The Yaa locus Confers Apoptosis, NF-κB and Rapamycin Signaling Resistance Through Multiple Receptors in C57BL/6J Mice (129.12)

Abstract

Abstract BXSB/MpJ mice develop a spontaneous SLE-like disease that is remarkably accelerated in males, due to the presence of the Y-linked-autoimmune accelerator locus (Yaa). Recent insights into the molecular nature of the Yaa mutation were provided when an additional copy of 17 distally located X chromosome genes were discovered on the Y-chromosome of Yaa mice. Included within this region is the gene TLR7, a toll receptor which binds ssRNA and is functionally expressed on B-cells and monocyte derived lineages. Previous reports have suggested that the SLE-like disease phenotype conveyed by Yaa is due to the duplication of TLR7, which causes a shift toward anti-nucleolar antigens in B6.FcγRIIB(−/−). We show here that B6, BXSB and MRL mice that carry Yaa rarely display the anti-nucleolar antibody pattern. We found that B cells of Yaa mice display novel phenotypes consistent with increased rapamycin and NF-κB signaling through receptors other than TLR7, including TLR4, TLR9, and the BCR. In addition, Yaa B cells are resistant to anti-IgM induced apoptosis. These results demonstrate that the copy number of a single receptor can influence the strength of signaling through other receptors and/orthat additional genes within the duplicated region contribute toward the Yaa phenotype. Funded by NIH R21DK074463 and DK56597 to DCR, Arthritis Foundation to JAB.