Receptor editing in peripheral B cell tolerance

Rice, Jeffrey S.; Newman, Jeffrey; Wang, Chuansheng; Michael, Daniel J.; Diamond, Betty

doi:10.1073/pnas.0409217102

Cited by 52 publications

(66 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a tetrameric form of this peptide, we are able to detect the tetramer-reactive (Tet + ) compartment, which is enriched in DNA-reactive B cells (16,17). In a previous study, we reported that RAG expression is detected in a subpopulation of the splenic antigen-reactive compartment within a short time window following immunization with DWEYS-MAP (17). In this study, we sought to further delineate the developmental stage of antigen-reactive RAG-expressing cells and to understand the mechanism and function of receptor editing in an ongoing response.…”

Section: Rag Is Induced In Postactivation Early Memory/preplasma B Cementioning

confidence: 99%

“…When it is part of a decapeptide octamerized on a polylysine backbone (DWEYS-MAP), it can induce a SLE-like serology in the nonautoimmune BALB/c mouse strain, while immunization with the polylysine backbone (MAP-core) alone does not (15). Because we are able to identify the antigen-specific B cells in the spleens of mice immunized with DWEYS-MAP using a fluorochrometagged tetrameric peptide (16), we were able to demonstrate RAG expression and l light chain expression in antigen-activated autoreactive B cells (17). Importantly, we failed to detect RAG expression in antigen-specific B cells in the response to a control peptide mimetope of phosphorylcholine that does not generate autoreactivity, despite provoking a robust anti-phosphorylcholine response.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Wang¹,

Diamond²

2008

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Autoreactive B cells are regulated in the BM during development through mechanisms, including editing of the B cell receptor (BCR), clonal deletion, and anergy. Peripheral B cell tolerance is also important for protection from autoimmune damage, although the mechanisms are less well defined. Here we demonstrated, using a mouse model of SLE-like serology, that during an autoimmune response, RAG was reinduced in antigen-activated early memory or preplasma B cells. Expression of RAG was specific to antigen-reactive B cells, required the function of the IL-7 receptor (IL-7R), and contributed to maintenance of humoral tolerance. We also showed that soluble antigen could diminish a non-autoreactive antibody response through induction of BCR revision. These data suggest that tolerance induction operates in B cells at a postactivation checkpoint and that BCR revision helps regulate autoreactivity generated during an ongoing immune response.

show abstract

Section: Rag Is Induced In Postactivation Early Memory/preplasma B Cementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Wang¹,

Diamond²

2008

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, and in contrast with this previous report, more than a half of included ͞ B cells showed a mature follicular phenotype (CD23 high ͞CD21 int ) and demonstrated that such cells are not necessarily trapped in the MZ. It has also been hypothesized that dual BCR expression resulted from receptor editing of an autoreactive primary Ig HC͞LC combination (22,23,25,26). In such models of LC inclusion, the expression of multiple antigen receptors was thought to dilute the autoreactive BCR and permit autoreactive cells to escape deletion.…”

Section: Discussionmentioning

confidence: 99%

“…Receptor editing also occurs in normal mice during the selection of immature B cells and may be a major pathway of tolerance induction by rescuing cells with autoreactive BCR from deletion (or anergy) provided that they express a new receptor (20,21). Nevertheless, this editing process intrinsically bears the risk of generating B cell clones that will migrate toward peripheral lymphoid organs while carrying dual or multiple antigen receptors, one of those potentially being autoreactive (22)(23)(24)(25)(26). Moreover, autoreactivity may not be the only way to promote receptor editing because some non-autoreactive knockin mice also showed extensive secondary rearrangements, likely due to a low expression of the knockin gene (27,28).…”

mentioning

confidence: 99%

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Sirac

Carrion

Duchez

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mice in which the J cluster was replaced with a V J rearranged gene were studied. More than 90% of B cells from homozygous mutant mice expressed the transgenic chain but showed a slightly reduced level of transcripts compared with WT B lymphocytes. Light chain inclusion was apparent in 10% of B cells from these mice and raised 25% in hemizygous mice with a still lower expression of the knockin chain. Beyond the rules of clonal selection, peripheral B cells developed in such animals, with included cells being activated and differentiating into class-switched or antibody-secreting cells. The high amount of included mature B cells was associated with an increase of hybrid ͞ immunoglobulins but not with the increased prevalence of autoantibodies. Altogether, these data suggest that light chain exclusion prevalent in normal B cells mostly results from ordered rearrangements and stochastic mechanisms but is neither tightly ensured by a stringent cell selection process nor absolutely required for normal B cell function.antibodies ͉ autoimmunity ͉ B lymphocytes ͉ gene regulation D uring B cell development, B cell receptor (BCR) assembly relies on an ordered process of rearrangements remodeling first the heavy chain (HC) locus and later on the and loci. Cells achieving expression of functional H and L chains and able to pair them can then express a unique form of functionally competent Ig at the cell surface and be selected according to the specificity of this receptor (1, 2). With very rare exceptions, B lymphocytes are thus monospecific and express a single H and L chain. This allelic and isotypic exclusion is fundamental to the establishment of the B cell repertoire and is in agreement with the clonal selection theory (3), first allowing during ontogeny the tolerization of clonal cells carrying a self-reactive BCR and later ensuring the specificity of antibody responses. Whereas this rule seems to be quite effective in the case of the HC (4, 5), it suffers remarkable exceptions at light chain (LC) loci. Indeed, several studies reported the presence of double-expressing ͞ B cells either at very low frequencies in normal mice or in human, and more abundantly in transgenic mice (6-9) and plasmocytomas (10). Little is known about the mechanisms involved in the allelic exclusion of LC even if recent studies highlighted the importance of asymmetric demethylation of the locus (11, 12) and feedback inhibition of the recombination machinery after the assembly and signaling by a non-self-reactive BCR (13-16). Beyond the initial rearrangements, exclusion also has to be maintained despite the accumulation of secondary rearrangements. The latter were first reported at high frequency in LC loci of mice transgenic for an autoreactive BCR, in which receptor editing restored self-tolerance (17-19). Receptor editing also occurs in normal mice during the selection of immature B cells and may be a major pathway of tolerance induction by rescuing cells with autoreactive BCR from deletion (or anergy) provided that they express a new recept...

show abstract

“…Subsequent experiments with GFP-Tg mice showed that RAG expression in spleens was restricted to immature transitional B cells [52,53]. However, recent studies on mice with spontaneous [54] or induced [55] autoimmunity have reported on RAG expression and receptor editing in the mature peripheral B cell population. Although we have not yet investigated individual peripheral B cell populations, our experiments clearly indicate that anti-DNA-autoreactive B cells express RAG-2 in peripheral B cells and have ongoing secondary L chain rearrangements in the periphery (as demonstrated by LM-PCR), which result in BCR editing.…”

mentioning

confidence: 99%

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

et al. 2006

View full text Add to dashboard Cite

CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22 -/-mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vj1-Jj1 or Vj8-Jj5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age-and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation. IntroductionSystemic lupus erythematosus (SLE) is a rheumatic disease of unknown etiology, usually occurring in young women of childbearing age. The presence of serum antibodies to a variety of self components and their possible involvement in the development of severe kidney disease (glomerulonephritis) has made SLE a prototype of systemic autoimmune diseases [1]. The autoantibodies in lupus sera react with a large variety of nuclear antigens, including DNA, RNA and nuclear proteins. The antibodies to dsDNA are mostly highaffinity IgG that appear almost exclusively in SLE and very rarely in other diseases [2, 3].Several mouse models which spontaneously develop a lupus-like disease have been studied extensively [4]. The NZB/NZW F1 mouse is considered to be the murine model most closely resembling human SLE [5]. The lupus-like disease in these mice is more severe in females and is accompanied by high-affinity IgG anti-dsDNA autoantibodies. Both NZB and NZW parents contribute multiple susceptibility genes to the immune abnormalities of the F1 hybrid mouse [6]. Additional mouse models of SLE include mouse strains with deficiencies in antigen disposal mechanisms and mice that are deficient in proteins regulating the thresholds for tolerance and activation of B and T lymphocytes [7].CD22 is a B cell-specific surface glycoprotein of the Ig superfamily expressed on mature B cells [8, 9]. It functions as an adhesion molecule, as a signal-transducing molecule and as a modulator of intracellular signaling through the B cell receptor (BCR) complex. Negative regulatory roles for CD22 in BCR signaling are proposed to be critical for normal B cell activation, since immunoreceptor tyrosine-based inhibitory motifs with- in CD22 recruit SHP-1, a potent intracellular phosphatase with inhibitory functions in BCR signaling [10,11]. CD22-deficient mice [12][13][14][15] were reported to have decreased numbers of circulating B cells and slightly increased numbers of peritoneal B-1 cells, as well as higher levels of serum IgM [12,14]. Significantly, mature B cells from CD22-deficient mice had decreased expression of cell surface IgM and augmented i...

show abstract

Receptor editing in peripheral B cell tolerance

Cited by 52 publications

References 42 publications

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

Contact Info

Product

Resources

About