Lessons from BXSB and Related Mouse Models

Abstract

The BXSB murine strain spontaneously develops an autoimmune syndrome with features of systemic lupus erythematosus (SLE) that affects males much earlier than females, due to the presence of an as yet unidentified mutant gene located on its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). The Yaa gene by itself is unable to induce significant autoimmune responses in mice without an apparent SLE background, while it can induce and accelerate the development of an SLE in combination with autosomal susceptibility alleles present in lupus-prone mice. Although the genes encoded within or closely linked to the MHC locus play an important role in the development or protection of SLE, the MHC effect can be completely masked by the presence of the Yaa gene in mice highly predisposed to SLE. The role of the Yaa gene for the acceleration of SLE is apparently two-fold; it enhances overall autoimmune responses against autoantigens to which mice respond relatively weakly, and promotes Th 1 responses against autoantigens to which mice respond relatively well, leading to the production of more pathogenic autoantibodies, i.e., FcgammaR-fixing IgG2a and cryoglobulin IgG3 autoantibodies. Yaa+ - Yaa- double bone marrow chimera experiments revealed that the Yaa defect is expressed in B cells, but not in T cells, and that T cells from non-autoimmune mice are capable of providing help for autoimmune responses by collaborating Yaa+ B cells. We speculate that the Yaa defect may decrease the threshold for antigen receptor-dependent stimulation, leading to the triggering and excessive stimulation of autoreactive T and B cells.

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

“…The mouse strains ((NZB Â NZW)F1, MRL/lpr, BXSB) spontaneously develop anti-dsDNA antibodies and an SLE-like disease, which evokes some of the symptoms of human SLE like proteinuria and glomerulonephritis [29][30][31][32][33][34]. However, these animal models do not reproduce the severe complicated clinical manifestation found in humans [35][36][37][38].…”

“…To circumvent this problem, we employed a dsDNA-mimicking decapeptide DWEYSVWLSN, which is recognized by the pathogenic antidsDNA antibodies and may be used instead of native DNA [27]. A protein chimeric molecule containing copies of the DNAmimotope peptide bound to anti-human CD35 mAb was constructed, able to cross-link cell surface BCR with the inhibitory CR1 on self-reactive DNA-specific B cells from SLE patients [28].The mouse strains ((NZB Â NZW)F1, MRL/lpr, BXSB) spontaneously develop anti-dsDNA antibodies and an SLE-like disease, which evokes some of the symptoms of human SLE like proteinuria and glomerulonephritis [29][30][31][32][33][34]. However, these animal models do not reproduce the severe complicated clinical manifestation found in humans [35][36][37][38].…”

A Study on the Glycan Specificity of Natural Antibody Repertoires in Rodents

“…As shown in Figures 4C and 4D, 2 out of 10 BXSB mice were high producers of -glucan-specific IgG, while 3 out of the 10 were high producers of anti--glucan IgA. It should also be noted that the prevalence of anti--glucan IgG and IgA Abs in aged BXSB mice was unrelated to sex, thereby excluding a possibility for direct association with murine lupus which mostly occurs in BXSB males rather than females (26)(27)(28).…”

“…BXSB mice represent one of the most extensively studied animal models for human systemic lupus erythematosus (SLE), a systemic autoimmune disorder characterized by the production of autoantibodies against a variety of autoantigens, particularly dsDNA and nuclear proteins (26)(27)(28). It was therefore of interest to investigate if the glycan-specificity of BXSB natural Abs differs from that of the other strains of mice.…”

Deletion of p21 (WAF-1/Cip1) Does Not Induce Systemic Autoimmunity in Female BXSB Mice

“…Male BXSB mice develop an early-life severe lupus-like disease promoted by an as yet undefined Y-chromosome-associated accelerator of autoimmunity (Yaa) (12). This accelerator is insufficient in itself to induce severe lupus, and many other genes within this background need to act in concert for full disease expression (12).…”