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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Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients

Blood ◽

10.1182/blood-2009-10-250514 ◽

2010 ◽

Vol 115 (23) ◽

pp. 4770-4777 ◽

Cited By ~ 22

Author(s):

Mirjam van der Burg ◽

Malgorzata Pac ◽

Magdalena A. Berkowska ◽

Bozenna Goryluk-Kozakiewicz ◽

Anna Wakulinska ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Gene Segment ◽

Cell Receptor ◽

Nijmegen Breakage Syndrome ◽

Immunoglobulin Gene ◽

B Cell Differentiation ◽

Receptor Repertoire ◽

Recombination Activating Gene ◽

Dna Ends

Abstract The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.

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Variability in the B cell–receptor repertoire across immune-mediated diseases

Kidney International ◽

10.1016/j.kint.2020.04.029 ◽

2020 ◽

Vol 98 (3) ◽

pp. 536-538

Author(s):

Brad H. Rovin ◽

Loren D. Erickson

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Repertoire ◽

Immune Mediated ◽

Cell 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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Non-response to rituximab therapy in rheumatoid arthritis is associated with incomplete disruption of the B cell receptor repertoire

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214898 ◽

2019 ◽

Vol 78 (10) ◽

pp. 1339-1345 ◽

Cited By ~ 3

Author(s):

Sabrina Pollastro ◽

Paul L Klarenbeek ◽

Marieke E Doorenspleet ◽

Barbera D C van Schaik ◽

Rebecca E E Esveldt ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cell ◽

Clinical Response ◽

Synovial Tissue ◽

Peripheral Blood ◽

Cell Receptor ◽

B Cell Receptor ◽

Mutation Load ◽

Tissue Samples ◽

Receptor Repertoire

ObjectiveTo gain more insight into the dynamics of lymphocyte depletion and develop new predictors of clinical response to rituximab in rheumatoid arthritis (RA).MethodsRNA-based next-generation sequencing was used to analyse the B cell receptor (BCR) repertoire in peripheral blood and synovial tissue samples collected from 24 seropositive patients with RA treated with rituximab. Clonal expansion, mutation load and clonal overlap were assessed in samples collected before, at week 4 and at week 16 or 24 after treatment and correlated to the patients’ clinical response.ResultsAfter 4 weeks of rituximab-induced B cell depletion, the peripheral blood BCR repertoire of treated patients consisted of fewer, more dominant and more mutated BCR clones. No significant changes in the synovial tissue BCR repertoire were detected until week 16 post-treatment, when a reduced clonal overlap with baseline and an increased mutation load were observed. In patients who were non-responders at month 3 (n=5) using the European League Against Rheumatism response criteria, peripheral blood samples taken at week 4 after rituximab treatment showed more dominant clones compared with moderate responders (n=9) (median (IQR): 36 (27–52) vs 18 (16–26); p<0.01) and more clonal overlap with the baseline (median (IQR): 5% (2%–20%) vs 0% (0%–0%); p≤0.01).ConclusionSignificant changes in BCR clonality are observed in peripheral blood of patients 4 weeks after rituximab treatment, while changes in synovial tissue were observed at later time points. Incomplete depletion of the dominant baseline peripheral blood BCR repertoire in the first month of treatment might predict clinical non-response at 3 months.

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Profiling Germline Adaptive Immune Receptor Repertoire with gAIRR Suite

10.1101/2020.11.27.399857 ◽

2020 ◽

Author(s):

Mao-Jan Lin ◽

Yu-Chun Lin ◽

Nae-Chyun Chen ◽

Allen Chilun Luo ◽

Sheng-Kai Lai ◽

...

Keyword(s):

T Cell Receptor ◽

Cell Receptor ◽

Clinical Applications ◽

Whole Genome ◽

High Genetic Diversity ◽

Immune Receptor ◽

Genetic Profiling ◽

Adaptive Immune ◽

Receptor Repertoire ◽

Genome Assemblies

ABSTRACTThe genetic profiling of germline Adaptive Immune Receptor Repertoire (AIRR), including T cell receptor (TR) and immunoglobulin (IG), might be medically important but currently insurmountable due to high genetic diversity and complex recombination. In this study, we developed the gAIRR Suite comprising three modules. gAIRR-seq, a probe capture-based targeted sequencing pipeline, profiles genomic sequences of TR and IG from individual DNA samples. The computational pipelines gAIRR-call and gAIRR-annotate call alleles from gAIRR-seq reads and whole-genome assemblies. We applied gAIRR-seq and gAIRR-call to genotype TRV and TRJ alleles of Genome in a Bottle (GIAB) DNA samples with 100% accuracy. gAIRR-annotate profiled the alleles of 13 high-quality whole-genome assemblies from 6 samples and further discovered 79 novel TRV alleles and 11 novel TRJ alleles. We validated a 65-kbp and a 10-kbp structural variant for HG002 on chromosomes 7 and 14, where TRD and J alleles reside. We also uncovered the disagreement of the human genome GRCh37 and GRCh38 in the TR regions; GRCh37 possesses a 270 kbp inversion and a 10 kbp deletion in chromosome 7 relative to GRCh38. The gAIRR Suite might benefit genetic study and future clinical applications for various immune-related phenotypes.

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