Immunomodulatory effects of heat shock protein 90 inhibition on humoral immune responses

Abstract

Heat shock protein 90 (Hsp90) inhibition blocks T-cell-linked inflammatory disease pathways and exhibits therapeutic activity in autoimmune disease mouse models, including the blistering disease epidermolysis bullosa acquisita. Although we previously showed that preformed autoreactive plasma cells do not seem to be directly affected by anti-Hsp90 treatment, immunomodulatory effects of Hsp90 inhibition on (auto-)antibody responses are not yet fully understood. In this study, the Hsp90 blocker 17-DMAG inhibited proliferation of activated total B cells and their IgG secretion in cultures of human peripheral B cells from healthy subjects, but IgG production was no longer affected when these activated B cells were allowed to differentiate prior to a deferred application of the inhibitor. 17-DMAG treatment was associated with induction of nuclear and cytoplasmic heat shock factor 1 and Hsp70 in stimulated human B cells, respectively. Type VII collagen (epidermolysis bullosa acquisita)-immunized mice early treated with 17-DMAG had reduced total B cells in spleens, a relative increase in splenic regulatory B cell fractions, higher serum IL-10 concentrations, and lower levels of circulating autoantibodies (paralleled by less pronounced disease induction) compared with vehicle-treated immunized mice. Autoantibody production was blunted in isolated and autoantigen-restimulated lymph node cells from immunized mice by either 17-DMAG or purified autologous splenic regulatory B cells. Thus, in addition to the previously described T cell inhibitory effects of Hsp90 blockade, this treatment potently modulates humoral immune responses at the B cell level, further supporting the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoantibody-mediated disorders.

Heat shock protein 90 inhibition: A potential double- or triple-edged sword in the treatment of mucous membrane pemphigoid

“…These future investigations could yield some relevant information about the role of Hsp90 in MMP and, together with already existing knowledge on the powerful anti-inflammatory and anti-scarring effects of anti-Hsp90 treatment [14][15][16][17][18][19][20][21]25,[28][29][30], possibly support the introduction of nontoxic Hsp90 inhibitors for future medical management of patients with this potentially devastating disease that may otherwise cause permanent damage when therapy is delayed or ineffective.…”

“…Based on the above, we hypothesize that pharmacological Hsp90 blockade could represent a double-edged sword in the treatment of MMP by pleiotropic targeting of the mentioned Hsp90 inhibitor-prone pathophysiological factors involved in both inflammatory subepidermal blister formation and cicatricial processes [19][20][21]25,[28][29][30]. Due to their additional anti-cancer activity, Hsp90 inhibitors could even be proclaimed as a triple-edged sword against the malignancy-associated anti-laminin 332 subtype of MMP [12].…”

“…These include that (i) Hsp90 inhibitors exhibit activity in mice with experimental epidermolysis bullosa acquisita and in a respective ex vivo human dermal-epidermal separation cryosection model by potently affecting inflammatory disease pathways (i.e., inhibition of effector T cells, B cells, and neutrophils; suppression of autoantibody, proinflammatory cytokine, and reactive oxygen species production; promotion of regulatory B cells) [19][20][21], (ii) secreted basement membrane-degrading and blister-provoking matrix metalloproteinases with partly profibrotic potential are complexed by extracellular Hsp90 in sera of patients with epidermolysis bullosa acquisita, thus representing additional treatment targets of Hsp90 antagonists [21][22][23], (iii) Hsp90 is aberrantly expressed and secreted in the skin and blood of patients with BP, and its blockade modulates anti-BP180 autoantibody-induced production of proinflammatory IL-8 by cultured keratinocytes [24,25], and (iv) circulating autoantibodies to Hsp90 are elevated and positively correlated with disease activity and serum anti-epidermal/tissue transglutaminase autoantibodies in patients with dermatitis herpetiformis [26]. With regard to MMP, it has previously been reported that, in contrast to healthy persons and those with atopic keratoconjunctivitis, Hsp90 expression is upregulated in the conjunctival stroma and vasculature of patients with ocular disease [27].…”

Heat shock protein 90 is required for ex vivo neutrophil‐driven autoantibody‐induced tissue damage in experimental epidermolysis bullosa acquisita

“…This allows for analysis of novel therapeutic agents intended to target granulocyte-dependent inflammatory pathways involved in autoimmune tissue damage, as it reproduces the efferent autoimmune response independently of T cells, B cells, and plasma cells (6). While we previously showed that pharmacological Hsp90 inhibition directly affects autoreactive T cells and B cells, but not plasma cells (1,2), the results of our current study extend these observations revealing that this treatment is also capable of directly inhibiting the effector phase of granulocyte-driven autoantibody-induced skin blistering.…”

Epidermolysis Bullosa Acquisita: From Pathophysiology to Novel Therapeutic Options

“…A novel strategy to inhibit autoreactive T cell responses is derived from experiments using inhibitors of the cell stressinducible chaperone heat shock protein 90 (Hsp90) in experimental EBA (Kasperkiewicz et al, 2011). Currently tested in clinical trials for therapy of cancer patients due to its inhibitory effects on malignant cells (Solárová et al, 2015), anti-Hsp90 treatment is also increasingly becoming a research focus in autoimmune diseases, including blistering disorders, as it exerts potent immunomodulatory actions (Collins et al, 2013;de Zoeten et al, 2011;Kasperkiewicz et al, 2011;Tukaj et al, 2014aTukaj et al, , 2014bTukaj et al, , 2014cTukaj et al, , 2015aTukaj et al, , 2015b. Application of Hsp90 inhibitors before and after disease onset blocked EBA development and induced clinical recovery associated with suppressed autoantibody production compared with vehicletreated animals in immunization-induced EBA, respectively.…”