Analysis of the B cell receptor repertoire in six immune-mediated diseases

Bashford-Rogers, Rachael; Bergamaschi, Laura; McKinney, Eoín; Pombal, DC; Mescia, Federica; Lee, James; Thomas, David; Flint, S. D.; Kellam, Paul; Jayne, David; Lyons, Paul; Smith, Kenneth G. C.

doi:10.1038/s41586-019-1595-3

Cited by 206 publications

(231 citation statements)

References 46 publications

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“…For instance, a recent study using bulk AIRR-Seq to investigate the use of RTX for treating AAV, demonstrated that persistent clonotypes are isotype-switched which we also observed in our study (52). However, because this analysis was not combined with single cell gene expression data, it is not clear if this was simply because the associated subsets that use these isotypes are more persistent (52). In this study, persistence is correlated with a specific gene expression signature e.g.…”

Section: Discussionsupporting

confidence: 88%

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Jiang

Fichtner

Hoehn

et al. 2019

Preprint

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One Sentence Summary: Disease relevant B cells during post-rituximab (RTX) relapse emerge from the unsuccessful depletion of pre-existing B cell clones; single-cell transcriptomic phenotyping combined with lineage tracing using paired B cell receptor repertoires identified both persistent antibody-secreting cell as well as memory B cell subsets.Abstract: Rituximab, an anti-CD20 B cell-depleting therapy, is indicated to treat a growing number of autoimmune disorders. However, disease relapses can occur when the B cell compartment is re-established after treatment. To explore the mechanism of relapse, we studied patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), a paradigm for B cellmediated autoimmune diseases in which pathology is directly associated with autoantibody production. Whether the failed depletion of specific clones leads to the persistence of autoantibody producing B cell subsets has yet to be elucidated. Here we show that rituximab (RTX) therapy is not fully effective at eliminating disease-associated B cells and provide a mechanistic understanding of relapse. We carried out single-cell transcriptional and B cell receptor (BCR) profiling on longitudinal B cell samples from the peripheral blood of MuSK MG patients who relapsed after rituximab therapy. Computational analysis of these data identified individual B cells that were refractory to rituximab depletion by linking them to clones that were present prior to therapy and continued to persist after therapy. These persistent B cell clones were present at high frequency, and included both antibody-secreting cells and memory B cells. They were disproportionately isotype switched with elevated somatic hypermutation frequencies and a gene expression signature associated with antigen-experience and B cell clonal expansion. We further identified both antibody-secreting cells and memory B cells with specificity for MuSK autoantigen that were clonally expanded during relapse and persistent. Our results provide evidence that post-rituximab relapse in MuSK MG is associated with the failed depletion of autoantigen-specific B cell subsets. This work provides insight into the durability of human B cells during treatment with therapeutic CD20-specific monoclonal antibodies. The transcriptional signatures associated with B cell resistance may represent new therapeutic avenues for treatment and biomarkers of depletion efficacy.

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Section: Discussionsupporting

confidence: 88%

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Jiang

Fichtner

Hoehn

et al. 2019

Preprint

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“…Therefore, the functions of blood and the immune system are inseparable. T cells and B cells are important in the pathogenesis of many-perhaps all-immune-mediated diseases (14)(15)(16)(17). A T cell receptor (TCR) mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs).…”

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confidence: 99%

Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19

Huang

Shi

Gong

et al. 2020

Preprint

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The coronavirus disease 2019 outbreak is an ongoing global health emergence, but the pathogenesis remains unclear. We revealed blood cell immune response profiles using 5' mRNA, TCR and BCR V(D)J transcriptome analysis with single-cell resolution. Data from 134,620 PBMCs and 83,387 TCR and 12,601 BCR clones was obtained, and 56 blood cell subtypes and 23 new cell marker genes were identified from 16 participants. The number of specific subtypes of immune cells changed significantly when compared patients with controls. Activation of the interferon-MAPK pathway is the major defense mechanism, but MAPK transcription signaling is inhibited in cured patients. TCR and BCR V(D)J recombination is highly diverse in generating different antibodies against SARS-CoV-2. Therefore, the interferon-MAPK pathway and TCR-and BCR-produced antibodies play important roles in the COVID-19 immune response. Immune deficiency or immune overresponse may result in the condition of patients with COVID-19 becoming critical or severe.

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“…As is the case with the TCR, understanding of the BCR repertoire in the context of IMD could provide us new insights into pathogenesis and therapy. Bashford-Rogers et al compared the BCR repertoire in SLE, AAV, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis [34]. The BCR repertoire of SLE showed an increase in clonality and a dominance of the IgA isotype, suggesting a microbial contribution to disease.…”

Section: T Cell Receptor and B Cell Receptor Repertoiresmentioning

confidence: 99%

Review: transcriptome and trans-omics analysis of systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE), which was recognized as a defined clinical entity more than 100 years ago, is an archetype for systemic autoimmune diseases. The 10-year survival of SLE patients has shown dramatic improvement during the last half-century. However, SLE patients receiving long-term prednisone therapy are at high risk of morbidity due to organ damage. Identification of key immune pathways is mandatory to develop a suitable therapy and to stratify patients based on their responses to therapy. Recently developed transcriptome and omic analyses have revealed a number of immune pathways associated with systemic autoimmunity. In addition to type I interferon, plasmablast and neutrophil signatures demonstrate associations with the SLE phenotype. Systematic investigations of these findings enable us to understand and stratify SLE according to the clinical and immunological features.

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Analysis of the B cell receptor repertoire in six immune-mediated diseases

Cited by 206 publications

References 46 publications

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19

Review: transcriptome and trans-omics analysis of systemic lupus erythematosus

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