Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice

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

“…Studies in Ig transgenic (Tg) mouse models have defined anergy as a state of unresponsiveness that regulates autoreactive B cells in the periphery (15)(16)(17)(18)(19). Anergic B cells fail to secrete Ab in response to LPS or Ag immunization due to receptor unresponsiveness (17,18,20).…”

mentioning

confidence: 99%

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

Gilbert¹,

Carnathan²,

Cogswell

et al. 2007

Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. We recently showed that during innate immune responses, secretion of IL-6 by dendritic cells (DCs) maintained autoreactive B cells in an unresponsive state. In this study, we describe that TLR4-activated DCs from lupus-prone mice are defective in repressing autoantibody secretion, coincident with diminished IL-6 secretion. Reduced secretion of IL-6 by MRL/lpr DCs reflected diminished synthesis and failure to sustain IL-6 mRNA production. This occurred coincident with lack of NF-κB and AP-1 DNA binding and failure to sustain IκBα phosphorylation. Analysis of individual mice showed that some animals partially repressed Ig secretion despite reduced levels of IL-6. This suggests that in addition to IL-6, DCs secrete other soluble factor(s) that regulate autoreactive B cells. Collectively, the data show that MRL/lpr mice are defective in DC/IL-6-mediated tolerance, but that some individuals maintain the ability to repress autoantibody secretion by an alternative mechanism.

“…Examples include mice that are transgenic for V H 81x-neonatal-derived Igh (47,48), or mice made transgenic for certain autoantibodies (e.g., Ig directed against DNA (1,49,50), phosphorylcholine (51), or nucleoprotein (52)). These findings indicate that transgenic lines with Ig genes derived from diverse sources can have larger MZ B cell compartments, suggesting that this feature is not the result of BCR specificity per se.…”

Section: Discussionmentioning

confidence: 99%

“…Most autoreactive B cells are deleted or rendered anergic at the immature stages in the marrow, as has been clearly demonstrated in studies of Ig transgenic mice (1)(2)(3)(4)(5). Autoreactive, nonanergic B cells that escape the marrow generally are eliminated upon encounter with autoantigen in the periphery (6 -8).…”

Section: T He Elimination Of B Cells Expressing Ig With Self-reactivitymentioning

confidence: 97%

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.