across a broad range of tissue types, most of which have not been studied for B and T cell receptor repertoires. We have also examined the compositional similarities of clonal populations between the GTEx tissues to track the flow of T- and B- clonotypes across immune-related tissues, including secondary lymphoid organs and organs encompassing mucosal, exocrine, and endocrine sites. The atlas of T- and B-cell receptor receptors, freely available at https://sergheimangul.wordpress.com/atlas-immune-repertoires/, is the largest collection of CDR3 sequences and tissue types. We anticipate this recourse will enhance future studies in areas such as immunology and advance development of therapies for human diseases. ImReP is freely available at https://sergheimangul.wordpress.com/imrep/ .

10: Genome-wide CRISPR screens in T helper cells reveal pervasive cross-talk between activation and differentiation
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Posted to bioRxiv 04 Oct 2017

Genome-wide CRISPR screens in T helper cells reveal pervasive cross-talk between activation and differentiation
2,859 downloads immunology

Johan Henriksson, Xi Chen, Tomás Gomes, Ubaid Ullah, Kerstin B Meyer, Ricardo Miragaia, Graham Duddy, Jhuma Pramanik, Kosuke Yusa, Riita Lahesmaa, Sarah A Teichmann

T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, auto-immunity and tumour immunology. Using a newly developed, genome-wide retroviral CRISPR knock-out (KO) library, combined with RNA-seq, ATAC-seq and ChIP-seq, we have dissected the regulatory circuitry governing activation (including proliferation) and differentiation of these cells. Our experiments distinguish cell activation versus differentiation in a quantitative framework. We demonstrate that these two processes are tightly coupled and are jointly controlled by many transcription factors, metabolic genes and cytokine/receptor pairs. There is only a small number of genes regulating differentiation without any role in activation. Our study provides an atlas for the T helper cell regulatory network, pinpointing key players of Th2 differentiation and demonstrating remarkable plasticity between the diverse T helper cell fates. We provide an online resource for interactive data querying at: http://data.teichlab.org.

11: Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
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Posted to bioRxiv 20 Jun 2018

Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
2,740 downloads immunology

Fan Zhang, Kevin Wei, Kamil Slowikowski, Chamith Y. Fonseka, Deepak A. Rao, Stephen Kelly, Susan M. Goodman, Darren Tabechian, Laura B. Hughes, Karen Salomon-Escoto, Gerald F. M. Watts, William Apruzzese, David J. Lieb, David L. Boyle, Arthur M. Mandelin, Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE, Brendan F. Boyce, Edward DiCarlo, Ellen M. Gravallese, Peter K. Gregersen, Larry Moreland, Gary S. Firestein, Nir Hacohen, Chad Nusbaum, James A. Lederer, Harris Perlman, Costantino Pitzalis, Andrew Filer, V. Michael Holers, Vivian P. Bykerk, Laura T. Donlin, Jennifer H. Anolik, Michael B. Brenner, Soumya Raychaudhuri

To define the cell populations in rheumatoid arthritis (RA) driving joint inflammation, we applied single-cell RNA-seq (scRNA-seq), mass cytometry, bulk RNA-seq, and flow cytometry to sorted T cells, B cells, monocytes, and fibroblasts from 51 synovial tissue RA and osteoarthritis (OA) patient samples. Utilizing an integrated computational strategy based on canonical correlation analysis to 5,452 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1+HLAhigh sublining fibroblasts (OR=33.8), IL1B+ pro-inflammatory monocytes (OR=7.8), CD11c+T-bet+ autoimmune-associated B cells (OR=5.7), and PD-1+ Tph/Tfh (OR=3.0). We also defined CD8+ T cell subsets characterized by GZMK+, GZMB+, and GNLY+ expression. Using bulk and single-cell data, we mapped inflammatory mediators to source cell populations, for example attributing IL6 production to THY1+HLAhigh fibroblasts and naive B cells, and ILB to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

12: Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders
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Posted to bioRxiv 18 Nov 2013

Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders
2,642 downloads immunology

Claudiu I Bandea

Despite decades of research, thousands of studies and numerous advances, the etiologies of Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD-U), Creutzfeldt-Jakob Disease (CJD), Reactive Systemic Amyloidosis (RSA) and many other neurodegenerative and systemic amyloid diseases have not been defined, nor have the pathogenic mechanisms leading to cellular death and disease. Moreover, the biological functions of APP/amyloid-β (Aβ), tau, α-synuclein, huntingtin, TAR DNA-binding protein 43 (TDP-43), prion protein (PrP), amyloid A (AA) and some of the other primary proteins implicated in amyloid diseases are not known. And, there are no successful preventive or therapeutic approaches. Based on a comprehensive analysis and new interpretation of the existing data in context of an evolutionary framework, it is proposed that: (i) Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system, (ii) the isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire, and (iii) the immune reactions and activities associated with the function of these proteins in innate immunity lead to AD, PD, HD, ALS, CJD, RSA and other related diseases, which are innate immunity disorders.

13: Antibody mediated epitope mimicry in the pathogenesis of Zika virus related disease
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Posted to bioRxiv 19 Mar 2016

Antibody mediated epitope mimicry in the pathogenesis of Zika virus related disease
2,488 downloads immunology

Jane Homan, Robert W Malone, Steven J Darnell, Robert D. Bremel

The association of Guillain-Barré syndrome with Zika virus infection raises suspicion of autoimmunity in the pathogenesis of Zika associated disease. Using computational analysis to identify predicted B and T cell epitopes, we assessed whether antibodies elicited by B cell epitopes in Zika virus may also target B cell epitopes in the human proteome. We detected amino acid motifs predicted to be B cell epitopes in Zika virus proteins which are also present in human proteins, including pro-neuropeptide Y (proNPY), NAV2 and other proteins with interacting neurophysiologic function. We examine the predicted MHC binding of peptides likely to provide T cell help to the potential mimic epitopes. Some potential mimic epitopes in Zika virus envelope have apparently strong T cell help, likely facilitating immunoglobulin class switch. We also identify epitope mimic commonalities with dengue serotypes 1 and 3. We hypothesize that antibodies to Zika virus epitopes may contribute to the pathogenesis of Zika-associated Guillain-Barré syndrome, microcephaly, and ocular lesions, and may be a driver of autoimmunity. The risk associated with responses to potential epitope mimics must be addressed in the development of vaccines and therapeutics for Zika virus infections.

14: A protocol for single-cell transcriptomics from cryopreserved renal tissue and urine for the Accelerating Medicine Partnership (AMP) RA/SLE network
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Posted to bioRxiv 05 Mar 2018

A protocol for single-cell transcriptomics from cryopreserved renal tissue and urine for the Accelerating Medicine Partnership (AMP) RA/SLE network
2,346 downloads immunology

Deepak A. Rao, Celine C Berthier, Arnon Arazi, Anne Davidson, Yanyan Liu, Edward P Browne, Thomas M. Eisenhaure, Adam Chicoine, David J. Lieb, Dawn E. Smilek, Patti Tosta, James A. Lederer, Michael B. Brenner, David Hildeman, E. Steve Woodle, David Wofsy, Jennifer H. Anolik, Matthias Kretzler, Accelerating Medicines Partnership RA/SLE Network, Nir Hacohen, Betty Diamond

OBJECTIVE: There is a critical need to define the cells that mediate tissue damage in lupus nephritis. Here we aimed to establish a protocol to preserve lupus nephritis kidney biopsies and urine cell samples obtained at multiple clinical sites for subsequent isolation and transcriptomic analysis of single cells. METHODS: Fresh and cryopreserved kidney tissue from tumor nephrectomies and lupus nephritis kidney biopsies were disaggregated by enzymatic digestion. Cell yields and cell composition were assessed by flow cytometry. Transcriptomes of leukocytes and epithelial cells were evaluated by low-input and single cell RNA-seq. RESULTS: Cryopreserved kidney tissue from tumor nephrectomies and lupus nephritis biopsies can be thawed and dissociated to yield intact, viable leukocytes and epithelial cells. Cryopreservation of intact kidney tissue provides higher epithelial cell yields compared to cryopreservation of single cell suspensions from dissociated kidneys. Cell yields and flow cytometric cell phenotypes are comparable between cryopreserved kidney samples and paired kidney samples shipped overnight on wet ice. High-quality single cell and low-input transcriptomic data were generated from leukocytes from both cryopreserved lupus nephritis kidney biopsies and urine, as well as from a subset of kidney epithelial cells. CONCLUSION: The AMP RA/SLE cryopreserved tissue analysis pipeline provides a method for centralized processing of lupus nephritis kidney biopsies and urine samples to generate robust transcriptomic analyses in multi-center studies.

15: The landscape of T cell epitope immunogenicity in sequence space
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Posted to bioRxiv 25 Jun 2017

The landscape of T cell epitope immunogenicity in sequence space
2,280 downloads immunology

Masato Ogishi, Hiroshi Yotsuyanagi

Epitopes bound to major histocompatibility complex (MHC) triggers T cell immunity. However, determinants of epitope immunogenicity remain poorly understood. Here, we describe sequence-based framework mimicking contacts between T cell receptors (TCRs) and peptides. Machine-learning compressed the simulated contact profiles of 21,162 and 31,693 human MHC-I and MHC-II-restricted peptides against public TCR repertoires into a linear coordinate system termed "immunogenicity score." Simulated contact profiles against individual TCRs showed remarkable consistency with observed affinities and contact footprints. Furthermore, comprehensive analysis untangled position- and residue-specific impact of single amino acid change on immunogenicity. Finally, patients with longer survival after checkpoint blockade immunotherapies exhibited higher-immunogenicity neoepitope profiles in addition to higher neoepitope burden. Overall, our framework quantitatively formulates T cell epitope immunogenicity by integrating structural and physicochemical parameters.

16: Predicting Peptide-MHC Binding Affinities With Imputed Training Data
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Posted to bioRxiv 22 May 2016

Predicting Peptide-MHC Binding Affinities With Imputed Training Data
2,132 downloads immunology

Alex Rubinsteyn, Timothy O'Donnell, Nandita Damaraju, Jeffrey Hammerbacher

Predicting the binding affinity between MHC proteins and their peptide ligands is a key problem in computational immunology. State of the art performance is currently achieved by the allele-specific predictor NetMHC and the pan-allele predictor NetMHCpan, both of which are ensembles of shallow neural networks. We explore an intermediate between allele-specific and pan-allele prediction: training allele-specific predictors with synthetic samples generated by imputation of the peptide-MHC affinity matrix. We find that the imputation strategy is useful on alleles with very little training data. We have implemented our predictor as an open-source software package called MHCflurry and show that MHCflurry achieves competitive performance to NetMHC and NetMHCpan.

17: Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
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Posted to bioRxiv 29 Aug 2018

Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
1,974 downloads immunology

David Schafflick, Chenling Xu, Maike Hartlehnert, Michael Cole, Tobias Lautwein, Andreas Schulte-Mecklenbeck, Jolien Wolbert, Michael O Heming, Sven G. Meuth, Tanja Kuhlmann, Catharina C Gross, Heinz Wiendl, Nir Yosef, Gerd Meyer zu Horste

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, we firstly provide a transcriptional map of single leukocytes in CSF compared to blood. Leukocyte composition and transcriptome were compartment-specific with CSF-enrichment of myeloid dendritic cells and a border-associated phenotype of monocytes. We secondly tested how multiple sclerosis (MS) - an autoimmune disease of the CNS - affected both compartments. MS increased transcriptional diversity in blood, while it preferentially increased cell type diversity in CSF. In addition to the known expansion of B lineage cells, we identified an increase of cytotoxic-phenotype and follicular T helper (TFH) cells in the CSF. In mice, TFH cells accordingly promoted B cell infiltration into the CNS and severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate local T/B cell interaction.

18: Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age
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Posted to bioRxiv 13 Jul 2017

Heterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli are Altered with Age
1,968 downloads immunology

Mati Mann, Arnav Mehta, Carl de Boer, Monika S. Kowalczyk, Kevin Lee, Noga Rogel, Abigail R. Knecht, Daneyal Farouq, Aviv Regev, David Baltimore

Long-term hematopoietic stem cells (LT-HSCs) maintain hematopoietic output throughout an animal's lifespan. With age, however, they produce a myeloid-biased output that may lead to poor immune responses to infectious challenge and the development of myeloid leukemias. Here, we show that young and aged LT-HSCs respond differently to inflammatory stress, such that aged LT-HSCs produce a cell-intrinsic, myeloid-biased expression program. Using single-cell RNA-seq, we identify a myeloid-biased subset within the LT-HSC population (mLT-HSCs) that is much more common amongst aged LT-HSCs and is uniquely primed to respond to acute inflammatory challenge. We predict several transcription factors to regulate differentially expressed genes between mLT-HSCs and other LT-HSC subsets. Among these, we show that Klf5, Ikzf1 and Stat3 play important roles in age-related inflammatory myeloid bias. These factors may regulate myeloid versus lymphoid balance with age, and can potentially mitigate the long-term deleterious effects of inflammation that lead to hematopoietic pathologies.

19: Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti TNF therapy
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Posted to bioRxiv 20 Dec 2018

Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti TNF therapy
1,898 downloads immunology

Jerome Christophe Martin, Gilles Boschetti, Christie Chang, Ryan Ungaro, Mamta Giri, Ling-Shiang Chuang, Shikha Nayar, Alexander Greenstein, Marla Dubinsky, Laura Walker, Andrew Leader, Jay Fine, Charles Whitehurst, Lamine Mbow, Subra Kugathasan, Lee Denson, Jeffrey Hyams, Joshua Friedman, Prerak Desai, Mabel Ko, Ilaria Laface, Guray Akturk, Eric Schadt, Sacha Gnjatic, Adeeb Rahman, Miriam Merad, Judy Cho, Ephraim Kenigsberg

Clinical benefits to cytokine blockade in ill Crohn's disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.

20: The immunologic V-gene repertoire in mammals
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Posted to bioRxiv 13 Feb 2014

The immunologic V-gene repertoire in mammals
1,841 downloads immunology

David N Olivieri, Bernardo von Haeften, Christian Sánchez-Espinel, Francisco Gambón-Deza

From recent whole genome shotgun data of 48 mammalian species, we have used our software VgenExtractor to obtain the functional V-gene sequence repertoire in order to conduct comparative phylogenetic studies. These studies reveal a large variation in the number of V-genes across mammalian species, ranging from a mere 36 V-genes in dolphins to nearly 600 V-genes in rats. Monotremes and marsupials are the only mammals possessing an additional locus, the TRMV, apart from the seven common loci found in mammals. Also, we show evidence for the loss of the light chain loci, specifically the V-kappa chain in one microbat, and the V-lambda chain in one rodent species. Finally, we suggest different features related to the evolution of immunoglobulin and T cell receptor loci, where frequent sequence duplications are seen in the former, while preserved and undiversified lineages are observed in the latter. All the V-gene sequences described in this study are available in the public database repository vgenerepertoire.org.

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