Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation

Tukaj, Stefan; Mantej, Jagoda; Sobala, Michał; Potrykus, Katarzyna; Tukaj, Zbigniew; Zillikens, Detlef; Ludwig, Ralf J.; Bieber, Katja; Kasperkiewicz, Michael

doi:10.3389/fimmu.2021.614320

Cited by 11 publications

(13 citation statements)

References 27 publications

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“…In the past, molecular mimicry hypothesis suggested that the immune response originally directed to the bacterial Hsps may be re-directed towards their human counterparts and in this way promote development of autoimmune reactions (Albani et al 1995 ). While immune cross-reactions between foreign and self-antigens were experimentally confirmed in the case of Hsp40, Hsp60, or Hsp70 chaperones (Kotlarz et al 2013 ; van Eden et al 2017 ), clinical consequences of such immune cross-reactions have brought ambiguous outcomes (Tukaj and Kaminski 2019 ; Tukaj et al 2021 ; van Eden et al 2017 ). Information on a potential contribution of the bacterial Hsp90 (HtpG) in autoimmunity and the immune cross-reactions between HtpG and human Hsp90, however, is generally lacking.…”

Section: Discussionmentioning

confidence: 99%

Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis

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Bednarek

Mantej

et al. 2021

Cell Stress and Chaperones

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Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses characterized by persistent itching and recurrent eczematous lesions. While the primary events and key drivers of AD are topics of ongoing debate, cutaneous inflammation due to inappropriate IgE (auto)antibody–related immune reactions is frequently considered. Highly conserved and immunogenic heat shock protein 90 (Hsp90), a key intra- and extracellular chaperone, can activate the immune response driving the generation of circulating anti-Hsp90 autoantibodies that are found to be elevated in several autoimmune disorders. Here, for the first time, we observed that serum levels of Hsp90 and anti-Hsp90 IgE autoantibodies are significantly elevated (p < 0.0001) in AD patients (n = 29) when compared to age- and gender-matched healthy controls (n = 70). We revealed a positive correlation (0.378, p = 0.042) between serum levels of Hsp90 and the severity of AD assessed by Scoring Atopic Dermatitis (SCORAD). In addition, seropositivity for anti-Hsp90 IgE has been found in 48.27% of AD patients and in 2.85% of healthy controls. Although further studies on a larger group of patients are needed to confirm presented data, our results suggest that extracellular Hsp90 and autoantibodies to Hsp90 deserve attention in the study of the mechanisms that promote the development and/or maintenance of atopic dermatitis.

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Section: Discussionmentioning

confidence: 99%

Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis

Sitko

Bednarek

Mantej

et al. 2021

Cell Stress and Chaperones

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“…no. ADI-SPP-770; Enzo Life Science) or previously purified recombinant Hsp70 (Tukaj et al 2021 ) proteins at a concentration of 0.5 μg/ml in 0.05 M bicarbonate buffer at 4°C overnight. The wells were blocked with 1% bovine serum albumin (BSA) in phosphate-buffered saline (PBS) at room temperature (RT) for 90 min.…”

Section: Methodsmentioning

confidence: 99%

Autoantibodies to heat shock protein 60, 70, and 90 are not altered in the anti-SARS-CoV-2 IgG-seropositive humans without or with mild symptoms

Mantej

Bednarek

Sitko

et al. 2021

Cell Stress and Chaperones

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Highly conserved heat shock proteins (Hsps) are localized in the cytoplasm and cellular organelles, and act as molecular chaperones or proteases. Members of Hsp families are released into the extracellular milieu under both normal and stress conditions. It is hypothesized that the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has the potential to elicit autoimmunity due to molecular mimicry between human extracellular Hsps and immunogenic proteins of the virus. To confirm the above hypothesis, levels of circulating autoantibodies directed to the key human chaperones i.e., Hsp60, Hsp70, and Hsp90 in the anti-SARS-CoV-2 IgG-seropositive participants have been evaluated. Twenty-six healthy volunteers who got two doses of the mRNA vaccine encoding the viral spike protein, anti-SARS-CoV-2 IgG-positive participants (n = 15), and healthy naïve (anti-SARS-CoV-2 IgG-negative) volunteers (n = 51) have been included in this study. We found that the serum levels of anti-Hsp60, anti-Hsp70, and anti-Hsp90 autoantibodies of the IgG, IgM, or IgA isotype remained unchanged in either the anti-COVID-19-immunized humans or the anti-SARS-CoV-2 IgG-positive participants when compared to healthy naïve volunteers, as measured by enzyme-linked immunosorbent assay. Our results showing that the humoral immune response to SARS-CoV-2 did not include the production of anti-SARS-CoV-2 antibodies that also recognized extracellular heat shock protein 60, 70, and 90 represent a partial evaluation of the autoimmunity hypothesis stated above. Further testing for cell-based immunity will be necessary to fully evaluate this hypothesis.

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“…A recent study revealed that TGF-b regulates iTreg and Th17 cell differentiation by both Smad3-and TAK1dependent pathways in OVA-induced airway inflammation (32). Conversely, evidence suggests the involvement of Hsp, including Hsp70, in the development of psoriasis, characterized by impaired immunological cell function with altered Th17/Treg balance, autoreactive T cells, and dysregulation of keratinocyte proliferation (33,34). Furthermore, Dnajb1 controls the substrate targeting HSP70 (35), and Dnajb1 overexpression downregulates Th17 differentiation in mouse spleen lymphocytes (36).…”

Section: Discussionmentioning

confidence: 99%

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

et al. 2022

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HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2+/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2+/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.

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Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation

Cited by 11 publications

References 27 publications

Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis

Circulating heat shock protein 90 (Hsp90) and autoantibodies to Hsp90 are increased in patients with atopic dermatitis

Autoantibodies to heat shock protein 60, 70, and 90 are not altered in the anti-SARS-CoV-2 IgG-seropositive humans without or with mild symptoms

Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

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