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Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis - a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential "biomarker" in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sitko, Mantej, Bednarek and Tukaj.)

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., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Heat shock proteins (HSP) have been reported to impact immune responses and to be associated with rheumatoid arthritis (RA). Recently, we provided evidence for a role of autoantibodies to Hsp40 in patients with RA. In this study, we aimed at investigating the humoral autoimmune response to Hsp60, Hsp70, and Hsp90 in RA patients (n = 39). In comparison with healthy controls (n = 40), circulating IgG, IgM, and IgA autoantibodies against Hsp60, Hsp70, and Hsp90 were significantly increased in RA patients. Non-parametric statistical analysis, however, revealed no significant association between anti-HSP and disease activity or disease progression. On the other hand, positive correlations between serum levels of anti-Hsp60 IgG and IL-4 (Th2-like cytokine) or between serum levels of anti-Hsp90 IgG and IFN-ɣ (Th1-like cytokine) were found to be statistically significant in RA. In addition, a significant inverse correlation was found for serum levels of anti-Hsp70 IgM and TNF-α (Th1-like cytokine) in RA. Our results suggest a pronounced anti-Hsp60, anti-Hsp70, and anti-Hsp90 humoral autoimmune response in RA patients that seems not to be directly linked to RA pathophysiology, however, may have a potential modulatory impact on inflammatory status in this disease. Further investigations are needed to clarify the role of anti-HSP autoantibodies in RA.

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. [ABSTRACT FROM AUTHOR]