scholarly journals Functionally Convergent B Cell Receptor Sequences in Transgenic Rats Expressing a Human B Cell Repertoire in Response to Tetanus Toxoid and Measles Antigens

2017 ◽  
Author(s):  
Jean-Philippe Büerckert ◽  
Axel R.S.X. Dubois ◽  
William J. Faison ◽  
Sophie Farinelle ◽  
Emilie Charpentier ◽  
...  
Keyword(s):  
Amino Acid ◽  
B Cell ◽  
Tetanus Toxoid ◽  
Measles Virus ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Transgenic Rats ◽  
Cell Repertoire ◽  
Environmental Carcinogen

AbstractThe identification and tracking of antigen-specific immunoglobulin (Ig) sequences within total Ig repertoires is central to high-throughput sequencing (HTS) studies of infections or vaccinations. In this context, public Ig sequences shared by different individuals exposed to the same antigen could be valuable markers for tracing back infections, measuring vaccine immunogenicity, and perhaps ultimately allow the reconstruction of the immunological history of an individual. Here, we immunized groups of transgenic rats expressing human Ig against tetanus toxoid (TT), Modified Vaccinia virus Ankara (MVA), measles virus hemagglutinin and fusion proteins expressed on MVA and the environmental carcinogen Benzo[a]Pyrene, coupled to TT. We showed that these antigens impose a selective pressure causing the Ig Heavy chain (IgH) repertoires of the rats to converge towards the expression of antibodies with highly similar IgH CDR3 amino acid sequences. We present a computational approach, similar to differential gene expression analysis, that selects for clusters of CDR3s with 80% similarity, significantly overrepresented within the different groups of immunized rats. These IgH clusters represent antigen-induced IgH signatures exhibiting stereotypic amino acid patterns including previously described TT and measles specific IgH sequences. Our data suggest, that with the presented methodology, transgenic Ig rats can be utilized as a model to identify antigen-induced, human IgH signatures to a variety of different antigens.

scholarly journals Functionally Convergent B Cell Receptor Sequences in Transgenic Rats Expressing a Human B Cell Repertoire in Response to Tetanus Toxoid and Measles Antigens

2017 ◽  
Vol 8 ◽  
Author(s):  
Jean-Philippe Bürckert ◽  
Axel R. S. X. Dubois ◽  
William J. Faison ◽  
Sophie Farinelle ◽  
Emilie Charpentier ◽  
...  
Keyword(s):  
B Cell ◽  
Tetanus Toxoid ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Transgenic Rats ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Human B Cell

scholarly journals OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

2019 ◽  
Vol 35 (17) ◽  
pp. 2974-2981 ◽  
Author(s):  
Zachary Sethna ◽  
Yuval Elhanati ◽  
Curtis G Callan ◽  
Aleksandra M Walczak ◽  
Thierry Mora
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
High Throughput Sequencing ◽  
Amino Acid Level ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Supplementary Information ◽  
Published Data ◽  
Cell Receptors

Abstract Motivation High-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. Since the function of a receptor really depends on its protein sequence, it is important to be able to predict this probability of generation at the amino acid level. However, brute-force summation over all the nucleotide sequences with the correct amino acid translation is computationally intractable. The purpose of this paper is to present a solution to this problem. Results We use dynamic programming to construct an efficient and flexible algorithm, called OLGA (Optimized Likelihood estimate of immunoGlobulin Amino-acid sequences), for calculating the probability of generating a given CDR3 amino acid sequence or motif, with or without V/J restriction, as a result of V(D)J recombination in B or T cells. We apply it to databases of epitope-specific T-cell receptors to evaluate the probability that a typical human subject will possess T cells responsive to specific disease-associated epitopes. The model prediction shows an excellent agreement with published data. We suggest that OLGA may be a useful tool to guide vaccine design. Availability and implementation Source code is available at https://github.com/zsethna/OLGA. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs

2018 ◽  
Author(s):  
Zachary Sethna ◽  
Yuval Elhanati ◽  
Curtis G. Callan ◽  
Aleksandra M. Walczak ◽  
Thierry Mora
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
High Throughput Sequencing ◽  
Amino Acid Level ◽  
Cell Receptor ◽  
Amino Acid Sequences ◽  
Published Data ◽  
Cell Receptors ◽  
Specific Nucleotide Sequence

MotivationHigh-throughput sequencing of large immune repertoires has enabled the development of methods to predict the probability of generation by V(D)J recombination of T- and B-cell receptors of any specific nucleotide sequence. These generation probabilities are very non-homogeneous, ranging over 20 orders of magnitude in real repertoires. Since the function of a receptor really depends on its protein sequence, it is important to be able to predict this probability of generation at the amino acid level. However, brute-force summation over all the nucleotide sequences with the correct amino acid translation is computationally intractable. The purpose of this paper is to present a solution to this problem.ResultsWe use dynamic programming to construct an efficient and flexible algorithm, called OLGA (Optimized Likelihood estimate of immunoGlobulin Amino-acid sequences), for calculating the probability of generating a given CDR3 amino acid sequence or motif, with or without V/J restriction, as a result of V(D)J recombination in B or T cells. We apply it to databases of epitope-specific T-cell receptors to evaluate the probability that a typical human subject will possess T cells responsive to specific disease-associated epitopes. The model prediction shows an excellent agreement with published data. We suggest that OLGA may be a useful tool to guide vaccine design.AvailabilitySource code is available at https://github.com/zsethna/OLGA

scholarly journals Mimicry between respiratory virus proteins and some human immune proteins

2020 ◽  
Vol 10 (2) ◽  
pp. 305-314
Author(s):  
I. N. Zhilinskaya
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Amino Acid ◽  
Measles Virus ◽  
Respiratory Infections ◽  
Viral Proteins ◽  
Cellular Protein ◽  
Amino Acid Sequences ◽  
Host Immune System ◽  
Human Immune

A comparative analysis on search for amino acid sequences in viral proteins causing respiratory infections (or respiratory infections syndrome) homologous to amino acid sequences from some human immune proteins was performed. The following viruses were used for comparative computer analysis: coronavirus (SARS-CoV), serotype C subgroup adenovirus C (adenoid 71 strain), measles virus (ICHINOSE-BA strain), rubella (Therien strain) and respiratory syncytial (B1 strain) virus. The search for homologous sequences in viral and human immune proteins was carried out by computer comparison of 12 amino acid fragments, which were assigned as homologous at identity in ≥ 8 positions. The data obtained showed that viral proteins contained homologous motifs in several host immune proteins involved in regulating both the inflammatory response and immune response. Mechanistically, all viruses studied were characterized by sequences homologous to host immune proteins such as complement system proteins, integrins, apoptosis inhibitory proteins, interleukins, and toll-like receptors. Such cellular proteins are actively involved in regulating host inflammatory process and immune response formation. Upon that, a set of host immune proteins, to which homologous fragments were found in viral proteins, was individual for each virus. Interestingly, the largest amount of homologous fragments (up to 20) was mainly concentrated in viral proteins with polymerase and protease activity suggesting that these proteins apart to their major role were involved in production of viral nucleic acids and might participate in regulating host immune system. Envelope, internal and non-structural viral proteins, homologous fragments were detected in much smaller quantities (from 1 to 4). In addition, two fragments homologous to various motifs of the same cellular protein were detected in some viral proteins. Thus, the data obtained further support our understanding that signs of immune system disorders in viral infections can result from multi-layered processes associated with modulation of host innate and adaptive immune system, and open up new approaches to study interaction of viruses with host immune system and identify new functions of viral proteins.

scholarly journals Signatures of B-cell receptor diversity in B lymphocytes following Epstein-Barr virus transformation

2019 ◽  
Vol 51 (6) ◽  
pp. 197-207
Author(s):  
Meimei Lai ◽  
Qiongdan Wang ◽  
Yutian Lu ◽  
Xi Xu ◽  
Ying Xia ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Epstein Barr Virus ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Human Virus ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Epstein-Barr virus (EBV) is a widespread human virus that establishes latent infection, potentially leading to tumors, hematological disorders, and other severe diseases. EBV infections are associated with diverse symptoms and affect various organs; therefore, early diagnosis and treatment are crucial. B cell receptor (BCR) repertoires of B cell surface immunoglobulins have been widely studied for their association with various infectious diseases. However, the specific genetic changes that modulate the BCR repertoires after an EBV infection are still poorly understood. In this study, we employed high-throughput sequencing (HTS) to investigate the diversity of BCR repertoires in an EBV-transformed lymphoblastic cell line (LCL). Compared with the noninfected control B cell line, the LCL exhibited a decrease in overall BCR diversity but displayed an increase in the expansion of some dominant rearrangements such as IGHV4-31/IGHJ4, IGHV4-59/IGHJ4, IGHV5-51/IGHJ3, and IGHV3-74/IGHJ3. A higher frequency of occurrence of these rearrangement types was confirmed in patients with EBV infection. Interestingly, the IGHV3-74 rearrangement was only detected in EBV-infected children, suggesting that our experimental observations were not coincidental. In addition, we identified a highly dominant consensus motif, CAR(xRx)YGSG(xYx)FD, in complementarity-determining region 3 (CDR3) sequences of the heavy chain in the LCL. Our findings demonstrated the utility of HTS technology for studying the variations in signature motifs of the BCR repertoires after EBV infection. We propose that the analysis of BCR repertoire sequences represents a promising method for diagnosing early EBV infections and developing novel antibody- and vaccine-based therapies against such infections.

scholarly journals Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1669
Author(s):  
Jiwon Koh ◽  
Insoon Jang ◽  
Seongmin Choi ◽  
Sehui Kim ◽  
Ingeon Jang ◽  
...  
Keyword(s):  
B Cell ◽  
High Throughput Sequencing ◽  
Marginal Zone ◽  
Progression Free Survival ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
Ki 67 ◽  
Genetic Characteristics ◽  
Recurrent Mutations ◽  
Nodal Marginal Zone Lymphoma

Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-κB pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.

P134 Amino acid sequences of T cell receptor reacting against multiple myeloma

Blood Reviews ◽  
2007 ◽  
Vol 21 ◽  
pp. S129
Author(s):  
S. Dudova ◽  
L. Kovarova ◽  
R. Horvath ◽  
M. Penka ◽  
R. Hajek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Amino Acid Sequences

scholarly journals Quantifying evolutionary constraints on B-cell affinity maturation

2015 ◽  
Vol 370 (1676) ◽  
pp. 20140244 ◽  
Author(s):  
Connor O. McCoy ◽  
Trevor Bedford ◽  
Vladimir N. Minin ◽  
Philip Bradley ◽  
Harlan Robins ◽  
...  
Keyword(s):  
B Cell ◽  
Empirical Bayes ◽  
High Throughput Sequencing ◽  
Sequence Data ◽  
Evolutionary Process ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Variable Regions ◽  
Empirical Bayes Estimators ◽  
Stochastic Mapping

The antibody repertoire of each individual is continuously updated by the evolutionary process of B-cell receptor (BCR) mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B-cell sequence data, and then apply them to a very deep short-read dataset of BCRs. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on BCRs using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.

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