Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

Grimsholm, Ola; Ren, Weicheng; Bernardi, Angelina I.; Chen, Hạixia; Park, Giljun; Camponeschi, Alessandro; Chen, Dongfeng; Bergmann, Berglind; Höök, Nina; Andersson, S.; Strömberg, Anneli; Gjertsson, Inger; Cardell, Susanna; Riva, Alessandra; Mårtensson, Inga‐Lill

doi:10.1038/ncomms8077

Cited by 15 publications

(35 citation statements)

References 69 publications

(102 reference statements)

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“…We find that the ABCs in the SLC −/− mice have undergone SHM, and from the sequence analyses of the expressed Ig heavy chains, we deduce that they are clonally diversified. In this regard, the ABCs in SLC −/− mice might derive from the GCs that form spontaneously in these mice . On this subject, we also find B cell clones of GC and ABC origin within a clone bearing the same VDJ rearrangement and H‐CDR3 (Table , Clone 8), which would argue for at least some ABCs being clonally related to GC B cells.…”

Section: Discussionmentioning

confidence: 58%

“…In our previous work, we found that several MBC populations can be distinguished in SLC −/− mice , of which the ABCs presumably represent a subset. We also uncovered the use of basic amino acid residues, e.g.…”

Section: Discussionmentioning

confidence: 84%

“…We also uncovered the use of basic amino acid residues, e.g. arginine in the H-CDR3 that is typical of lupus autoantibodies [19], to be high in GC B cells but comparably low in MBCs based on high throughput sequencing of GC and MBCs from other pools of SLC −/− mice [13]. The data presented here confirm these findings in that the use of basic amino acids indicated are the mouse strain, hybridoma clone, V H , D H and J H usage, isotype, and reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…arginine (R) and lysine (K) in the H-CDR3 has been found in antibodies binding to DNA and nuclear antigens [19]. We have previously shown that the IgM + GC B cells from SLC −/− mice have a higher proportion of basic amino acids in the H-CDR3 than the previously identified population of MBCs [13]. In line with this, the proportion of basic amino acids in the H-CDR3 from the ABCs is lower than in the GC B cells (Fig.…”

Section: Abcs Express a H-cdr3 Repertoire With A Relatively Low Levelmentioning

confidence: 99%

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Age‐associated B cells expanded in autoimmune mice are memory cells sharing H‐CDR3‐selected repertoires

et al. 2018

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Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21 ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21 B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-B cell receptor (SLC ). However, the nature of the CD21 B cells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild-type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC mice, a majority of the ABCs are IgM , their V genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H-CDR3 repertoires.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Abcs Express a H-cdr3 Repertoire With A Relatively Low Levelmentioning

confidence: 99%

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Age‐associated B cells expanded in autoimmune mice are memory cells sharing H‐CDR3‐selected repertoires

et al. 2018

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“…In line with our studies in mice [10,11], we included the CD23 marker in our analysis. A CD21 -/ low CD23 -subset was clearly present (Fig.…”

Section: A Cd21 -/Low B Cell Subset Is Present In Peripheral Blood Frmentioning

confidence: 99%

CD21–/low B cells in human blood are memory cells

Thorarinsdottir

Camponeschi

Cavallini

et al. 2016

Clinical and Experimental Immunology

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Summary The complement receptor 2 (CR2, CD21) is part of a complex (CD21/CD19/CD81) acting as a co‐receptor to the B cell receptor (BCR). Simultaneous triggering of the BCR and CD21 lowers the threshold for B cell activation. Although CD21 is important, B cells that express low amounts or lack surface CD21 (CD21–/low) are increased in conditions with chronic inflammation, e.g. autoimmune diseases. However, little is known about the CD21–/low B cell subset in peripheral blood from healthy donors. Here, we show that CD21–/low cells represent approximately 5% of B cells in peripheral blood from adults but are barely detectable in cord blood, after excluding transitional B cells. The CD21–/low subset can be divided into CD38–24+ and CD38–24low cells, where most of the CD38–24+ are CD27+immunoglobulin (Ig)M+IgD+ and the CD38–24low are switched CD27–. Expression levels of additional markers, e.g. CD95 and CD62L, are similar to those on classical memory B cells. In contrast to naive cells, the majority of CD21–/low cells lack expression of the ABCB1 transporter. Stimulation with a combination of BCR, Toll‐like receptor (TLR)−7/8 and interleukin (IL)−2 induces proliferation and differentiation of the CD21–/low B cells comparable to CD21+CD27+ memory B cells. The response excluding BCR agonist is not on par with that of classical memory B cells, although clearly above that of naive B cells. This is ascribed to a weaker response by the CD38–24low subset, implying that some memory B cells require not only TLR but also BCR triggering. We conclude that the CD21–/low cells in healthy donors are memory B cells.

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Distorted antibody repertoire developed in the absence of pre-B cell receptor formation

Sun

Kono

Shimizu

et al. 2018

Biochemical and Biophysical Research Communications

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The pre-B cell receptor (pre-BCR), consisting of the μ heavy chain (μHC) and the surrogate light chain (SLC, Vpre-B and λ5), plays important roles during B cell development. The formation of the pre-BCR, which enables the nascent immunoglobulin HC to associate with the SLC, is considered a prerequisite for B cell development. However, a significant number of peripheral mature (leaky) B cells exist in SLC-deficient mice. These leaky B cells develop in the absence of pre-BCR and do not undergo the pre-BCR checkpoint. The antibody repertoires of leaky B cells thus reflect the absence of pre-BCR function. To investigate how the absence of the pre-BCR is circumvented by these leaky-B cells and examine the effect of the pre-BCR checkpoint on the antibody system, we analyzed the antibody repertoires of λ5-deficient (λ5) mice using next-generation sequencing. In λ5 mice, spleen B cells displayed different patterns of VDJ-usage, relative to those in wild-type (WT) mice. Moreover, leaky B cells were neither derived from unusual B2 cells, characterized by particular LC gene rearrangements in the absence of pre-BCR signaling, nor from B1 cells, originating from different B cell progenitors. Analysis of the CDR-H3 amino acid sequences of μ-chain repertoires revealed that certain bone marrow B cells with particular CDR-H3 profiles undergo clonal expansion in λ5 mice. Part of these CDR-H3s contain arginine(s) in the middle of the CDR-H3 loop in λ5 mice, whereas few arginine(s) exist in this middle loop in WT CDR-H3s in the absence of clonal expansion. This CDR-H3 feature in λ5 mice presumably reflects the role of the pre-BCR in autoantibody regulation, since arginine(s) are often found in the antigen-binding site of autoantibodies. Here, we present a unique viewpoint on the role of pre-BCR, by assessing the whole antibody repertoire formed in SLC-deficient mice.

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Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

Cited by 15 publications

References 69 publications

Age‐associated B cells expanded in autoimmune mice are memory cells sharing H‐CDR3‐selected repertoires

Age‐associated B cells expanded in autoimmune mice are memory cells sharing H‐CDR3‐selected repertoires

CD21–/low B cells in human blood are memory cells

Distorted antibody repertoire developed in the absence of pre-B cell receptor formation

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