scholarly journals Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Spyridon Megremis ◽  
Thomas D. J. Walker ◽  
Xiaotong He ◽  
James O’Sullivan ◽  
William E. R. Ollier ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Signalling Pathways ◽  
Antibody Repertoire ◽  
Biological Processes ◽  
Adult Onset ◽  
Epitope Spreading ◽  
Human Proteins ◽  
Antibody Repertoires ◽  
Trim Proteins ◽  
Disease Specific

AbstractWe investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

scholarly journals Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

2020 ◽  
Author(s):  
Spyridon Megremis ◽  
Thomas D. J. Walker ◽  
Xiaotong He ◽  
James O’Sullivan ◽  
William E.R. Ollier ◽  
...  
Keyword(s):  
Shared Epitope ◽  
Molecular Mimicry ◽  
Signalling Pathways ◽  
Antibody Repertoire ◽  
Biological Processes ◽  
Adult Onset ◽  
Epitope Spreading ◽  
Human Proteins ◽  
Trim Proteins ◽  
Disease Specific

SummaryWe investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. Increased microbial diversity was observed in dermatomyositis. Viruses were over-represented and species of the Poxviridae family were significantly enriched. The autoantibodies identified recognised a large portion of the human proteome, including interferon regulated proteins; these proteins were clustered in specific biological processes. Apart from TRIM33, autoantibodies against eleven further TRIM proteins, including TRIM21, were identified. Some of these TRIM proteins shared epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a significant role in the pathogenesis of dermatomyositis.

scholarly journals Benchmarking evolutionary tinkering underlying human–viral molecular mimicry shows multiple host pulmonary–arterial peptides mimicked by SARS-CoV-2

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
A. J. Venkatakrishnan ◽  
Nikhil Kayal ◽  
Praveen Anand ◽  
Andrew D. Badley ◽  
George M. Church ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Herd Immunity ◽  
Computational Framework ◽  
Human Lungs ◽  
Human Proteins ◽  
Peptide Mimicry ◽  
Pulmonary Arterial ◽  
Binding Peptides ◽  
Human Viruses

Abstract The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A*03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.

scholarly journals Signatures of selection in the human antibody repertoire: Selective sweeps, competing subclones, and neutral drift

2019 ◽  
Vol 116 (4) ◽  
pp. 1261-1266 ◽  
Author(s):  
Felix Horns ◽  
Christopher Vollmers ◽  
Cornelia L. Dekker ◽  
Stephen R. Quake
Keyword(s):  
B Cell ◽  
Binding Affinity ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Selective Sweeps ◽  
Human Immune System ◽  
Evolutionary Processes ◽  
Neutral Drift ◽  
Cell Lineages ◽  
Antibody Repertoires

Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.

scholarly journals The miR-302/367 cluster: a comprehensive update on its evolution and functions

Open Biology ◽  
2015 ◽  
Vol 5 (12) ◽  
pp. 150138 ◽  
Author(s):  
Zeqian Gao ◽  
Xueliang Zhu ◽  
Yongxi Dou
Keyword(s):  
Evolutionary History ◽  
Regulation Of Gene Expression ◽  
Embryonic Stem ◽  
Signalling Pathways ◽  
Transcriptional Level ◽  
Biological Processes ◽  
Related Protein ◽  
Non Coding Rnas ◽  
Cycle Regulation ◽  
Fine Tune

microRNAs are a subclass of small non-coding RNAs that fine-tune the regulation of gene expression at the post-transcriptional level. The miR-302/367 cluster, generally consisting of five members, miR-367, miR-302d, miR-302a, miR-302c and miR-302b, is ubiquitously distributed in vertebrates and occupies an intragenic cluster located in the gene La-related protein 7 ( LARP7 ). The cluster was demonstrated to play an important role in diverse biological processes, such as the pluripotency of human embryonic stem cells (hESCs), self-renewal and reprogramming. This paper provides an overview of the mir-302/367 cluster, discusses our current understanding of the cluster's evolutionary history and transcriptional regulation and reviews the literature surrounding the cluster's roles in cell cycle regulation, epigenetic regulation and different cellular signalling pathways.

scholarly journals Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest

2021 ◽  
Author(s):  
Praveen Anand ◽  
Patrick J. Lenehan ◽  
Michiel Niesen ◽  
Unice Yoo ◽  
Dhruti Patwardhan ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Clinical Phenotype ◽  
South Asians ◽  
Viral Evolution ◽  
Cardiac Injury ◽  
Protein Coding ◽  
Cardiac Inflammation ◽  
Splicing Variants ◽  
Human Proteins ◽  
Low Prevalence

AbstractAcute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.

scholarly journals Regulatory Approved Monoclonal Antibodies Contain Framework Mutations Predicted From Human Antibody Repertoires

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian M. Petersen ◽  
Sophia A. Ulmer ◽  
Emily R. Rhodes ◽  
Matias F. Gutierrez-Gonzalez ◽  
Brandon J. Dekosky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
High Frequency ◽  
In Silico ◽  
Sequence Data ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Therapeutic Antibodies ◽  
T Cell Epitopes ◽  
Antibody Repertoires ◽  
Dynamics Simulations

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using baseline human antibody repertoire sequences. Our analysis shows that human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from baseline human antibody sequence data. We find that mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in baseline human antibody repertoires. In addition, high frequency mutations in baseline human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that baseline human antibody repertoires may be useful as predictive tools to guide mAb development in the future.

scholarly journals SweetOrigins: Extracting Evolutionary Information from Glycans

2020 ◽  
Author(s):  
Daniel Bojar ◽  
Rani K. Powers ◽  
Diogo M. Camacho ◽  
James J. Collins
Keyword(s):  
Machine Learning ◽  
Phylogenetic Trees ◽  
Capsular Polysaccharide ◽  
Molecular Mimicry ◽  
Language Model ◽  
Major Influence ◽  
Evolutionary Information ◽  
Biological Processes ◽  
Host Pathogen Interactions ◽  
Host Pathogen

AbstractGlycans, the most diverse biopolymer and crucial for many biological processes, are shaped by evolutionary pressures stemming in particular from host-pathogen interactions. While this positions glycans as being essential for understanding and targeting host-pathogen interactions, their considerable diversity and a lack of methods has hitherto stymied progress in leveraging their predictive potential. Here, we utilize a curated dataset of 12,674 glycans from 1,726 species to develop and apply machine learning methods to extract evolutionary information from glycans. Our deep learning-based language model SweetOrigins provides evolution-informed glycan representations that we utilize to discover and investigate motifs used for molecular mimicry-mediated immune evasion by commensals and pathogens. Novel glycan alignment methods enable us to identify and contextualize virulence-determining motifs in the capsular polysaccharide of Staphylococcus aureus and Acinetobacter baumannii. Further, we show that glycan-based phylogenetic trees contain most of the information present in traditional 16S rRNA-based phylogenies and improve on the differentiation of genetically closely related but phenotypically divergent species, such as Bacillus cereus and Bacillus anthracis. Leveraging the evolutionary information inherent in glycans with machine learning methodology is poised to provide further – critically needed – insights into host-pathogen interactions, sequence-to-function relationships, and the major influence of glycans on phenotypic plasticity.

scholarly journals Dual UMIs and Dual Barcodes With Minimal PCR Amplification Removes Artifacts and Acquires Accurate Antibody Repertoire

2021 ◽  
Vol 12 ◽  
Author(s):  
Qilong Wang ◽  
Huikun Zeng ◽  
Yan Zhu ◽  
Minhui Wang ◽  
Yanfang Zhang ◽  
...  
Keyword(s):  
Pcr Amplification ◽  
Antibody Repertoire ◽  
Consensus Building ◽  
Chain Reaction ◽  
Single Nucleotide ◽  
False Discovery ◽  
Novel Approach ◽  
Repertoire Sequencing ◽  
Polymerase Chain ◽  
Antibody Repertoires

Antibody repertoire sequencing (Rep-seq) has been widely used to reveal repertoire dynamics and to interrogate antibodies of interest at single nucleotide-level resolution. However, polymerase chain reaction (PCR) amplification introduces extensive artifacts including chimeras and nucleotide errors, leading to false discovery of antibodies and incorrect assessment of somatic hypermutations (SHMs) which subsequently mislead downstream investigations. Here, a novel approach named DUMPArts, which improves the accuracy of antibody repertoires by labeling each sample with dual barcodes and each molecule with dual unique molecular identifiers (UMIs) via minimal PCR amplification to remove artifacts, is developed. Tested by ultra-deep Rep-seq data, DUMPArts removed inter-sample chimeras, which cause artifactual shared clones and constitute approximately 15% of reads in the library, as well as intra-sample chimeras with erroneous SHMs and constituting approximately 20% of the reads, and corrected base errors and amplification biases by consensus building. The removal of these artifacts will provide an accurate assessment of antibody repertoires and benefit related studies, especially mAb discovery and antibody-guided vaccine design.

scholarly journals Molecular Mimicry Map (3M) of SARS-CoV-2: Prediction of potentially immunopathogenic SARS-CoV-2 epitopes via a novel immunoinformatic approach

2020 ◽  
Author(s):  
Hyunsu An ◽  
Jihwan Park
Keyword(s):  
T Cell ◽  
Autoimmune Diseases ◽  
Web Application ◽  
Molecular Mimicry ◽  
Sequence Similarity ◽  
Protein Structures ◽  
Cross Reactivity ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
Human Proteins

ABSTRACTCurrently, more than 33 million peoples have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than a million people died from coronavirus disease 2019 (COVID-19), a disease caused by the virus. There have been multiple reports of autoimmune and inflammatory diseases following SARS-CoV-2 infections. There are several suggested mechanisms involved in the development of autoimmune diseases, including cross-reactivity (molecular mimicry). A typical workflow for discovering cross-reactive epitopes (mimotopes) starts with a sequence similarity search between protein sequences of human and a pathogen. However, sequence similarity information alone is not enough to predict cross-reactivity between proteins since proteins can share highly similar conformational epitopes whose amino acid residues are situated far apart in the linear protein sequences. Therefore, we used a hidden Markov model-based tool to identify distant viral homologs of human proteins. Also, we utilized experimentally determined and modeled protein structures of SARS-CoV-2 and human proteins to find homologous protein structures between them. Next, we predicted binding affinity (IC50) of potentially cross-reactive T-cell epitopes to 34 MHC allelic variants that have been associated with autoimmune diseases using multiple prediction algorithms. Overall, from 8,138 SARS-CoV-2 genomes, we identified 3,238 potentially cross-reactive B-cell epitopes covering six human proteins and 1,224 potentially cross-reactive T-cell epitopes covering 285 human proteins. To visualize the predicted cross-reactive T-cell and B-cell epitopes, we developed a web-based application “Molecular Mimicry Map (3M) of SARS-CoV-2” (available at https://ahs2202.github.io/3M/). The web application enables researchers to explore potential cross-reactive SARS-CoV-2 epitopes alongside custom peptide vaccines, allowing researchers to identify potentially suboptimal peptide vaccine candidates or less ideal part of a whole virus vaccine to design a safer vaccine for people with genetic and environmental predispositions to autoimmune diseases. Together, the computational resources and the interactive web application provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune disease following COVID-19.

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