The F1 generation of a NZB (New Zeland Black) and NZW (New Zealand White) cross produce anti-double stranded DNA antibodies and also generate immune complexes that result in glomerulonephritis, which is very similar to what we see in patients with SLE. Another mouse strain, NZM2410, is a recombinant inbred strain derived from the NZBxNZW F1 generation that develops a severe case of lupus-like disease and usually will die by 1 year from the products of the disease (anti-nuclear antibodies and renal disease). In the NZM2410 mouse, there are three loci that are linked to lupus development called Sle1, Sle2 and Sle3.
In the lab I work in we are looking at Complement Receptor 2 (CR2) as a lupus susceptibility gene, and it just so happens that the gene encoding CR2 in mice is in the Sle1 loci, and more specifically Sle1c, a subinterval of Sle1. It was determined that Sle1c was derived from the NZW strain. CR2 can be found primarily on mature B cells and follicular dendritic cells (FDCs) and binds C3 degradation products covalently bound to antigen.
What a member of the lab showed was that when a NZB mouse was crossed with a B6.Sle1c congenic mouse, the offspring expressed lupus-like symptoms at an accelerated rate compared to NZBxB6 mice. The NZBxB6.Sle1c mice showed higher titers and an earlier onset of both anti-chromatin antibodies and anti-dsDNA antibodies. And although renal dysfunction was not observed in either group, the NZBxB6.Sle1c mice did show increased immune complex deposits in glomeruli. We believe that it is CR2 in the Sle1c interval derived from NZW that is contributing to this acceleration of disease and believe that CR2 may have a role in regulating autoimmunity by lowering the threshold of B cell activation and tolerance. We are currently looking at NZBxB6.Sle1c recombinant mice that have a smaller part of the Sle1c inteval, and still contains the gene for CR2, to see if the phenotypes described above are still observed. This would strengthen our stance that CR2 contributes to lupus-like disease in mice. we are also beginning to look at CR2 on FDCs to figure out how they may contribute to SLE as well.
No comments:
Post a Comment