Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: Evidence that nonmalignant plasma cells are not therapeutic targets

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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43 Citations (Scopus)

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 hasnoimpactonnormal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.

Original languageEnglish
Pages (from-to)6135-6142
Number of pages8
JournalBlood
Volume117
Issue number23
DOIs
Publication statusPublished - Jun 9 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kasperkiewicz, M., Müller, R., Manz, R., Magens, M., Hammers, C. M., Somlai, C., Westermann, J., Schmidt, E., Zillikens, D., Ludwig, R. J., & Orosz, A. (2011). Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: Evidence that nonmalignant plasma cells are not therapeutic targets. Blood, 117(23), 6135-6142. https://doi.org/10.1182/blood-2010-10-314609