The molecular evolution of the immune response: idiotope‐specific suppression indicates that B cells express germ‐line‐encoded V genes prior to antigenic stimulation

2002

Self Cite

To examine the effect of B cell Ag receptor (BCR) surface density on B cell development, we studied multiple lines of mice containing various copy numbers of an IgHμδ transgene. The VH gene in this transgene encodes multireactive BCRs with low affinity for self Ags. These BCRs promote differentiation to a B cell subpopulation that shares some, but not all of the properties of marginal zone (MZ) B cells. Surface BCR level was found to be related to transgene gene copy number in these mice. In mice containing 1–15 copies of the transgene, elevated surface BCR levels were correlated with increased numbers of B cells in the MZ-like subset. However, in mice containing 20–30 copies of the transgene, massive clonal deletion of B cells was observed in the bone marrow, few B cells populated the spleen, and B cells were essentially absent from the lymph nodes. These data support the idea that autoantigens mediate not only negative, but positive selection of developing B cells as well. More importantly, they illustrate the profound influence of BCR surface density on the extent to which either of these selective processes take place.

Section: Phenotypic Differences In Peripheral B Cell Compartmentsmentioning

confidence: 99%

Level of B Cell Antigen Receptor Surface Expression Influences Both Positive and Negative Selection of B Cells During Primary Development

Heltemes

2002

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“…In HKIR single transgenic mice, canonical HKIR B cells are present at a frequency of ϳ5% of splenic B cells, due to the expression of endogenous L chains (22). Canonical B cells in these mice can be directly detected using the anti-clonotypical mAb E4 (21,35).…”

Section: Resultsmentioning

confidence: 99%

Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs

Coffey

Liu

2007

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Recent findings support a central role for TLRs in both foreign Ag-driven immune responses and systemic autoimmune diseases mediated by B lymphocytes. In vitro studies have shown that the Ag receptors (BCRs) on B cells specific for nuclear autoantigens can facilitate the delivery of these autoantigens to the endocytic compartment, resulting in activation of the nucleic acid-specific TLRs present in this subcellular locale. If this pathway is operative in vivo it might promote the development, survival, or activation of such autoreactive B cells. To test this idea, we evaluated the influence of a deficiency in the CpG DNA-specific TLR, TLR9, or all MyD88-dependent TLRs on the primary development and foreign Ag-driven immune response of B cells in a line of VH knockin mice that contains a high frequency of “dual reactive” B cells specific for DNA-based autoantigens such as chromatin, as well as the hapten arsonate. We found that although development and activation of these B cells in vitro are clearly influenced by DNA-based autoantigens, TLR9 or MyD88 deficiencies had no apparent effect on the primary development and participation in the anti-arsonate response of these B cells in vivo. We discuss these results in the context of previous models for the role of TLR9 and other TLRs in the regulation of antinuclear Ag B cell development and activity.

“…Both versions of this V H gene, in combination with a single, endogenous L chain gene, encode Abs that we term "canonical." Canonical Abs bind the hapten arsonate and can be specifically detected using the monoclonal anti-clonotypic Ab E4 (36,37). Abs with the R55 form of the V domain also display reactivity for nuclear autoantigens such as chromatin and can cause kidney dysfunction via glomerular deposition in vivo.…”

mentioning

confidence: 99%

Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor during Development to Mature, Follicular Phenotype Do Not Display Features of Anergy In Vitro

Liu

2005

Self Cite

We previously demonstrated that B cells expressing a transgenic BCR with “dual reactivity” for the hapten arsonate and nuclear autoantigens efficiently complete development to follicular phenotype and stably reside in follicles in vivo. These B cells express very low levels of surface IgM and IgD, suggesting that they avoid central deletion and peripheral anergy by reducing their avidity for autoantigen via surface BCR (sBCR) down-regulation. Since a variety of states of B cell anergy have been previously described, a thorough examination of the functional capabilities of these B cells was required to test this hypothesis. In this study, we show that surface Ig cross-linking induces amounts of proximal BCR signaling in these B cells commensurate with their reduced sBCR levels. Functionally, however, they are comparable to nonautoreactive B cells in cell cycle progression, up-regulation of activation and costimulatory molecules, and Ab-forming cell differentiation when treated with a variety of stimuli in vitro. In addition, these B cells can efficiently process and present Ag and are capable of undergoing cognate interaction with naive TCR-transgenic T cells, resulting in robust IL-2 production. Together, these data reveal a lack of intrinsic anergy involving any known mechanism, supporting the idea that this type of antinuclear Ag B cell becomes indifferent to cognate autoantigen by down-regulating sBCR.