Nucleic acid (NA)–sensing TLRs (NA-TLRs) promote the induction of anti-nuclear Abs in systemic lupus erythematosus. However, the extent to which other nonnuclear pathogenic autoantibody specificities that occur in lupus and independently in other autoimmune diseases depend on NA-TLRs, and which immune cells require NA-TLRs in systemic autoimmunity, remains to be determined. Using Unc93b13d lupus-prone mice that lack NA-TLR signaling, we found that all pathogenic nonnuclear auto-antibody specificities examined, even anti-RBC, required NA-TLRs. Furthermore, we document that NA-TLRs in B cells were required for the development of antichromatin and rheumatoid factor. These findings support a unifying NA-TLR–mediated mechanism of autoantibody production that has both pathophysiological and therapeutic implications for systemic lupus erythematosus and several other humoral-mediated autoimmune diseases. In particular, our findings suggest that targeting of NA-TLR signaling in B cells alone would be sufficient to specifically block production of a broad diversity of autoantibodies.

Impairments in learning and memory occur in as many as 50% of patients following traumatic brain injury (TBI). Similar impairments occur in rodent models of TBI, and the development of new memory testing procedures provides an opportunity to examine how TBI affects memory processing in specific neural memory systems. Specifically, metric, topological, and temporal ordering tasks are object-based tests for memory of spatial orientation and temporal sequencing working memory developed for use in rodents. Previous studies demonstrated that specific lesions of the dentate gyrus/CA3 of the hippocampus and the parietal cortex resulted in deficits in the metric and topological spatial orientation tasks, respectively. Lesions of the CA1 impaired a rat's ability to recall the temporal order of odors. The purpose of the following study was to determine whether moderate lateral fluid percussion TBI would generate deficits in these working memory tasks, and whether observed deficits were associated with cell loss in the CA2/3 and/or CA1 of the hippocampus. Two weeks following a moderate lateral fluid percussion TBI, adult rats demonstrated significant deficits in both the metric and temporal ordering tasks (p<0.05) but not in the topological task. Stereological analysis identified a significant reduction in neurons in the CA2/3 (p<0.05) but not the CA1 of the hippocampus. These data demonstrate the utility of three object-based tasks to expand our understanding of how different neural memory systems are affected by TBI.

SLE is associated with a diversity of autoAbs, of which some are relatively specific for SLE, whereas others are also found in other autoimmune diseases. Nucleic acid sensing-TLRs (TLR3, 7-9; NA-TLRs) through the engagement of NA-containing material alone or in immune-complexes have been shown to play a critical role in lupus pathogenesis. However it is unclear to what extent NA-TLR signaling also promotes autoAbs to self-antigens (Ags) unrelated to NA. Here, we studied the role of NA-TLRs in MRL-lpr mice using the 3d mutation that abolishes NA-TLR signaling. In 3d mice, IgG and IgM antibodies to nuclear and RNA-associated Ags were essentially completely abolished, whereas other autoAbs with potential to cross-react to NAs (cardiolipin, and β2-GP1) were reduced to a lesser extent, and Abs unrelated to NAs (desmoglein3) were unaffected. Using a novel model that addresses loss of tolerance to B cells that acquire self-reactivity after class-switch recombination, it was found that NA-TLRs did not play an essential role in this process. Absence of NA-TLR signaling reduced lymphoproliferation, splenomegaly, and glomerulonephritis, but did not affect the incidence or severity of skin disease consistent with no reduction in cryoglobulins. Thus, in the MRL-lpr model, NA-TLRs are necessary for nucleic acid-associated autoantibody specificities and glomerulonephritis, but to varying degrees for other autoAb specificities and cutaneous disease.

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