TLR 9 / MyD 88 signaling is required for class switching to pathogenic IgG 2 a and 2 b autoantibodies in SLE

JEM © The Rockefeller University Press $8.00 Vol. 203, No. 3, March 20, 2006 553–561 www.jem.org/cgi/doi/10.1084/jem.20052438 553 Genetic susceptibility and environmental factors are responsible for the development of systemic lupus erythematosus (SLE). Mouse models of SLE, in particular, have provided signifi cant insights into the identifi cation of critical checkpoints and the molecular pathways that mediate the generation of this autoimmune disease (1–12). These models have demonstrated that the loss of tolerance that initiates SLE results from the accumulated eff ect of multiple genetic defects, which culminates in the deposition of pathogenic IgG autoantibodies in end-organs such as the kidney, where they induce infl ammation resulting in pathological events (6). IgG anti-DNA autoantibodies are a general feature of lupus and the molecular mechanisms that result in the selection and expansion of antiDNA autoantibodies have been suggested to involve the Toll-like receptors (TLRs). In particular, TLR9 and its signaling molecule MyD88 can provide a costimulatory signal in vitro for B cell stimulation by DNA (13, 14). The DNA ligand for TLR9 may be provided in vivo by apoptotic bodies that are incompletely cleared in lupus and could thus lead to uncontrolled activation of the TLR9–MyD88 pathway and promote anti-DNA autoantibody generation (13–15). It has recently been shown that pediatric SLE patients have a failure to establish B cell tolerance early during B cell development, leading to increased numbers of antinuclear, anticytoplasmic, and polyreactive cells in the naive peripheral B cell pool (16, 17). The increased frequency of autoreactive, naive B cells is thus suggested to be a prerequisite for the generation of autoantibodies and the development of lupus (17). A similar situation has been discussed in murine models of SLE with polyreactive autoantibodies deposited in the kidneys of these mice (18, 19). These polyreactive antibodies recognize DNA as well as glomerular antigens (18, 19) and are believed to be responsible for inducing proteinurea and thereby contribute to the pathology of SLE (19). We have recently described a strain-specifi c SLE model in which loss of the IgG inhibitory Fcγ receptor RIIB molecule on the C57BL/6 background resulted in the accumulation of pathogenic autoantibodies in the kidney with the development of glomerulonephritis and premature mortality (2). Through the use of a B cell–intrinsic, anti-DNA knockin model (the 56R VDJ4 heavy chain transgene on the C57BL/6 background), we have shown that the C57BL/6 strain provided a susceptible background by virtue of its inability to The online version of this article contains supplemental material. <doi>10.1084/jem.20052438</doi><aid>20052438</aid>TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE