Evidence for a role of extracellular heat shock protein 70 in epidermolysis bullosa acquisita

Tukaj, Stefan; Mantej, Jagoda; Sitko, Krzysztof; Bednarek, Marta; Zillikens, Detlef; Ludwig, Ralf J.; Bieber, Katja; Kasperkiewicz, Michael

doi:10.1111/exd.14495

Cited by 5 publications

(17 citation statements)

References 29 publications

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“…Levels of circulating anti-Hsp70 Ig were evaluated by enzyme-linked immunosorbent assay (ELISA) as shown previously ( 4 , 5 ).…”

Section: Methodsmentioning

confidence: 99%

“…♀ BALB/c mice (6 weeks of age) were purchased from the Tri-City University Animal Facility — Research Service Center (Poland). Induction of EBA by repetitive anti-COL7 IgG transfer in mice followed published protocols ( 5 , 9 ). Disease activity was expressed as the percentage of body surface area covered by skin lesions and determined at three time points as described previously ( 5 , 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…6 μm tissue sections were stained with hematoxylin and eosin (H&E). Dermal neutrophil infiltration was scored blindly by an independent researcher on a scale from 0 to 4, i.e., 0, none; 1, slight; 2, moderate; 3, marked; and 4, very marked as described previously ( 5 ).…”

Section: Methodsmentioning

confidence: 99%

“…Hydrogen peroxide (H 2 O 2 ) levels were assayed using the Amplex ® UltraRed fluorochrome (Molecular Probes) and Varioskan Reader (Thermo Fisher Scientific) as described previously ( 5 ).…”

Section: Methodsmentioning

confidence: 99%

“…In fact, increased serum levels of these autoantibodies were recorded in some autoimmune diseases including dermatitis herpetiformis ( 2 ), coeliac disease ( 3 ), and rheumatoid arthritis ( 4 ). In addition, our recent studies revealed that extracellular autologous Hsp70 represents a pathophysiological factor in epidermolysis bullosa acquisita (EBA) ( 5 ). EBA is one of the less common autoimmune blistering skin diseases characterized by the presence of autoantibodies to type VII collagen (COL7) of the cutaneous basal membrane zone.…”

Section: Introductionmentioning

confidence: 99%

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Pathological Relevance of Anti-Hsp70 IgG Autoantibodies in Epidermolysis Bullosa Acquisita

et al. 2022

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Stress-induced heat shock protein 70 (Hsp70) is a key intra- and extracellular molecular chaperone implicated in autoimmune processes. Highly immunogenic extracellular Hsp70 can activate innate and acquired (adaptive) immune responses driving the generation of anti-Hsp70 autoantibodies that are frequently observed in inflammatory/autoimmune disorders. We recently described the direct pathological role of extracellular Hsp70 in epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-mediated autoimmune blistering skin disease. Here, we determined the role of anti-Hsp70 autoantibodies in EBA. We observed that circulating anti-Hsp70 IgG autoantibodies were significantly elevated in EBA patients compared to healthy individuals and positively correlated with serum levels of pro-inflammatory interferon gamma (IFN-γ). The pathophysiological relevance of anti-Hsp70 IgG autoantibodies was demonstrated in an antibody transfer-induced EBA mouse model in which elevated serum levels of anti-Hsp70 IgG were found. In addition, anti-Hsp70 IgG-treated animals had a more intense clinical and histological disease activity, as well as upregulated nuclear factor kappa B (NF-κB) activation in skin biopsies compared to isotype-treated animals. Our results suggest that autoantibodies to Hsp70 may contribute to EBA development via enhanced neutrophil infiltration to the skin and activation of the NF-κB signaling pathway in an IFN-γ-associated manner.

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“…Levels of circulating anti-Hsp70 Ig were evaluated by enzyme-linked immunosorbent assay (ELISA) as shown previously ( 4 , 5 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathological Relevance of Anti-Hsp70 IgG Autoantibodies in Epidermolysis Bullosa Acquisita

et al. 2022

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Heat shock protein 90 (Hsp90) inhibitor STA-9090 (Ganetespib) ameliorates inflammation in a mouse model of atopic dermatitis

Sitko,

Starke,

Tukaj

2023

Cell Stress and Chaperones

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Molecular chaperones belonging to the heat shock protein 90 (Hsp90) family are implicated in inflammatory processes and described as potential novel therapeutic targets in autoimmune/inflammatory skin diseases. While the pathological role of circulating Hsp90 has been recently proposed in patients with atopic dermatitis (AD), a chronic inflammatory skin disease characterized by intense itching and recurrent skin lesions, studies aimed at investigating the role of Hsp90 as a potential target of AD therapy have not yet been conducted. Here, the effects of the Hsp90 blocker STA-9090 (Ganetespib) applied systemically or topically were determined in an experimental mouse model of dinitrochlorobenzene (DNCB)-induced AD. Intraperitoneal administration of STA-9090 ameliorated clinical disease severity, histological epidermal thickness, and dermal leukocyte infiltration in AD mice which was associated with reducing the scratching behavior in DNCB-treated animals. Additionally, topically applied STA-9090 led to lowered disease activity in AD mice, reduced serum levels of IgE, and up-regulated filaggrin expression in lesional skin samples. Our observations suggest that Hsp90 may be a promising therapeutic target in atopic dermatitis and potentially other inflammatory or autoimmune dermatoses.

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Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19

Kasperkiewicz

Tukaj

2022

Front. Immunol.

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Heat shock proteins (Hsps), including Hsp90 and Hsp70, are intra- and extracellular molecules implicated in cellular homeostasis and immune processes and are induced by cell stress such as inflammation and infection. Autoimmune bullous disorders (AIBDs) and COVID-19 represent potentially life-threatening inflammatory and infectious diseases, respectively. A significant portion of AIBDs remain refractory to currently available immunosuppressive therapies, which may represent a risk factor for COVID-19, and suffer from treatment side-effects. Despite advances in vaccination, there is still a need to develop new therapeutic approaches targeting SARS-CoV-2, especially considering vaccine hesitancy, logistical distribution challenges, and breakthrough infections. In this mini review, we briefly summarize the role of targeting Hsp90/70 as a promising double-edged sword in the therapy of AIBDs and COVID-19.

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Evidence for a role of extracellular heat shock protein 70 in epidermolysis bullosa acquisita

Cited by 5 publications

References 29 publications

Pathological Relevance of Anti-Hsp70 IgG Autoantibodies in Epidermolysis Bullosa Acquisita

Pathological Relevance of Anti-Hsp70 IgG Autoantibodies in Epidermolysis Bullosa Acquisita

Heat shock protein 90 (Hsp90) inhibitor STA-9090 (Ganetespib) ameliorates inflammation in a mouse model of atopic dermatitis

Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19

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