TheYaa gene-mediated acceleration of murine lupus:Yaa− T cells from non-autoimmune mice collaborate withYaa+ B cells to produce lupus autoantibodiesin vivo
ABSTRACT The BXSB Y chromosome-linked mutant gene, Yaa, promotes autoimmune responses in mice predisposed to a lupus-like autoimmune disease. We have previously shown that a cognate interaction of T cells with B cells expressing the Yaa gene appears to be responsible for the accelerated production of autoantibodies. To investigate whether T cells that provide help for autoantibody production by Yaa+ B cells need to express the Yaa gene, we have made radiation bone marrow chimeras containing two sets of T and B cells from mice with or without the Yaa gene and differing by the Thy-1 and Igh allotypes. We then determined autoantibody production following the selective elimination of T cells of Yaa+ origin by treating mice with allele-specific anti-Thy-1 monoclonal antibody. Our results demonstrated that the selective production of autoantibodies by Yaa+ B cells in Yaa(+)-Yaa- double bone marrow chimeras can be mediated as efficiently by T cells from non-autoimmune mice lacking the Yaa gene as by T cells from autoimmune mice bearing the Yaa gene. This indicates that T cells from non-autoimmune Yaa- mice are capable of providing help for autoimmune responses by collaborating with Yaa+ B cells. These data thus strongly suggest that the Yaa gene defect is not functionally expressed in T cells, but only in B cells, and contrast with parallel experiments in the lpr model, in which defects of the Fas antigen in both T and B cells are crucial for the lpr gene-mediated promotion of autoantibody production.
- SourceAvailable from: Edward K Wakeland
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- "The yaa gene, which has been shown to result from the abnormal expression of TLR7 due to a translocation event, is a unique feature of this strain (Subramanian et al., 2006). Investigators have demonstrated that yaa is dysregulated in the B cell lineage and that CD4 Tcells were necessary for disease but need not carry the yaa mutation (Fossati et al., 1995; Lawson et al., 2001; Merino et al., 1991). BSXB male mice develop high levels of circulating IgG autoantibodies to a variety of nuclear antigens leading to IC deposition in the kidney and fatal (GN). "
ABSTRACT: Systemic lupus erythematosus (SLE) is a complex polygenic autoimmune disease characterized by the presence of anti-nuclear autoantibodies (ANAs) that are often detectable years prior to the onset of clinical disease. The disease is associated with a chronic activation of the immune system, with the most severe forms progressing to inflammatory damage that can impact multiple organ systems in afflicted individuals. Current therapeutic strategies poorly control disease manifestations and are generally immunosuppressive. Recent studies in human patient populations and animal models have associated elements of the innate immune system and abnormalities in the immature B lymphocyte receptor repertoires with disease initiation. A variety of cytokines, most notably type I interferons, play important roles in disease pathogenesis and effector mechanisms. The genetic basis for disease susceptibility is complex, and analyses in humans and mice have identified multiple susceptibility loci, several of which are located in genomic regions that are syntenic between humans and mice. The complexities of the genetic interactions that mediate lupus have been investigated in murine model systems by characterizing the progressive development of disease in strains expressing various combinations of susceptibility alleles. These analyses indicate that genetic epistasis dramatically impact disease development and support the feasibility of identifying molecular pathways that can suppress disease progression without completely impairing normal immune function.Advances in Immunology 02/2006; 92:1-69. DOI:10.1016/S0065-2776(06)92001-X · 5.96 Impact Factor