title: Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway.
abstract: Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed "circulating DNA-containing ICs"), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.
authors.affiliation: Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Zhenke
authors.initials: Z
authors.lastname: Wen
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Gao
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology*; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D024243:HMGB1 Protein; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D050784:Proto-Oncogene Protein c-ets-1; D051195:Toll-Like Receptor 2; D004247:DNA