Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus

Hehle, Verena; Fraser, Louise D.; Tahir, Romeeza; Kipling, David; Wu, Yu-Chang Bryan; Lutalo, Pamela; Cason, John; Choong, LeeMeng; D’Cruz, David; Cope, Andrew P.; Dunn-Walters, Deborah K.; Spencer, Jo

doi:10.1016/j.molimm.2015.01.017

Cited by 15 publications

(11 citation statements)

References 27 publications

(40 reference statements)

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“…It is possible that the IGHV4 biases found in other autoimmune diseases similarly originate within the naïve compartment. Previous studies have observed an increase in IGKV4 usage in SLE, celiac disease and type 1 diabetes (73), but we did not observe this hallmark in MG light chain repertoires. In fact, the naïve repertoires of both AChR-MG and MuSK-MG subjects showed a decrease in IGKV4 usage compared to healthy controls.…”

Section: Discussioncontrasting

confidence: 99%

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing

Heiden

Stathopoulos

Zhou

et al. 2017

The Journal of Immunology

103

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Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20–50 per 100,000 people. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the B cell receptor repertoire of AChR-MG, MuSK-MG and healthy subjects to generate approximately 518,000 unique VH and VL sequences from sorted naïve and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naïve and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the H-CDR regions and altered H-CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V/J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naïve and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.

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Section: Discussioncontrasting

confidence: 99%

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing

Heiden

Stathopoulos

Zhou

et al. 2017

The Journal of Immunology

103

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“…While some of these genes are involved in human disease (51,52), other genes would benefit from a more in-depth analysis (V2-5, V3-74, and V6 -1). Additionally, we showed several kappa and lambda V genes as differentially expressed between subsets; some have human disease associations validated by the literature (53)(54)(55)(56) whereas others merit additional study (KV2D-29, LV10 -54, LV2-8, LV3-1, LV3-25, LV4 -60, LV4 -69).…”

Section: Discussionsupporting

confidence: 54%

Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing

Mitsunaga

Snyder

2020

Molecular & Cellular Proteomics

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Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.

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“…Indeed, IGKV4-1 has previously been shown to be overrepresented in systemic lupus erythromatosus, celiac disease, and type 1 diabetes (46, 47), and we have also shown that its actual expression in the peripheral repertoire is significantly lower than its frequency of rearrangement in the genomic DNA (48). IGKV3-11 may possibly be a rescue gene, showing a significant increase in use, and our previous analysis also showed an increase in expression of this gene in the expressed repertoire compared to its expected frequency of rearrangement (48). Two IGLV2 lambda genes were noted as being increased within the lambda repertoire, presumably in preference to the IGLV1 family genes that showed a slight decrease.…”

Section: Discussionmentioning

confidence: 64%

Transitional B Cells in Early Human B Cell Development – Time to Revisit the Paradigm?

Martin

Townsend

et al. 2016

Front. Immunol.

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The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes and consequently an equally large number of potential specificities for antigen. As the process is essentially random, the cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre-B ≫ immature ≫ transitional ≫ naïve phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood, and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire and can be seen both in gene usage and in CDRH3 characteristics. Age-related changes are small, and only the size of the CDRH3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B ≫ immature ≫ transitional ≫ naïve development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naïve stages.

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Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus

Cited by 15 publications

References 27 publications

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing

Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing

Transitional B Cells in Early Human B Cell Development – Time to Revisit the Paradigm?

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