NZB/BINJ and NZW/LACJ Embryonic Chimeras Develop Strong Autoimmunity Dependent on NZB/BINJ T Cells

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2018-09-25

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Abstract

The NZB/NZW F1 hybrid develops systemic lupus erythematosus (SLE), displaying features of human disease including spontaneous anti-nuclear antibodies, glomerulonephritis, earlier and more penetrant expression of disease in females, and polygenic etiology. The autoimmunity that develops in these mice must result from epistatic interactions between NZB and NZW alleles at specific loci in the hybrid mice. However, the causative alleles and pathways have remained elusive. In the present study we sought to determine whether incompatibility between cells of the two parental strains causes autoimmunity. We generated chimeras (here designated NZB;NZW) by injecting embryonic stem cells from NZB/BINJ (NZB) mice into NZW/LacJ (NZW) blastocysts. These chimeras developed an accelerated form of autoimmunity characterized by the presence of autoantibodies 3 months earlier, and at titers 10-fold greater, than the NZB/NZW F1 hybrids. The chimeras also developed mild glomerulonephritis and severe lymphadenopathy and splenomegaly. The observed cellular incompatibility was specific for the NZB;NZW combination (not observed in NZB;C57BL/6J or NZW;C57BL/6J), and occurred despite the fact that each parental type does not develop SLE features in a non-chimeric environment. Within each chimera, an expansion of activated T cells from the NZB strain and a predominance of B cells from NZW were observed. Furthermore, the expanded NZB T cells correlated with autoimmunity, and removing these T cells in NZB(Cd3e-/-);NZW chimeras prevented disease. Thus, NZB and NZW cells are inherently incompatible with one another, though compatible with C57BL/6J cells. Pathogenic intercellular transactions cause this strong autoimmunity in chimeric mice, dependent upon the presence of NZB T cells.

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Autoimmune Diseases, Autoimmunity, Chimera, Lupus Erythematosus, Systemic, Mice, Inbred NZB

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