For instance, in lupus nephritis (LN) immune complex deposition induces local immune cell activation and increases immune cell influx leading to tissue damage. Both systems are involved in organ damage resulting from autoimmunity. Furthermore, erroneous recognition of nucleic acids, e.g., by toll-like receptors (TLRs) and the subsequent type I interferons secretion by dendritic cells and macrophages confirm an essential role of innate immunity in the pathogenesis of SLE. In established disease, a misguided “self-directed” adaptive immune response provokes autoantibody production and lymphadenopathy. Genetic susceptibility, female sex-specific factors, and environmental triggers, e.g., viral infections are key determinants of SLE onset. Systemic lupus erythematosus (SLE) is a classic example of systemic autoimmunity. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. Splenocytes of phenotypically overall-normal Gdf15−/− C57BL/6 and lupus-prone C57BL/6 lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6 lpr/lpr) backgrounds. Still, its role in systemic autoimmune disease remains elusive. Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis.
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