Document Detail


Heat shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that non-malignant plasma cells are not therapeutic targets.
MedLine Citation:
PMID:  21490339     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Blocking heat shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response (UPR), a signaling pathway activated by accumulation of misfolded proteins within the endoplasmatic reticulum. We hypothesized that non-transformed plasma cells are also hypersensitive to Hsp90 inhibition owing to their high amount of protein biosynthesis. To study this, two different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG or 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 autoantibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cells 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 reduced response of isolated lymph node cells from immunized mice to in vitro re-stimulation with anti-CD3/CD28 antibody or autoantigen in 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:
Michael Kasperkiewicz; Ralf Müller; Rudolf Manz; Moritz Magens; Christoph M Hammers; Csaba Somlai; Jürgen Westermann; Enno Schmidt; Detlef Zillikens; Ralf J Ludwig; Antal Orosz
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-13
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Dermatology, University of Luebeck, Luebeck, Germany;
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