B cell receptor editing in tolerance and autoimmunity

Prak, Eline T. Luning; Monestier, Marc; Eisenberg, Robert A.

doi:10.1111/j.1749-6632.2010.05877.x

Cited by 79 publications

(56 citation statements)

References 203 publications

(452 reference statements)

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“…In heterozygous 564Igi mice, which carry a single copy of the knock-in H and K chain, ~50% of circulating B cells express the knock-in BCR (identified by anti-idiotype [Id] Ab staining). The remaining half are Id negative (Id − ) due to receptor editing or allelic inclusion (Berland et al, 2006; Chatterjee et al, 2013; Das et al, 2017; Luning Prak et al, 2011). The mice have high titers of IgG against nuclear-associated Ags, but do not exhibit disease until late in life.…”

Section: Resultsmentioning

confidence: 99%

Clonal Evolution of Autoreactive Germinal Centers

Degn

Poel

Firl

et al. 2017

Cell

115

153

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SUMMARY Germinal centers (GCs) are the primary sites of clonal B cell expansion and affinity maturation, directing the production of high-affinity antibodies. This response is a central driver of pathogenesis in autoimmune diseases, such as systemic lupus erythematosus (SLE), but the natural history of autoreactive GCs remains unclear. Here, we present a novel mouse model where the presence of a single autoreactive B cell clone drives the TLR7-dependent activation, expansion, and differentiation of other autoreactive B cells in spontaneous GCs. Once tolerance was broken for one self-antigen, autoreactive GCs generated B cells targeting other self-antigens. GCs became independent of the initial clone and evolved towards dominance of individual clonal lineages, indicating affinity maturation. This process produced serum autoantibodies to a breadth of self-antigens, leading to antibody deposition in the kidneys. Our data provide insight into the maturation of the self-reactive B cell response, contextualizing the epitope spreading observed in autoimmune disease.

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Section: Resultsmentioning

confidence: 99%

Clonal Evolution of Autoreactive Germinal Centers

Degn

Poel

Firl

et al. 2017

Cell

115

153

View full text Add to dashboard Cite

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“…Thus, polyreactivity is an additional, albeit non-specific, mechanism for IgM B cell cross-reactivity to Dsg3 and VP6. Ultimately, most autoreactive or polyreactive B cells are eliminated from the B cell repertoire at various tolerance checkpoints during B cell maturation due to receptor editing, somatic mutation away from autoreactivity, or other mechanisms that prevent the maturation of autoreactive IgG class-switched B cells (34,35). Our finding that Dsg3-VP6 cross-reactive clonotypes are not identified after high throughput screening of IgG B cell repertoires, as well as previously published data indicating that anti-Dsg3 IgG clonotypes are not found in non-PV individuals (22) supports that these mechanisms are largely effective to prevent anti-Dsg3 autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6

Cho

Ellebrecht

Hammers

et al. 2016

The Journal of Immunology

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Shared VH1-46 gene usage has been described in B cells reacting to desmoglein 3 (Dsg3) in the autoimmune disease pemphigus vulgaris (PV), as well as B cells responding to rotavirus capsid protein VP6. In both diseases, VH1-46 B cells bearing few to no somatic mutations can recognize the disease antigen. This intriguing connection between an autoimmune response to self-antigen and an immune response to foreign antigen prompted us to investigate whether VH1-46 B cells may be predisposed to Dsg3-VP6 cross-reactivity. Focused testing of VH1-46 mAbs previously isolated from PV and rotavirus-exposed individuals indicates that cross-reactivity is rare, found in only one of seven VH1-46 IgG clonotypes. High-throughput screening of IgG B cell repertoires from 2 PV patients identified no additional cross-reactive clonotypes. Screening of IgM B cell repertoires from one non-PV and 3 PV patients identified specific cross-reactive Abs in one PV patient, but notably all 6 cross-reactive clonotypes utilized VH1-46. Site directed mutagenesis studies indicate that amino acid residues predisposing VH1-46 Abs to Dsg3 reactivity reside in CDR2. However, somatic mutations only rarely promote Dsg3-VP6 cross-reactivity; most mutations abolish VP6 and/or Dsg3 reactivity. Nevertheless, functional testing identified two cross-reactive VH1-46 Abs that both disrupt keratinocyte adhesion and inhibit rotavirus replication, indicating the potential for VH1-46 Abs to have both pathologic autoimmune and protective immune functions. Taken together, these studies suggest that certain VH1-46 B cell populations may be predisposed to Dsg3-VP6 cross-reactivity, but multiple mechanisms prevent the onset of autoimmunity after rotavirus exposure.

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“…Moreover, the variety of Ags potentially recognized by the BCR is broader than that of Ags recognized by the TCR, being not limited to peptides, but also including carbohydrates, nucleic acids, and other types of Ags (29). Therefore, B cells could play an important role in early cell-mediated immune responses during inflammatory and neoplastic processes (30,31). As IBD-related inflammation is associated with intestinal epithelial damage (3), in this article we examined whether B cells/ plasma cells infiltrating the IBD mucosa express GrB and are able to kill epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Plasma Cells in the Mucosa of Patients with Inflammatory Bowel Disease Produce Granzyme B and Possess Cytotoxic Activities

Cupi

Sarra

Marafini

et al. 2014

The Journal of Immunology

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In both Crohn’s disease (CD) and ulcerative colitis (UC), the gut is massively infiltrated with B cells and plasma cells, but the role of these cell types in the pathogenesis of gut tissue damage remains largely unknown. Human B cells express granzyme B (GrB) when cultured with IL-21, a cytokine overproduced in CD and UC mucosa. We therefore examined whether mucosal B cells express GrB and have cytotoxic activity in inflammatory bowel disease (IBD). GrB-expressing CD19+ and IgA+ cells were seen in the normal intestinal mucosa, but they were significantly more frequent in both CD and UC. In contrast, only a minority of CD19+ and IgA+ cells expressed perforin with no difference between IBD and controls. GrB-producing CD19+ cells expressed CD27 and were CD38high and CD20 negative. CD19+ B cells from IBD patients induced HCT-116 cell death. IL-21 enhanced GrB expression in control CD19+ B cells and increased their cytotoxic activity. These data indicate that IBD-related inflammation is marked by mucosal accumulation of cytotoxic, GrB-expressing CD19+ and IgA+ cells, suggesting a role for these cells in IBD-associated epithelial damage.

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B cell receptor editing in tolerance and autoimmunity

Cited by 79 publications

References 203 publications

Clonal Evolution of Autoreactive Germinal Centers

Clonal Evolution of Autoreactive Germinal Centers

Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6

Plasma Cells in the Mucosa of Patients with Inflammatory Bowel Disease Produce Granzyme B and Possess Cytotoxic Activities

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