Glatiramer acetate treatment does not modify the clinical course of (NZB x BXSB)F1 lupus murine model.

Glatiramer acetate (GA, copolymer-1, Copaxone), a therapy approved for treatment of multiple sclerosis (MS), prevents and reverses experimental autoimmune encephalomyelitis, the animal model of MS. In central nervous system autoimmune disease, GA is thought to act through modulation of antigen-presenting cells, such as monocytes, mediating an antigen-independent T(h)2 shift and development of FoxP3+ regulatory T cells. Recent reports indicate that GA may also be effective in models of other autoimmune diseases such as uveoretinitis, inflammatory bowel disease and graft rejection. To date, the potential effect of GA in lupus animal models has not been described. (NZB x BXSB)F1, male mice bearing Y-linked autoimmune acceleration , is a lupus-prone mouse model which is associated with a monocytosis accelerating disease progression. These mice were treated with GA before disease onset until death and both mortality rate and biological parameters were assessed to investigate whether GA may be beneficial in this spontaneous model of systemic lupus erythematosus. GA exerted no beneficial effect on the median survival after up to 7 months of treatment. Humoral and cellular parameters used as markers for lupus progression, such as anti-chromatin, anti-double-stranded DNA and anti-erythrocytes antibodies, hematocrit and monocytosis, were similarly unchanged. Our study demonstrates that GA has no significant effect on the progression of the (NZB x BXSB)F1 lupus-prone animal model. These results reinforce the hypothesis that GA may exert its beneficial effect in some specific autoimmune diseases only.

Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus.

The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.