Differential role of nucleic acid-sensing toll-like receptors in autoantibody production. (44.29)

Abstract

Abstract 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.