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The early marginal zone B cell initiated T independent type 2 response resists the proteasome inhibitor bortezomib
  1. V Lang1,
  2. D Mielenz2,
  3. H Martin Jäck2,
  4. K Neubert1,
  5. C Böhm1,3,
  6. G Schett3,
  7. R E Voll1,3,
  8. S Meister1
  1. 1Interdisciplinary Center for Clinical Research, Research Group N2, Nikolaus Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Erlangen, Germany
  2. 2Division of Molecular Immunology, Department of Internal Medicine3, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Internal Medicine3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

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The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. Recently, we demonstrated that bortezomib eliminates autoreactive plasma cells in SLE mice, thereby representing a promising novel treatment for antibody-mediated diseases. Here, we investigated the effect of bortezomib on the developing and pre-existing T dependent antibody response towards dinitrophenylated keyhole limpet hemocyanin and the T independent type 2 response towards NIP-Ficoll in BALB/c mice. Bortezomib treatment strongly reduced T dependent antibody titres mainly due to depletion of plasma cells. In contrast, the early T independent type 2 response, predominantly initiated by marginal zone (MZ) B cells, resisted bortezomib. Immunoproteasomal subunits and the antiapoptotic unfolded protein response were induced in NIP-Ficoll-stimulated MZ B cells after bortezomib treatment, but not in plasma cells. This induction might be cell autonomous and not a consequence of the microenvironment since mobilisation of MZ B cells out of the spleen did not render them susceptible towards bortezomib. We conclude that the resistance of MZ B cells against bortezomib leaves early T independent responses protecting against bloodborne pathogens largely intact. This fact may account for a relatively low risk of bacterial infections compared to most other immunosuppressants and cytotoxic drugs.

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