Altered repertoire of endogenous immunoglobulin gene expression in transgenic mice containing a rearranged Mu heavy chain gene

Weaver, David T.; Reis, Moema H.; Albanese, Christopher; Costantini, Frank; Baltimore, David; Imanishi‐Kari, Thereza

doi:10.1016/0092-8674(86)90389-2

Cited by 92 publications

(23 citation statements)

References 37 publications

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“…Recently, a series of studies has been published using transgenic mice carrying a functionally rearranged ,u heavy chain gene to test this hypothesis (6)(7)(8)(9)(10)(11). Data from these studies have generally appeared consistent with the overall hypothesis; however, it is difficult to draw a firm conclusion from the evidence presented.…”

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confidence: 66%

“…2 11 Although sera from all transgenic animals tested had substantial levels of mixed IgM molecules, no mixed mole- . These authors conclude that the Igh-S transgene markedly blocks endogenous Igh-6 rearrangement; however, approximately a third of the splenic B cells in these mice express endogenous Igh-6, and a significant fraction of these coexpress endogenous Igh-6 and the transgenic Igh-S. Hybridoma studies have also revealed the existence of cells expressing endogenous Igh genes in transgenic mice (8,11). Thus, although less attention has been paid to cells producing endogenous immunoglobulin in earlier studies of transgenic mice, rearrangement of the endogenous chromosome has not been completely suppressed in any Igh transgenic line studied.…”

mentioning

confidence: 96%

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Rearrangement and expression of endogenous immunoglobulin genes occur in many murine B cells expressing transgenic membrane IgM.

Stall

Kroese²,

Gadus³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Transgenic mice carrying immunoglobulin genes coding for it heavy chain and K light chain have been used to study the mechanisms involved in allelic and isotypic exclusion. We report here that individual cells from transgenic mice carrying a functionally rearranged la heavy chain gene (capable of generating both membrane and secreted forms of IgM) can rearrange an endogenous ,u heavy chain gene and simultaneously produce both transgenic and endogenous IgM. These "double-producing" cells express both endogenous and transgenic IgM in the cytoplasm (detected by immunohistology) and on the cell surface (detected by multiparameter fluorescence-activated cell sorter analysis). In addition, they secrete mixed IgM molecules containing both transgenic and endogenous 1L heavy chains (detected in serum by radioimmune assay). The transgenic mice studied also have relatively large numbers of cells that produce endogenous immunoglobulin in the absence of detectable transgenic immunoglobulin ("endogenous-only cells"). The mechanisms that generate double-producing cells and endogenous-only cells appear to be under genetic control because the frequencies of these B-cell populations are characteristic for a given transgenic line. Thus, our frndings indicate that more is involved in triggering allelic exclusion than the simple presence or absence of membrane ja heavy chains (as has been previously postulated).

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confidence: 66%

mentioning

confidence: 96%

Rearrangement and expression of endogenous immunoglobulin genes occur in many murine B cells expressing transgenic membrane IgM.

Stall

Kroese²,

Gadus³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…The functional significance of this finding has been unclear since most of the rearrangements analyzed were nonproductive . Also, VH81X is rarely found in an expressed antibody (20,21), except that observed in a transgenic mouse model (42) . Moreover, Reth et al .…”

Section: Discussionmentioning

confidence: 99%

Comparison of the fetal and adult functional B cell repertoires by analysis of VH gene family expression.

Jeong

Teale

1988

The Journal of Experimental Medicine

102

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The functional B cell repertoire in BALB/c mice was assessed at various stages in ontogeny. This was done by analyzing VH gene family expression using the sensitive technique of in situ hybridization. The B cell repertoire was probed with the mitogen, LPS, and the antigen DNP. DNP was chosen because B cells responsive to this hapten appear very early in ontogeny. The APCs that developed after stimulation with LPS or DNP were analyzed for VH gene expression by in situ hybridization of individual cells using radiolabeled VH gene family probes. The results indicated that VH gene expression in fetal B cells after stimulation was distinct from adult B cells in that there was a biased expression of D proximal families. The results indicated that this bias was associated with developmental age and not a given differentiation stage in the B cell lineage. In addition, stimulation of fetal B cells with DNP resulted in a large increase in expression of member(s) of VH 36-60, suggesting that the early appearance of DNP-responsive B cells is not strictly correlated with preferential rearrangement of D proximal families, VH 7183 and VH Q52. However, the results suggested that a large proportion of pre-B cells that preferentially rearrange D proximal families early in ontogeny become part of the functional developing repertoire.

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“…[For example, thejoint action of TH(VHAb) and TH(VLAb) could yield maximum stimulation of B(Ab) cells but TH(VHAb) could also stimulate B(Ab') cells where Ab' shares the same VH chain as Ab.] Recent data with transgenic mice carrying exogenous VH genes could be interpreted in this way (24).…”

Section: Working Principlesmentioning

confidence: 99%

Working principles in the immune system implied by the "peptidic self" model.

Kourilsky¹,

Chaouat²,

Rabourdin–Combe³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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The hypothesis that self as well as foreign proteins are processed into peptides and presented by major histocompatibility complex antigens leads to a set of working principles that could govern cellular interactions in immune responses. In particular, "idiopeptides," derived from immunoglobulins and T-cell receptors and recognized by appropriate T cells, are expected to play an important regulatory role. We show here that these speculations fit into a consistent view of the immune system.In the past few years, a remarkable series of experiments has cast light on the function of class I and class II molecules of the major histocompatibility complex (MHC). A growing body of evidence enforces the view that class II MHC molecules bind peptides derived from "processed" (i.e., partially degraded) antigen and expose them on the cell surface (1-3). Importantly, recent experiments indicate that class I MHC molecules could do the same (4-6). The primary function of MHC molecules might thus be to present peptides derived from processed proteins.Assigning a molecular function to MHC molecules is a major accomplishment because they play a pivotal role in regulatory interactions between cells of the immune system. It is well established that the activation and action of various types of T lymphocytes (TH, helper; Ts, suppressor; CTL, cytolytic) requires recognition by T-cell receptors (TCR) of (processed) antigen in association with MHC molecules on the surface of antigen-presenting cells (APCs) or target cells.Under the assumption that the actual function of MHC molecules relies on peptide presentation, we have proposed a logical generalization based on an interpretation of results by Townsend et al. (4, 5)-namely, that self, as well as foreign proteins, can yield peptides presented by MHC molecules (7,8). Cells expressing MHC molecules would thus be permanently coated with a set of distinct peptides somehow reflecting their protein content. For example, somatic cells, most of which express class I MHC molecules, would display myriads of self peptides associated to the latter. APCs (i.e., macrophages, dendritic cells, B cells), which express both class I and class II MHC molecules, would be loaded with antigen-derived peptides in addition to self peptides. Finally, B cells producing a given antibody would expose peptides derived from it, called antibody idiopeptides (designated Ab), while T cells expressing TCR could expose TCR idiopeptides (designated TCR). Therefore, the generalization proposed under our initial peptidic self model (7, 8) leads to two major predictions: (i) the presentation of self peptides by MHC molecules, and (it) the existence of idiopeptides, which, as discussed below, could constitute an important class of regulatory elements. Here, we delineate the implications arising from these premises and show that they lead to a consistent view of the immune system. WORKING PRINCIPLESPresentation by MHC Molecules. So far, little is known about the mechanisms of antigen presentation, but they are likely...

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Altered repertoire of endogenous immunoglobulin gene expression in transgenic mice containing a rearranged Mu heavy chain gene

Cited by 92 publications

References 37 publications

Rearrangement and expression of endogenous immunoglobulin genes occur in many murine B cells expressing transgenic membrane IgM.

Rearrangement and expression of endogenous immunoglobulin genes occur in many murine B cells expressing transgenic membrane IgM.

Comparison of the fetal and adult functional B cell repertoires by analysis of VH gene family expression.

Working principles in the immune system implied by the "peptidic self" model.

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