Non‐tolerant B cells cause autoimmunity in anti‐CD8 IgG2a‐transgenic mice

Abstract

Using a pair of gamma 2a/chi immunoglobulin genes, transgenic mice were generated to study tolerance induction in B cells that express IgG2a autoantibodies. The transgenic IgG2a specifically binds CD8 alpha chains of the CD8.2 allotype expressed on the surface of CD8+ T cells, but not CD8 molecules expressed by the CD8.1 allele. Thus, IgG2a transgenic mice expressing the CD8.1 allele were used as controls to monitor B cell development and mice expressing CD8.2 were used to study B cell tolerance. Both types of mice showed transgenic gamma 2a expression on the surface of B cells. Expression of endogenous heavy chain alleles was strongly inhibited in immature B cell subsets, whereas mature B cells co-expressed transgenic gamma 2a and endogenous IgM/D. The transgenic chi chain expression leads only to partial allelic exclusion of endogenous light chains. B cells that express high levels of transgenic CD8.2-specific IgG2a were identified using soluble CD8-Ig. In CD8.1+ and in CD8.2+ mice, we found no differences in expression and maturation of transgenic anti-CD8.2 IgG2a+ B cells. High levels of serum anti-CD8.2 IgG2a antibodies led to the elimination of CD8+ T cells, causing a severe defect in cytotoxic immune responses. These results show that tolerance induction is incomplete in the CD8.2+ mice, either because IgG2a+ B cells are resistant to censoring mechanisms or because the secreted CD8-specific IgG2a antibodies render the CD8 autoantigen inaccessible to the B cells. This contrasts strongly with the efficient induction of B cell tolerance in mice expressing anti-CD8.2 IgM autoantibodies.

Induction of CD4+ T cell depletion in mice doubly transgenic for HIV gp120 and human CD4

“…Furthermore, these mice were induced to produce antibodies to gp120 by immunization with denatured gp120. This demonstrates that T and B cells specific for gp120 can escape tolerance [30]. Therefore, the relevant and unique features of this animal model are the continuous interaction of hCD4, gp120 and anti-gpl20 antibodies in vivo, and the opportunity to study the effects of gp120 and specific antibodies in the absence of the potentially misleading effects of other viral factors.…”

“…Received January 30,1997; in revised form February 24, 1997; accepted February 28,1997. To investigate the effects of cross-linking of CD4/gp120 complexes by antibodies in vivo, we have generated double-transgenic mice in which T cells express human CD4 (hCD4) and secrete HIV gp120.…”

Development of Myelin Oligodendrocyte Glycoprotein Autoreactive Transgenic B Lymphocytes: Receptor Editing In Vivo After Encounter of a Self-Antigen Distinct from Myelin Oligodendrocyte Glycoprotein

“…4 and data not shown). Finally, some B cells expressing autoreactive IgG but not IgM are viable and provoke autoimmunity in transgenic mice (42,43). There is the possibility that under the conditions of repeated immunization, rare, autoreactive, MOG-specific B cell clones, like 8.18C5, sneaking through tolerogenesis in bone marrow were recruited to undergo isotype switch and escape tolerance.…”

B lymphocytes producing demyelinating autoantibodies: Development and function in gene-targeted transgenic mice

“…We replaced in embryonic stem (ES) cells the genomic region containing the J H segments and the DQ52 el-ement with the rearranged VDJ gene of the H chain from the MOG-specific hybridoma 8.18-C5 (18). This strategy, rather than the construction of conventional transgenic mice, was chosen to allow study of all aspects of B cell differentiation, in particular H chain isotype switch as well as tolerizing events within the natural context of the Ig H genes, such as V gene editing (19,20) and the different tolerogenic potential of different Ig isotypes (21).…”