title: Immunomodulatory effects of heat shock protein 90 inhibition on humoral immune responses.
abstract: Heat shock protein 90 (Hsp90) inhibition blocks T-cell-linked inflammatory disease pathways and exhibits therapeutic activity in autoimmune disease mouse models, including the blistering disease epidermolysis bullosa acquisita. Although we previously showed that preformed autoreactive plasma cells do not seem to be directly affected by anti-Hsp90 treatment, immunomodulatory effects of Hsp90 inhibition on (auto-)antibody responses are not yet fully understood. In this study, the Hsp90 blocker 17-DMAG inhibited proliferation of activated total B cells and their IgG secretion in cultures of human peripheral B cells from healthy subjects, but IgG production was no longer affected when these activated B cells were allowed to differentiate prior to a deferred application of the inhibitor. 17-DMAG treatment was associated with induction of nuclear and cytoplasmic heat shock factor 1 and Hsp70 in stimulated human B cells, respectively. Type VII collagen (epidermolysis bullosa acquisita)-immunized mice early treated with 17-DMAG had reduced total B cells in spleens, a relative increase in splenic regulatory B cell fractions, higher serum IL-10 concentrations, and lower levels of circulating autoantibodies (paralleled by less pronounced disease induction) compared with vehicle-treated immunized mice. Autoantibody production was blunted in isolated and autoantigen-restimulated lymph node cells from immunized mice by either 17-DMAG or purified autologous splenic regulatory B cells. Thus, in addition to the previously described T cell inhibitory effects of Hsp90 blockade, this treatment potently modulates humoral immune responses at the B cell level, further supporting the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoantibody-mediated disorders.
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Stefan
authors: S
authors: Tukaj
authors: Benjamin
authors: B
authors: Tiburzy
authors: Rudolf
authors: R
authors: Manz
authors: Andreia
authors: A
authors: de Castro Marques
authors: Antal
authors: A
authors: Orosz
authors: Ralf J
authors: RJ
authors: Ludwig
authors: Detlef
authors: D
authors: Zillikens
authors: Michael
authors: M
authors: Kasperkiewicz
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016227:Benzoquinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects* / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D016227:Benzoquinones; D024143:Collagen Type VII; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007074:Immunoglobulin G; D007155:Immunologic Factors; D047029:Lactams, Macrocyclic; D014157:Transcription Factors; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D016753:Interleukin-10
keywords: B cell; autoantibody; autoimmunity; heat shock protein