Abstract
A recognizing self RNA and dsDNA are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anti-RNA and anti-dsDNA IgG are thought to be TLR 7/8and TLR 9-dependent, respectively. Paradoxically, recent results show TLR 9 is protective in murine models of SLE, calling into question the pathogenicity and/or the mechanism of anti-dsDNA antibody generation. We study SLE “564Igi” mice that express knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an RNAspecific antibody. Our preliminary results indicate that aged 564Igi mice shift their antibody repertoire from anti-RNA IgG to antidsDNA IgG. Surprisingly, the production of this anti-dsDNA antibody is TLR 7/8-dependent and TLR 9-independent. Our hypothesis is that these anti-dsDNA antibodies arise via somatic hypermutation (SHM) of Ig genes in B cells that are activated via the RNA-sensing TLR 7/8 pathway yet are polyreactive to dsDNA in addition to RNA. This work defines a novel mechanism for the generation of selfreactive IgG antibodies and may explain why RNA reactivity precedes polyreactivity in SLE, as is suggested by human data.
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