Autoantigen-B Cell Antigen Receptor Interactions That Regulate Expression of B Cell Antigen Receptor Loci

Abstract

Levels of AgR (BCR) expression are regulated during B cell development, activation, and induction of tolerance. The mechanisms responsible for and consequences of this regulation are poorly understood. We have described a class of DNA-based autoantigen-reactive B cell that down-regulates BCR expression during development to mature follicular phenotype. In this study, we show that at immature stages of primary differentiation, individual B cells of this type can dynamically modulate levels of expression of BCR in inverse proportion to degree of autoantigen engagement and induced BCR signaling. These adjustments in BCR expression are not associated with cell death, BCR revision, or altered development, and do not require TLR 9. Strikingly, modulation of BCR subunit gene RNA levels and transcription parallels these changes in BCR expression, indicating a direct link between autoantigen-BCR interactions of this type and regulation of transcription of BCR-encoding loci. We propose that this adaptive process allows this class of autoreactive B cell to avoid conventional tolerance pathways and promotes development to mature phenotype.

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

“…inhibited in bone marrow cultures by the monovalent form of Ars, Ars-Tyr (25). Our finding that Ars-Tyr treatment also decreased the level of binding of a FITC-labeled form of DNase I to the surface of canonical HKIR B cells supported the idea that downregulation was due to reduction of binding of canonical HKIR BCRs to a DNA-based autoantigen present in the cultures.…”

“…We previously reported that the rate of BCR internalization in immature HKIR/V10 B cells was higher than in control B cells in bone marrow cultures, but that these differences disappeared when Ars-Tyr was added to the HKIR/V10 cultures (25). Combined with the data presented, these findings suggested that the canonical HKIR BCR might mediate efficient uptake of a DNA-based autoantigen, allowing delivery to endosomes and activation of TLR9.…”

“…As previously described (25), the precursor frequency of canonical B cells in HKIR mice can be dramatically increased by crossing HKIR mice with a line of conventional Ig transgenic mice expressing the canonical L chain gene (V10A). We refer to the resulting double transgenic mice as HKIR/V10.…”

“…However, these B cells express very low levels of both surface IgM and IgD (22)(23)(24), indicating that they are not "ignorant" of self-Ags. Indeed, we previously showed that modulation of BCR levels on canonical HKIR B cells developing in vitro is regulated by both endocytosis and a feedback loop in which BCR engagement by a DNA-based autoantigens is linked to transcriptional control of BCR-encoding loci (25). In addition, our previous studies demonstrated that canonical HKIR B cells residing in the follicles of the spleen do not display features of anergy in vitro and participate normally in the primary immune response to Ars in vivo (21)(22)(23)26).…”

Quantitatively Reduced Participation of Anti-Nuclear Antigen B Cells That Down-Regulate B Cell Receptor during Primary Development in the Germinal Center/Memory B Cell Response to Foreign Antigen

“…1). In addition, neither HKIR/Vk10 nor HKI65/Vk10 clonotypes displayed any evidence of an anergic phenotype in in vitro studies analogous to those previously conducted on canonical clonotypes in HKIR and HKI65 mice (53).…”