Neubert et al19 reported that bortezomib is also capable of depleting normal

In EBA and most other subepidermal autoimmune bullous diseases, autoantibodies alone are not sufficient to induce blisters, but require an Fcdependent engagement of humoral and cellular inflammatory factors.4 In addition, a key role of T cells in the initiation of autoimmunity against type VII collagen JAK Signaling Pathway has been demonstrated recently.5 Experimental EBA, which reproduces both the autoimmune response and immunopathologic, histologic, and clinical findings in patients with EBA, can be induced in susceptible mice by immunization with recombinant murine type VII collagen.6 Therefore, EBA emerges as a model disease to study fundamental biologically and clinically crucial aspects of antibodymediated, organspecific autoimmune diseases.
Heatshock proteins are molecular chaperones essential for Nilotinib maintaining cellular functions by preventing misfolding and aggregation of nascent polypeptides and by facilitating protein folding.7 Pharmacologic inhibition of the Hsp family member Hsp90 has been primarily implicated in the context of cancer treatment because this chaperone is used by many cancer cells to facilitate the function of numerous oncoproteins.8 Several Hsp90 inhibitors with different sideeffect profiles have been identified,9,10 of which newly synthesized, shortpeptide derivatives are of particular interest because in vivo toxicity has so far not been reported.10 Recently, Hsp90 has been reported to play important roles in antigen presentation, activation of lymphocytes and macrophages, and activation and maturation of dendritic cells, indicating a potential treatment target of inflammatory diseases, including autoimmune diseases.
11 Indeed, tissues pharmacologic inhibition of Hsp90 has recently been successfully applied in mouse models of autoimmune encephalomyelitis,12 rheumatoid arthritis,13 and systemic lupus erythematosus–like autoimmune disease.14 Although the inhibitory effects of Hsp90 inhibitors on various immune cells, including T cells, have been reported in autoimmunity, 1214 the direct impact of antiHsp90 treatment on autoantibodyproducing plasma cells has not been studied in vivo. Plasma cells producing high levels of protein are dependent on the unfolded protein response , which maintains protein homeostasis within the endoplasmic reticulum to ensure cell survival.
15 Activation of the UPR results in a bias of translation toward the synthesis of chaperone proteins involved in protein folding, an increase in the degradation of misfolded proteins via the ubiquitin proteasome pathway, and the delivery of a survival signal. If these objectives are not achieved within a certain time frame or if the disruption is prolonged, an ER stress signal is generated and apoptosis ensues.16 It has been shown that the proteasome inhibitor bortezomib can induce a UPR, leading to apoptosis of malignant plasma cells in vitro.17 Hsp90b1, the ER paralog of the cytosolic Hsp90, is believed to be one of the key molecular chaperones controlling the UPR.16 Similar to proteasome inhibition, blockade of Hsp90 has been associated with activation of the UPR pathway and apoptosis caused by an overload of unfolded monoclonal paraproteins in myeloma plasma cell lines.18 Recently, Neubert et al19 reported that bortezomib is also capable of depleting normal .