Autoreactive B Cell Regulation: Peripheral Induction of Developmental Arrest by Lupus-Associated Autoantigens

Positive selection is required for B cell differentiation, as indicated by the requirement for expression of the pre-B cell receptor (pre-BCR) and the BCR at the pre-B and immature B cell stages, respectively. Positive selection mediated by a tonic signal from these receptors is sufficient to drive B cell differentiation beyond the pre-B and immature B cell stages, but it is unclear whether additional positive selection signals are required for differentiation to a mature B-2 cell. We have identified a population of Ig transgenic B cells that differentiatively arrest at a transitional B cell stage in the spleen. They exhibit no evidence of Ag encounter or negative selection and can differentiate to mature B-2 cells in vivo upon weak BCR stimulation or adoptive transfer to irradiated hosts. These data are consistent with a requirement for a ligand-mediated BCR signal for differentiation to a mature B-2 cell.

mentioning

confidence: 99%

Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

Wang

Clarke

2003

“…Induction of B cell tolerance is a multifaceted process, involving a variety of "checkpoint" mechanisms operative at numerous stages of primary and Ag-driven B cell development (4,6,8,10,14). Among these, receptor editing and anergy have been documented to be associated with down-modulation of sBCR, particularly sIgM, levels (9,50,(65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

“…Defects in BCR-mediated signaling have been suggested to be responsible for the suboptimal proliferation and Ab secretion of anergic B cells in response to anti-BCR stimulation in vitro (8,13,18). The molecular mechanism underlying this unresponsiveness was suggested to be Ag receptor complex destabilization, preventing Ig-␣ and Syk phosphorylation (46).…”

Section: Hkir E4 ϩ B Cells Are Competent In Bcr Proximal Signaling Stmentioning

confidence: 99%

“…Numerous investigations have shown that Ig-transgenic B cells with particular types of autospecificities, in some cases associated with autoimmune disease, can exit the bone marrow and populate the periphery (8 -13). However, these B cells often display distinct phenotypes and reduced responsiveness (4,8,10,14), a condition commonly referred to as "anergy" (2)(3)(4)15).…”

mentioning

confidence: 99%

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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

Manser

2005

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.

“…The B cells of 2-12H anti-Sm mice, which express a low-affinity Ig specific for an Ag associated with systemic lupus erythematosus, are anergic as a consequence of maturational arrest at the T1 transitional stage of development, and have low levels of transgene in the sera (43)(44)(45). However, an interesting similarity with SMI is that ϳ30% of the peritoneal B cells of anti-Sm mice are B-1 B cells (44).…”

Section: Discussionmentioning

confidence: 99%

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

Widhopf

Brinson

Kipps

et al. 2004

We generated transgenic mice, designated SMI, expressing unmutated H and L chain Ig genes encoding a low-affinity, polyreactive human (h)IgM/κ rheumatoid factor. These animals were compared with control AB29 transgenic mice expressing a hIgM/κ rheumatoid factor specific for human IgG, with no detectable reactivity with mouse proteins. SMI B cells expressed significantly lower levels of surface hIgM/κ than did the B cells of AB29 mice, but still could be induced to proliferate by surface Ig cross-linking in vitro and could be deleted with anti-Id mAb in vivo. Transgene-expressing B cells of AB29 mice had a B-2 phenotype and were located in the primary follicle. In contrast, a relatively high proportion of hIgM-expressing B cells of SMI mice had the phenotype of B-1 B cells in the peritoneum or marginal zone B cells in the spleen, where they were located in the periarteriolar sheath, marginal zone, and interfollicular areas that typically are populated by memory-type B cells. Although the relative proportions of transgene-expressing B cells in both types of transgenic mice declined with aging, SMI mice experienced progressive increases in the serum levels of IgM transgene protein over time. Finally, SMI transgene-expressing B cells, but not AB29 transgene-expressing B cells, were induced to secrete Ab when cultured with alloreactive T cells. These results indicate that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic, but instead have a phenotype of memory-type or Ag-experienced B cells that respond to nonspecific immune activation.