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Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern.

Li Y, Li H, Ni D, Weigert M - J. Exp. Med. (2002)

Bottom Line: This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R.In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor.Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

ABSTRACT
We have studied the regulation of anti-DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor. A minor population of B cells (30%) bind dsDNA and express the lambda1 light chain (known to sustain 3H9H/56R DNA binding). These 3H9/56R/lambda1 B cells coexpress a kappa editor, and we propose that the down-regulation of the anti-DNA BCR caused by the dual L chain expression may prevent activation of this kappa/lambda population. These kappa/lambda B cells are sequestered in the marginal zone. Here, we studied the influence of autoimmunity on expression and regulation of 3H9H/56R. In 3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent. Our results suggest that improper editing and failure to sequester autoreactive B cells may contribute to the breakdown of tolerance in MRL/lpr mice.

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CD21 and CD1 expression levels of κ/λ double-positive cells are different between 3H9H/56R BALB/c and 3H9H/56R MRL/lpr. Spleen cells from 3H9H/56R BALB/c and 3H9H/56R MRL/lpr were stained with anti-CD21, CD1, κ, and λ. Histograms of CD21 and CD1 expression are shown for the κ/λ double-positive (filled area) and κ single-positive (thin line) populations.
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fig5: CD21 and CD1 expression levels of κ/λ double-positive cells are different between 3H9H/56R BALB/c and 3H9H/56R MRL/lpr. Spleen cells from 3H9H/56R BALB/c and 3H9H/56R MRL/lpr were stained with anti-CD21, CD1, κ, and λ. Histograms of CD21 and CD1 expression are shown for the κ/λ double-positive (filled area) and κ single-positive (thin line) populations.

Mentions: The peak frequency of κ/λ double-positive B cells is lower in 3H9H/56R MRL/lpr (7.6% of the CD19+ spleen B cell) than in 3H9H/56R BALB/c (19.4%; Fig. 4) . The κ/λ double-positive B cells of 3H9H/56R BALB/c are in the marginal zone shown by markers such as CD21high and CD1high. Most of the κ/λ double-positive B cells in 3H9H/56R MRL/lpr are CD21low and CD1low, indicating that they are not in the marginal zone (Fig. 5) . As has been previously reported, there is a general decrease in CD21 and CD23 level in MRL/lpr mice (28). However, there is no generalized defect in MZ B cell development. As shown in Fig. 6 A, non-tg MRL/lpr mice has a larger MZ B cell population (CD21high, CD23low; 10.8% of lymphoid gate) compared with non-tg BALB/c (1.9%). The exaggerated MZ of MRL/lpr mice has also been reported before (29). Most interestingly, although the 3H9H/56R transgene causes a big increase of the MZ B cells population in BALB/c, it dramatically reduces that population in MRL/lpr (Fig. 6 A). Several mouse strains with transgene have shown larger MZ B cell compartment, which can accommodate self-reactive B cells (for review see reference 30). The reduction of MZ B cell population in3H9H/56R MRL/lpr shows some unique feature of MRL/lpr not only different from BALB/c, but also different from other autoimmune mice such as NZB/W, as pronounced marginal zone compartment was observed NZB/W mice with an anti-DNA μH transgene (31).


Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern.

Li Y, Li H, Ni D, Weigert M - J. Exp. Med. (2002)

CD21 and CD1 expression levels of κ/λ double-positive cells are different between 3H9H/56R BALB/c and 3H9H/56R MRL/lpr. Spleen cells from 3H9H/56R BALB/c and 3H9H/56R MRL/lpr were stained with anti-CD21, CD1, κ, and λ. Histograms of CD21 and CD1 expression are shown for the κ/λ double-positive (filled area) and κ single-positive (thin line) populations.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196070&req=5

fig5: CD21 and CD1 expression levels of κ/λ double-positive cells are different between 3H9H/56R BALB/c and 3H9H/56R MRL/lpr. Spleen cells from 3H9H/56R BALB/c and 3H9H/56R MRL/lpr were stained with anti-CD21, CD1, κ, and λ. Histograms of CD21 and CD1 expression are shown for the κ/λ double-positive (filled area) and κ single-positive (thin line) populations.
Mentions: The peak frequency of κ/λ double-positive B cells is lower in 3H9H/56R MRL/lpr (7.6% of the CD19+ spleen B cell) than in 3H9H/56R BALB/c (19.4%; Fig. 4) . The κ/λ double-positive B cells of 3H9H/56R BALB/c are in the marginal zone shown by markers such as CD21high and CD1high. Most of the κ/λ double-positive B cells in 3H9H/56R MRL/lpr are CD21low and CD1low, indicating that they are not in the marginal zone (Fig. 5) . As has been previously reported, there is a general decrease in CD21 and CD23 level in MRL/lpr mice (28). However, there is no generalized defect in MZ B cell development. As shown in Fig. 6 A, non-tg MRL/lpr mice has a larger MZ B cell population (CD21high, CD23low; 10.8% of lymphoid gate) compared with non-tg BALB/c (1.9%). The exaggerated MZ of MRL/lpr mice has also been reported before (29). Most interestingly, although the 3H9H/56R transgene causes a big increase of the MZ B cells population in BALB/c, it dramatically reduces that population in MRL/lpr (Fig. 6 A). Several mouse strains with transgene have shown larger MZ B cell compartment, which can accommodate self-reactive B cells (for review see reference 30). The reduction of MZ B cell population in3H9H/56R MRL/lpr shows some unique feature of MRL/lpr not only different from BALB/c, but also different from other autoimmune mice such as NZB/W, as pronounced marginal zone compartment was observed NZB/W mice with an anti-DNA μH transgene (31).

Bottom Line: This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R.In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor.Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

ABSTRACT
We have studied the regulation of anti-DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor. A minor population of B cells (30%) bind dsDNA and express the lambda1 light chain (known to sustain 3H9H/56R DNA binding). These 3H9/56R/lambda1 B cells coexpress a kappa editor, and we propose that the down-regulation of the anti-DNA BCR caused by the dual L chain expression may prevent activation of this kappa/lambda population. These kappa/lambda B cells are sequestered in the marginal zone. Here, we studied the influence of autoimmunity on expression and regulation of 3H9H/56R. In 3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent. Our results suggest that improper editing and failure to sequester autoreactive B cells may contribute to the breakdown of tolerance in MRL/lpr mice.

Show MeSH
Related in: MedlinePlus