Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs.
Genetic dissection of lupus pathogenesis in the NZM2410 strain has recently revealed that Sle1 is a potent locus that triggers the formation of IgG anti-histone/DNA antibodies, when expressed on the B6 background as a congenic interval. B6.lpr mice, in contrast, exhibit distinctly different cellular and serological phenotypes. Both strains, however, do not usually exhibit pathogenic autoantibodies, or succumb to lupus nephritis. In this study, we show that the epistatic interaction of Sle1 (in particular, Sle1/Sle1) with FAS lpr leads to massive lymphosplenomegaly (with elevated numbers of activated CD4 T cells, CD4−CD8− double negative (DN) T cells, and B1a cells), high levels of IgG and IgM antinuclear (including anti-ssDNA, anti-dsDNA, and anti-histone/DNA), and antiglomerular autoantibodies, histological, and clinical evidence of glomerulonephritis, and >80% mortality by 5–6 mo of age. Whereas FAS lpr functions as a recessive gene, Sle1 exhibits a gene dosage effect. These studies indicate that Sle1 and FAS lpr must be impacting alternate pathways leading to lymphoproliferative autoimmunity.
Objective. Studies in mice and humans have implicated type I interferon (IFN-I) in the pathogenesis of lupus. Given that the locus for IFN-I is positioned within the Sle2 murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus.Methods. IFN-I, anti-IFN-I, isotype control antibody, or phosphate buffered saline was administered to C57BL/6 and B6.Sle2 mice, and the serologic and cellular phenotypes were studied. In addition, B6.Sle2 mice were examined for structural and expression polymorphisms in the IFN-I gene.Results. In both B6.Sle2 congenic mice and C57BL/6 control mice, antibody-mediated blockade of IFN-I augmented serum autoantibody levels and boosted B1a cell numbers. Administration of IFN-I ameliorated these 2 features previously attributed to this disease locus. Importantly, compared with B6 controls, B6.Sle2 mice had reduced levels of IFN-I in their sera and cell culture supernatants, following stimulation. Although several sequence polymorphisms were noted in the Sle2 alleles of various IFN-I genes, it was not established whether any of the noted sequence variations were causally related to the observed phenotypes.Conclusion. Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval. Placing these findings in the context of other studies, the effect of IFN-I on systemic autoimmunity appears to be far more complex than originally perceived.
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