Association between nuclear antigens and endogenous retrovirus in the generation of autoantibody responses in murine lupus
Rebecca M. Tucker
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorChristina L. Roark
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorMarie-Laure Santiago-Raber
Centre Medical Universitaire, Geneva, Switzerland
Search for more papers by this authorCorresponding Author
Brian L. Kotzin
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320Search for more papers by this authorRebecca M. Tucker
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorChristina L. Roark
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorMarie-Laure Santiago-Raber
Centre Medical Universitaire, Geneva, Switzerland
Search for more papers by this authorCorresponding Author
Brian L. Kotzin
University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, Colorado
Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320Search for more papers by this authorAbstract
Objective
(NZB × NZW)F1 (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 double-stranded 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.
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