Seven Chain Adaptive Immune Receptor Repertoire Analysis in Rheumatoid Arthritis: Association to Disease and Clinically Relevant Phenotypes

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease characterized by a defective adaptive immune receptor repertoire (AIRR) that fails to distinguish self from non-self antigens. The AIRR is vast, encompassing four T cell receptor (TCR) and three B cell receptor (BCR) chains, each of which displays an extraordinary amino acid sequence variability in the antigen-binding site. How the concerted action of T and B cell clones is associated with the development and clinical evolution of immune-mediated diseases is still not known. Using a new immunosequencing technology that allows the unbiased amplification of the seven receptor chains, we conducted an in-depth quantitative analysis of the seven-receptor chain variability in RA. Compared to healthy controls, the AIRR in RA was found to be characterized by a lower BCR diversity, the depletion of highly similar BCR clones, an isotype-specific signature as well as a skewed IGL chain and gene segment usage. A predictor based on quantitative multi-chain AIRR information was able to accurately predict disease, including the elusive seronegative subset of RA patients. AIRR features of the seven immune receptor chains were also different between patients with distinct clinically relevant phenotypes. Incorporating HLA variation data, we were able to identify the TCR clones that are specifically associated with disease risk variants. The longitudinal analysis of the AIRR revealed that treatment with Tumor Necrosis Factor (TNF) inhibitors selectively restores the diversity of B cell clones in RA patients by reducing the frequency of clones with a similar biochemical profile. The biochemical properties of the TNFi-modulated clones were also found to differ between responders and non-responders, supporting a different antigenic reactivity in the B cell compartment of these two groups of RA patients. Our comprehensive analysis of the TCR and BCR repertoire reveals a complex T and B cell architecture in RA, and provides the basis for precision medicine strategies based on the highly informative features of the adaptive immune response.

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The Diagnostic, Prognostic, and Therapeutic Potential of Adaptive Immune Receptor Repertoire Profiling in Cancer

Cancer Research ◽

10.1158/0008-5472.can-19-1457 ◽

2019 ◽

Vol 80 (4) ◽

pp. 643-654 ◽

Cited By ~ 1

Author(s):

Lindsay G. Cowell

Keyword(s):

Therapeutic Potential ◽

Immune Receptor ◽

Adaptive Immune ◽

Receptor Repertoire

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Reproducibility and Reuse of Adaptive Immune Receptor Repertoire Data

Frontiers in Immunology ◽

10.3389/fimmu.2017.01418 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 54

Author(s):

Felix Breden ◽

Eline T. Luning Prak ◽

Bjoern Peters ◽

Florian Rubelt ◽

Chaim A. Schramm ◽

...

Keyword(s):

Immune Receptor ◽

Adaptive Immune ◽

Receptor Repertoire

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Tools for adaptive immune receptor repertoire sequencing

Current Opinion in Systems Biology ◽

10.1016/j.coisb.2020.10.003 ◽

2020 ◽

Vol 24 ◽

pp. 86-92 ◽

Cited By ~ 1

Author(s):

William D. Lees

Keyword(s):

Immune Receptor ◽

Adaptive Immune ◽

Receptor Repertoire ◽

Repertoire Sequencing

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Antigen discovery tools for adaptive immune receptor repertoire research

Current Opinion in Systems Biology ◽

10.1016/j.coisb.2020.10.002 ◽

2020 ◽

Vol 24 ◽

pp. 64-70

Author(s):

Djenet Bousbaine ◽

Hidde L. Ploegh

Keyword(s):

Immune Receptor ◽

Antigen Discovery ◽

Adaptive Immune ◽

Receptor Repertoire

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VDJbase: an adaptive immune receptor genotype and haplotype database

Nucleic Acids Research ◽

10.1093/nar/gkz872 ◽

2019 ◽

Vol 48 (D1) ◽

pp. D1051-D1056 ◽

Cited By ~ 7

Author(s):

Aviv Omer ◽

Or Shemesh ◽

Ayelet Peres ◽

Pazit Polak ◽

Adrian J Shepherd ◽

...

Keyword(s):

T Cell Receptor ◽

Scientific Community ◽

Cell Receptor ◽

Web Based ◽

Immune Receptor ◽

Adaptive Immune ◽

Receptor Repertoire ◽

Online Tools ◽

Haplotype Data ◽

Repertoire Sequencing

Abstract VDJbase is a publicly available database that offers easy searching of data describing the complete sets of gene sequences (genotypes and haplotypes) inferred from adaptive immune receptor repertoire sequencing datasets. VDJbase is designed to act as a resource that will allow the scientific community to explore the genetic variability of the immunoglobulin (Ig) and T cell receptor (TR) gene loci. It can also assist in the investigation of Ig- and TR-related genetic predispositions to diseases. Our database includes web-based query and online tools to assist in visualization and analysis of the genotype and haplotype data. It enables users to detect those alleles and genes that are significantly over-represented in a particular population, in terms of genotype, haplotype and gene expression. The database website can be freely accessed at https://www.vdjbase.org/, and no login is required. The data and code use creative common licenses and are freely downloadable from https://bitbucket.org/account/user/yaarilab/projects/GPHP.

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OGRDB: a reference database of inferred immune receptor genes

Nucleic Acids Research ◽

10.1093/nar/gkz822 ◽

2019 ◽

Vol 48 (D1) ◽

pp. D964-D970 ◽

Cited By ~ 6

Author(s):

William Lees ◽

Christian E Busse ◽

Martin Corcoran ◽

Mats Ohlin ◽

Cathrine Scheepers ◽

...

Keyword(s):

High Throughput Sequencing ◽

Reference Database ◽

Supporting Evidence ◽

Immune Receptor ◽

Expert Review ◽

Adaptive Immune ◽

Receptor Repertoire ◽

Public Resource ◽

Animal Populations ◽

Genomic Regions

Abstract High-throughput sequencing of the adaptive immune receptor repertoire (AIRR-seq) is providing unprecedented insights into the immune response to disease and into the development of immune disorders. The accurate interpretation of AIRR-seq data depends on the existence of comprehensive germline gene reference sets. Current sets are known to be incomplete and unrepresentative of the degree of polymorphism and diversity in human and animal populations. A key issue is the complexity of the genomic regions in which they lie, which, because of the presence of multiple repeats, insertions and deletions, have not proved tractable with short-read whole genome sequencing. Recently, tools and methods for inferring such gene sequences from AIRR-seq datasets have become available, and a community approach has been developed for the expert review and publication of such inferences. Here, we present OGRDB, the Open Germline Receptor Database (https://ogrdb.airr-community.org), a public resource for the submission, review and publication of previously unknown receptor germline sequences together with supporting evidence.

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Biological controls for standardization and interpretation of adaptive immune receptor repertoire profiling

eLife ◽

10.7554/elife.66274 ◽

2021 ◽

Vol 10 ◽

Author(s):

Johannes Trück ◽

Anne Eugster ◽

Pierre Barennes ◽

Christopher M Tipton ◽

Eline T Luning Prak ◽

...

Keyword(s):

Immune System ◽

High Throughput ◽

Working Group ◽

Current Status ◽

Immune Receptor ◽

Adaptive Immune ◽

Receptor Repertoire ◽

Repertoire Sequencing ◽

Diagnostic Applications ◽

Future Work

Use of adaptive immune receptor repertoire sequencing (AIRR-seq) has become widespread, providing new insights into the immune system with potential broad clinical and diagnostic applications. However, like many high-throughput technologies, it comes with several problems, and the AIRR Community was established to understand and help solve them. We, the AIRR Community’s Biological Resources Working Group, have surveyed scientists about the need for standards and controls in generating and annotating AIRR-seq data. Here, we review the current status of AIRR-seq, provide the results of our survey, and based on them, offer recommendations for developing AIRR-seq standards and controls, including future work.

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