Association between nuclear antigens and endogenous retrovirus in the generation of autoantibody responses in murine lupus

Abstract

Objective. (NZB ؋ NZW)F 1 (NZB/NZW) mice and other strains of mice with experimental lupus frequently produce autoantibodies to both chromatin constituents and murine leukemia virus envelope gp70. These autoantibody responses are involved in the glomerulonephritis that develops in these mice. This study was undertaken to explore possible connections between these 2 antigen systems.Methods. We used monoclonal antibodies (mAb) derived from unmanipulated NZB/NZW mice to investigate the specificity of anti-gp70 and antichromatin autoantibodies for chromatin constituents, recombinant gp70, NZB retroviruses, and retrovirally infected cells. NZB mice were also immunized with retroviral particles and followed up for study of autoantibody responses.Results. Spontaneous autoantibody production in NZB/NZW mice reflects high-level autoimmune responses to nuclear antigens and gp70 that do not cross-react with the other antigen. However, both types of autoantibodies have the capability to bind to the endogenous xenotropic virions NZB-X1 or NZB-X2. The mAbs to recombinant gp70 cross-reacted only with the NZB-X2 virus, whereas the antichromatin mAb frequently bound to both retroviruses. The binding of antichromatin autoantibodies was mediated by nuclear material complexed to the retrovirus, and studies showed that this material can be acquired through the budding process. Immunization with NZB-X1 or NZB-X2 virions induced strong responses to gp70 and was much more effective than chromatin at inducing autoantibody responses to chromatin and doublestranded DNA in NZB mice.Conclusion. These studies suggest that retroviral virions may harbor nuclear antigens and may link together the autoimmune responses to the disparate antigens, chromatin and gp70.The F 1 hybrid of NZB and NZW mice spontaneously develops an autoimmune disease characterized by production of IgG autoantibodies and development of a severe immune complex (IC)-mediated glomerulonephritis (1). These (NZB ϫ NZW)F 1 (NZB/NZW) mice are considered to be an excellent model of human systemic lupus erythematosus. The major known targets of autoantibodies in this model are chromatin and its major constituents (DNA and histones) and the murine leukemia virus (MuLV)-derived serum glycoprotein gp70 (1-5). Both antichromatin and anti-gp70 autoantibodies, the latter measured as gp70-anti-gp70 ICs (gp70 ICs), have been implicated in the development of the progressive lupus nephritis in these mice (1-10). Interestingly, in other murine models of lupus nephritis, such as MRL-Fas lpr and BXSB mice, the mice also produce high levels of autoantibodies to both nuclear antigens and gp70 (1,(11)(12)(13)(14)(15).Although serum gp70 may be critical for the formation of pathogenic gp70 ICs, it is not the only gp70 produced in these mice. Numerous functional and nonfunctional copies of MuLV are inherited in mouse

Priming Protective CD8 T Cell Immunity by DNA Vaccines Encoding Chimeric, Stress Protein-Capturing Tumor-Associated Antigen

“…nuclear Ags can trigger autoimmune responses to chromatin and gp70 (55). We detected no clinical evidence of autoimmune disease during a Ͼ8-mo observation period in which our mice were (repeatedly) vaccinated and challenged with large tumor inocula and developed high specific CD8 T cell immunity.…”

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

“…However, an endogenous retrovirus is not a likely source of dsRNA in B6.NZBc13 mice, as almost all endogenous retroviruses are not replication competent due to post-integration mutations and deletions, suggesting a lack of active viral infection. Moreover, the Sgp3 locus was found to control the gp70 expression of a modified polytropic (mPT) provirus (ssRNA virus), and not of the xenotropic proviruses (NZB-X1 or NZB-X2) shown to accelerate anti-chromatin antibody production in NZB mice [28][29][30]. Interestingly, it has been previously reported that in vivo exposure to poly(I:C) potently increases serum gp70 levels in NZB mice, which suggested a potential role for gp70 as an acute phase reactant [31].…”

The Bxs6 Locus of BXSB Mice Is Sufficient for High-Level Expression of gp70 and the Production of gp70 Immune Complexes

“…It has been demonstrated that, in addition to anti-gp70 Abs, Abs to nuclear material can also bind to NZB xenotropic retroviruses (14), due to the presence of this material on the surface of the retrovirus. The correlation between gp70IC and ANA levels, consistent with both phenotypes being reliant on high levels of gp70, provides support for this theory.…”

“…In crosses with the NZB and New Zealand White (NZW) parental strains of the autoimmune (NZB ϫ NZW)F 1 strain, gp70IC levels were linked to the MHC on chromosome 17 (8,12) and to a locus on chromosome 7 (13). Crosses with these strains have also shown linkage of gp70 levels to chromosome 4 (14,15). Furthermore, in crosses with the NZB strain, both gp70 and gp70IC levels were linked to chromosome 13 (8,16).…”