title: Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets.
abstract: Blocking heat-shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum. We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG and the nontoxic peptide derivative TCBL-145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermal-epidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen-immunized mice, suppressed auto-antibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen-specific plasma cells, and germinal center B cells were unaffected by anti-Hsp90 treatment in vivo. However, T-cell proliferation was potently inhibited, as evidenced by the reduced response of isolated lymph node cells from immunized mice to in vitro restimulation with anti-CD3/CD28 antibody or autoantigen in the presence of Hsp90 inhibitors. Our results suggest that Hsp90 blockade has no impact on normal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. Michael.Kasperkiewicz@uk-sh.de
authors.forename: Michael
authors.initials: M
authors.lastname: Kasperkiewicz
authors.forename: Ralf
authors.initials: R
authors.lastname: Müller
authors.forename: Rudolf
authors.initials: R
authors.lastname: Manz
authors.forename: Moritz
authors.initials: M
authors.lastname: Magens
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Hammers
authors.forename: Csaba
authors.initials: C
authors.lastname: Somlai
authors.forename: Jürgen
authors.initials: J
authors.lastname: Westermann
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.forename: Antal
authors.initials: A
authors.lastname: Orosz
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016227:Benzoquinones / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000276:immunology* / Q000378:metabolism; D020405:Dermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016107:Epidermolysis Bullosa Acquisita / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016227:Benzoquinones; D024141:Collagen Type IV; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; C000607511:TCBL-145 peptide; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin