Heat shock protein 90: a pathophysiological factor and novel treatment target in autoimmune bullous skin diseases

Abstract

The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.

Autoantibodies of non‐inflammatory bullous pemphigoid hardly deplete type XVII collagen of keratinocytes

“…While the blistering relevance of autoantibodies against NC16A has been well studied in BP, the pathogenicity of autoantibodies against the non‐NC16A domain remains unclear. The precise mechanisms lead to find novel therapeutic targets, e.g protein kinase C or heat‐shock protein 90 …”

Postpartum bullous pemphigoid – A case report

“…In 2015, studies performed by Stephan Tukaj et al provide an important insight that Hsp90 were highly expressed in the epidermis of BP patients, but its serum levels were decreased and inversely associated with autoantibodies against BP180 NC16A. It may be speculated that anti-BP180 NC16A autoantibodies indirectly lead to an enhanced intracellular expression of Hsp90 by generation of an inflammatory response comprising soluble pro-inflammatory mediators (cytokines and ROS) and simultaneously cause a direct inhibition of its cellular release [14,15].…”

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.…”