scholarly journals Balancing sensitivity and specificity in distinguishing TCR groups by CDR sequence similarity

2019 ◽  
Author(s):  
Neerja Thakkar ◽  
Chris Bailey-Kellogg
Keyword(s):  
Predictive Power ◽  
Sequence Similarity ◽  
Structural Similarity ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
The Third ◽  
Repertoire Sequencing ◽  
Complementarity Determining Regions ◽  
Cellular Immune

AbstractRepertoire sequencing is enabling deep explorations into the cellular immune response, including the characterization of commonalities and differences among T cell receptor (TCR) repertoires from different individuals, pathologies, and antigen specificities. In seeking to understand the generality of patterns observed in different groups of TCRs, it is necessary to balance how well each pattern represents the diversity among TCRs from one group (sensitivity) vs. how many TCRs from other groups it also represents (specificity). The variable complementarity determining regions (CDRs), particularly the third CDRs (CDR3s) interact with MHC-presented epitopes from putative antigens, and thus encode the determinants of recognition. We here systematically characterize the predictive power that can be obtained from CDR3 sequences, using representative, readily interpretable methods for evaluating CDR sequence similarity and then clustering and classifying sequences based on similarity. An initial analysis of CDR3s of known structure, clustered by structural similarity, helps calibrate the limits of sequence diversity among CDRs that might have a common mode of interaction with presented epitopes. Subsequent analyses demonstrate that this same range of sequence similarity strikes an appropriate specificity/sensitivity balance in distinguishing twins from non-twins based on overall CDR3 repertoires, classifying CDR3 repertoires by antigen specificity, and distinguishing general pathologies. We conclude that within this fairly broad range of sequence similarity, matching CDR3 sequences are likely to share specificities.

scholarly journals A framework for annotation of antigen specificities in high-throughput T-cell repertoire sequencing studies

2019 ◽  
Author(s):  
Mikhail V Pogorelyy ◽  
Mikhail Shugay
Keyword(s):  
T Cell ◽  
Large Scale ◽  
Cell Receptor ◽  
Specific Response ◽  
Clustering Methods ◽  
Sequencing Data ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Sequencing Studies ◽  
Repertoire Sequencing

AbstractRecently developed molecular methods allow large-scale profiling of T-cell receptor (TCR) sequences that encode for antigen specificity and immunological memory of these cells. However, it is well known, that the even unperturbed TCR repertoire structure is extremely complex due to the high diversity of TCR rearrangements and multiple biases imprinted by VDJ rearrangement process. The latter gives rise to the phenomenon of “public” TCR clonotypes that can be shared across multiple individuals and non-trivial structure of the TCR similarity network. Here we outline a framework for TCR sequencing data analysis that can control for these biases in order to infer TCRs that are involved in response to antigens of interest. Using an example dataset of donors with known HLA haplotype and CMV status we demonstrate that by applying HLA restriction rules and matching against a database of TCRs with known antigen specificity it is possible to robustly detect motifs of an epitope-specific responses in individual repertoires. We also highlight potential shortcomings of TCR clustering methods and demonstrate that highly expanded TCRs should be individually assessed to get the full picture of antigen-specific response.

scholarly journals Characterization of human rheumatoid factors with seven antiidiotypes induced by synthetic hypervariable region peptides.

1985 ◽  
Vol 162 (2) ◽  
pp. 487-500 ◽  
Author(s):  
P P Chen ◽  
F Gõni ◽  
R A Houghten ◽  
S Fong ◽  
R Goldfien ◽  
...  
Keyword(s):  
Rheumatoid Factor ◽  
Synthetic Peptides ◽  
Hypervariable Region ◽  
Rheumatoid Factors ◽  
Immunoblot Assay ◽  
The Third ◽  
Antiidiotypic Antibodies ◽  
Vh Genes ◽  
Complementarity Determining Regions

Recently, we have used synthetic peptides corresponding to the complementarity-determining regions (CDR) of Ig molecules to induce antiidiotypic antisera. Peptide PSH3, representing the third CDR of the IgM rheumatoid factor (RF) Sie heavy (H) chain, induced a private antiidiotype that reacted with only one out of five IgM-RF. Peptide PSL2, corresponding to the second CDR of Sie light (L) chain, induced an antibody against a crossreactive idiotype (CRI), expressed by 10 out of 12 human IgM-RF analyzed. Herein, we report that five additional antiidiotypic antibodies were generated by immunization with synthetic peptides identical to the third L chain CDR of IgM-RF Sie (PSL3), the second and third H chain CDR of IgM-RF Wol, and the second and third CDR of IgM-RF Pom. As analyzed by immunoblot assay, both anti-PSL3 and anti-PSL2 reacted with the majority of 16 IgM-RF. In contrast, all five antiidiotypes induced by the H chain peptides reacted only with the parent proteins, except anti-PSH3, which reacted weakly with one additional RF. These results suggest that one (or very few) VL gene(s), but a larger number of VH genes, are used to encode IgM-RF autoantibodies.

scholarly journals A Limited Antigen-Specific Cellular Response Is Sufficient for the Early Control of Mycobacterium tuberculosis in the Lung but Is Insufficient for Long-Term Survival

2004 ◽  
Vol 72 (7) ◽  
pp. 3759-3768 ◽  
Author(s):  
Joanne Turner ◽  
Karen M. Dobos ◽  
Marc A Keen ◽  
Anthony A. Frank ◽  
Stefan Ehlers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cellular Response ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Term Survival ◽  
Potent Inducer ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACT Mice that were transgenic for a T-cell receptor (TCR) specific for ovalbumin peptide323-339 (DO11.10) were able to survive an infection with Mycobacterium tuberculosis for approximately 80 days. This limited early control of infection was associated with gamma interferon production, inducible nitric oxide synthase expression within the lung, and an influx of clonotypic lymphocytes. The control of M. tuberculosis was lost in DO11.10 mice bred in a rag mutant background, demonstrating that the immune responsiveness was recombinase dependent and likely to be associated with the expression of an alternative α TCR by DO11.10 mice. A characterization of the antigen specificity in DO11.10 TCR transgenic mice demonstrated that the specificity was limited and dominated by the 26-kDa (Rv1411c) lipoprotein of M. tuberculosis. This study identifies this lipoprotein as an important and potent inducer of protective T cells within the lungs of mice infected with M. tuberculosis and therefore as a possible target for vaccination.

Gaunilo Parodies Anselm

2014 ◽  
Vol 17 (1) ◽  
pp. 45-71
Author(s):  
Geo Siegwart
Keyword(s):  
Detailed Comparison ◽  
The Third ◽  
Common Structure ◽  
Logical Reconstruction ◽  
Points Of View ◽  
And Function

The main objective is an interpretation of the island parody, in particular a logical reconstruction of the parodying argument that stays close to the text. The parodied reasoning is identified as the proof in the second chapter of the Proslogion, more specifically, this proof as it is represented by Gaunilo in the first chapter of his Liber pro insipiente. The second task is a detailed comparison between parodied and parodying argument as well as an account of their common structure. The third objective is a tentative characterization of the nature and function of parodies of arguments. It seems that parodying does not add new pertinent points of view to the usual criticism of an argument.

scholarly journals Structure Unveils Relationships between RNA Virus Polymerases

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 313
Author(s):  
Heli A. M. Mönttinen ◽  
Janne J. Ravantti ◽  
Minna M. Poranen
Keyword(s):  
Phylogenetic Tree ◽  
Rna Viruses ◽  
Rna Virus ◽  
Sequence Similarity ◽  
Protein Structures ◽  
Structural Similarity ◽  
Functional Differentiation ◽  
Comparison Method ◽  
Homologous Structure ◽  
Biological Entities

RNA viruses are the fastest evolving known biological entities. Consequently, the sequence similarity between homologous viral proteins disappears quickly, limiting the usability of traditional sequence-based phylogenetic methods in the reconstruction of relationships and evolutionary history among RNA viruses. Protein structures, however, typically evolve more slowly than sequences, and structural similarity can still be evident, when no sequence similarity can be detected. Here, we used an automated structural comparison method, homologous structure finder, for comprehensive comparisons of viral RNA-dependent RNA polymerases (RdRps). We identified a common structural core of 231 residues for all the structurally characterized viral RdRps, covering segmented and non-segmented negative-sense, positive-sense, and double-stranded RNA viruses infecting both prokaryotic and eukaryotic hosts. The grouping and branching of the viral RdRps in the structure-based phylogenetic tree follow their functional differentiation. The RdRps using protein primer, RNA primer, or self-priming mechanisms have evolved independently of each other, and the RdRps cluster into two large branches based on the used transcription mechanism. The structure-based distance tree presented here follows the recently established RdRp-based RNA virus classification at genus, subfamily, family, order, class and subphylum ranks. However, the topology of our phylogenetic tree suggests an alternative phylum level organization.

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