Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis

Bourcy, Charles F. A. de; Dekker, Cornelia L.; Davis, Mark M.; Nicolls, Mark R.; Quake, Stephen R.

doi:10.1126/sciimmunol.aan8289

Cited by 49 publications

(39 citation statements)

References 43 publications

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“…The B‐cell depletion approach is an approved therapy for lymphoma patients and for some autoimmune diseases (Salles et al, ; Schioppo & Ingegnoli, ). A recent article has shown that B‐cell depletion in systemic sclerosis patients not only promotes remission but also temporarily reverses the disease‐restricted B‐cell repertoire due to new B‐cell generation (Bourcy, Dekker, Davis, & Nicolls, ). The present study proposes that this rejuvenation may be also induced in elderly population, where B lymphopoiesis is suppressed.…”

Section: Discussionmentioning

confidence: 99%

Depletion of B cells rejuvenates the peripheral B‐cell compartment but is insufficient to restore immune competence in aging

et al. 2019

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Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B‐cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B‐cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B‐cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals, were vaccinated against hepatitis B (HBV) after undergoing a detailed analysis for B‐cell compartments. B‐cell depletion in old mice resulted in rejuvenated B‐cell population that was derived from de novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"‐like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B‐cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly depleted patients showed a "young"‐like repertoire, population dynamics, and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and nondepleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B‐cell compartment in aging, through B‐cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population.

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Section: Discussionmentioning

confidence: 99%

Depletion of B cells rejuvenates the peripheral B‐cell compartment but is insufficient to restore immune competence in aging

et al. 2019

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“…An AIRR-seq investigation revealed that differential expression of IGHV genes in the repertoires from SSc cohorts relative to a healthy cohort are present in the IgD/IgM compartment. 84 These…”

Section: Toler An Ce Check P Oint Defec Ts Alter the Naive B-cell Rmentioning

confidence: 99%

“…81 ities. 84 These F I G U R E 4 Variable region family usage is skewed in the naive BCR repertoire of patients with myasthenia gravis who suffer from impaired early B-cell tolerance checkpoints. 84 These F I G U R E 4 Variable region family usage is skewed in the naive BCR repertoire of patients with myasthenia gravis who suffer from impaired early B-cell tolerance checkpoints.…”

Section: Toler An Ce Check P Oint Defec Ts Alter the Naive B-cell Rmentioning

confidence: 99%

Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

Meffre

O’Connor

2019

Immunological Reviews

103

100

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A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered Bcell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27 − CD21 −/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens. K E Y W O R D Sautoantibodies, autoimmune disease, B-cell development, immune tolerance checkpoint

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“…Currently, targeted Adaptive Immune Receptor Repertoire sequencing assays (AIRR-seq) methods are routinely employed to sequence these transcripts and investigate the human immune system [20][21][22] . Specialized assays are required because the diversity and unique nature of these transcripts make them practically impossible to analyze at full length using standard RNA-seq protocols.…”

Section: Introductionmentioning

confidence: 99%

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

Cole

Byrne

Adams

et al. 2019

Preprint

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ABSTRACTThe human immune system relies on highly complex and diverse transcripts and the proteins they encode. These include transcripts for Human Leukocyte Antigen (HLA) class I and II receptors which are essential for self/non-self discrimination by the immune system as well as transcripts encoding B cell and T cell receptors (BCR and TCR) which recognize, bind, and help eliminate foreign antigens.HLA genes are highly diverse within the human population with each individual possessing two of thousands of different alleles in each of the 9 major HLA genes. Determining which combination of alleles an individual possesses for each HLA gene (high-resolution HLA-typing) is essential to establish donor-recipient compatibility in organ and bone-marrow transplantations. BCR and TCR genes in turn are generated by recombining a diverse set of gene segments on the DNA level in each maturing B and T cell, respectively. This process generates adaptive immune receptor repertoires (AIRR) of composed of unique transcripts expressed by each B and T cells. These repertoires carry a vast amount of health relevant information. Both short-read RNA-seq based HLA-typing1 and adaptive immune receptor repertoire sequencing2–5 currently rely heavily on our incomplete knowledge of the genetic diversity at HLA6 and BCR/TCR loci7,8.Here we used our nanopore sequencing based Rolling Circle toConcatemeric Consensus (R2C2) protocol9 to generate over 10,000,000 full-length cDNA sequences at a median accuracy of 97.9%. We used this dataset to demonstrate that deep and accurate full-length cDNA sequencing can - in addition to providing isoform-level transcriptome analysis for over 9,000 loci - be used to generate accurate sequences of HLA alleles for HLA allele typing and discovery as well as detailed AIRR data for the analysis of the adaptive immune system without requiring specific knowledge of the diversity at HLA and BCR/TCR loci.

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Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis

Cited by 49 publications

References 43 publications

Depletion of B cells rejuvenates the peripheral B‐cell compartment but is insufficient to restore immune competence in aging

Depletion of B cells rejuvenates the peripheral B‐cell compartment but is insufficient to restore immune competence in aging

Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

Complete characterization of the human immune cell transcriptome using accurate full-length cDNA sequencing

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