Bcl-2 leads to expression of anti-DNA B cells but no nephritis: a model for a clinical subset

Abstract

Transgenic mice expressing anti‐DNA antibodies have been extensively studied as a model for understanding B cell regulation in systemic lupus erythematosus (SLE). BALB / c mice transgenic for the R4A‐γ2b heavy chain of an anti‐double‐stranded DNA (dsDNA) antibody produce two populations of high‐affinity anti‐dsDNA B cells, one deleted, and the other anergized. We generated double‐transgenic BALB / c mice expressing both the R4A‐γ2b heavy chain and the anti‐apoptotic bcl‐2 gene in the B cell compartment to study whether bcl‐2 overexpression differentially affected anergic and deleted B cells. The double‐transgenic mice (R4A / bcl‐2) express elevated serum titers of both high‐ and low‐affinity anti‐dsDNA antibodies and display rescue of autoreactive B cells that are normally either deleted or anergized. Despite the presence of anti‐dsDNA antibodies in their serum, R4A / bcl‐2‐transgenic mice do not develop nephritis, demonstrating that overexpression of bcl‐2 is not by itself sufficient to allow disease progression. This phenotype resembles that of some SLE patients who have high titers of anti‐DNA antibodies without nephritis.

Experimental Models of Lupus Nephritis

“…Transgenic mice that overexpress the cell survival protein bcl-2 gene develop lymphocytic infiltrates in arteries and solid organs, autoantibodies and immune complex-mediated renal disease [84]. The autoantibodies appear to be generated through inappropriate survival of autoreactive B cell clones that are normally lost through negative selection and apoptosis [84,85].…”

Hormonal regulation of B-cell function and systemic lupus erythematosus

“…12 The transgenic heavy chain can pair with a variety of light chains to produce B-cell receptors (BCRs) with affinities for dsDNA ranging from nondetectable to high. [13][14][15] Many transgene-encoded antibodies have no detectable affinity for DNA. A population of transgene expressing B cells with low affinity for DNA is not tolerized and matures to immunocompetence in peripheral lymphoid organs 14 ; the antibodies made by this population are non-pathogenic.…”

“…Its existence has been identified in BALB/c mice transgenic for both R4A and Bcl-2 and in R4A NZB/W mice. [13][14][15] In these strains, these high-affinity autoreactive B cells mature to immunocompetence; the antibodies they secrete are pathogenic. Thus, R4A BALB/c mice possess well-characterized populations of autoreactive B cells that make them a suitable model for studying the effects of sex hormones on B-cell development.…”

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes

“…In these transgenic, untreated mice, high-affinity anti-DNA B cells are rendered tolerant, and lupus does not develop [112,[209][210][211]. When subjected to a 6-week treatment with estrogen that leads to a serum concentration similar to the peak estrogen concentration during the estrus cycle (75 pg/ml), these transgenic mice develop an increased number of DNA-reactive B cells that spontaneously secrete autoantibodies, along with elevated serum anti-DNA antibody levels and glomerular IgG deposition.…”