Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis.

A comprehensive understanding of atopic dermatitis (AD) pathogenesis is desired, especially in the current era of novel biologics and small molecule drugs. In recent years, new cytokines have emerged that may play a significant role in the pathogenesis of AD. Using the tape stripping (TS) method, this study analyzed the gene expression of IL-35 and IL-36α in lesional and nonlesional AD skin compared with healthy skin and their association with the clinical features of AD among the Polish population. Ten AD patients and seven healthy individuals were enrolled. The lesional skin of the AD patients showed significantly higher expression levels of IL-35 compared to healthy skin (p = 0.0001). The expression level of IL-36α was significantly higher in lesional AD skin than in nonlesional AD skin (p = 0.0039) and healthy skin (p = 0.0045). There was a significant negative correlation between AD severity and the expression level of IL-35 in both lesional (R = −0.66, p = 0.048) and nonlesional skin (R = −0.9, p = 0.0016). In summary, both IL-35 and IL-36α appear to play a role in the pathogenesis of AD. Furthermore, it might be speculated that IL-35 and IL-36α may be potential candidates for disease biomarkers. However, further studies are needed to verify these assumptions and comprehensively elucidate their importance in the pathogenesis of AD.

Heat shock proteins belonging to the HSP90 family promote inflammation and are potential therapeutic targets in inflammatory and autoimmune diseases. Here the effects of the HSP90 inhibitor 17-AAG applied topically were evaluated in a DNCB-induced murine model of atopic dermatitis (AD). The use of 17-AAG improved clinical disease activity without causing toxicity in the animals. Topical application of 17-AAG resulted in reduced epidermal hyperplasia, decreased expression of TSLP, IL-5, and IL-6, as well as reduced activation of NF-κB in the skin. In addition, the eosinophil proportion in the blood and eosinophil peroxidase (EPX) activity in the skin were significantly reduced in 17-AAG-treated AD mice. The inhibitory effects of 17-AAG on the production of epidermal alarmins, T-helper cell-associated cytokines, and ROS release were demonstrated in cultures of activated human keratinocytes, CD4 ⁺ T lymphocytes, and eosinophils, respectively. Finally, next-generation sequencing metagenomic approaches revealed that topical application of 17-AAG partially restored the normal gut microbiome in AD mice. Moreover, 17-AAG inhibited Staphylococcus aureus biofilm formation in vitro. The findings of this study, combined with the observed increase in HSP90 and EPX activity in the leukocytes of the analyzed cohort of AD patients, support the potential therapeutic use of HSP90 inhibitors in individuals with AD.

Atopic dermatitis (AD) is characterized by heterogeneous immune activation extending beyond clinically apparent lesions. Interleukin-19 (IL-19) has been implicated in cytokine-responsive keratinocyte activation, whereas interleukin-37 (IL-37) has endogenous anti-inflammatory functions. Their superficial epidermal expression patterns in lesional and clinically non-lesional AD skin have not been extensively characterized within the same cohort. To compare IL19 and IL37 mRNA expression in lesional and clinically non-lesional, lesion-adjacent AD skin with healthy control skin and to explore associations between transcript abundance and clinical characteristics. In this exploratory cross-sectional study, tape strip samples were collected from lesional and clinically non-lesional skin of 32 patients with AD and from corresponding skin of 35 healthy controls. IL19 expression did not differ significantly among healthy control, lesional, and clinically non-lesional AD skin in the overall cohort. In contrast, IL37 transcript abundance was significantly higher in lesional AD skin than in healthy control skin (p = 0.0002) and was also increased in clinically non-lesional skin (p = 0.0387). In severity-stratified analyses, lesional IL37 expression was increased in both moderate and severe-to-very severe AD, whereas lower lesional IL19 expression relative to healthy control skin was observed in severe-to-very severe AD (p = 0.0412). Lesional IL19 expression showed an inverse association with EASI severity category (p = 0.045), while lesional IL37 expression was positively associated with sleep-disturbance scores (p = 0.0203). The two transcripts showed distinct expression patterns in this cohort. Increased IL37 mRNA was compatible with, but did not establish, a compensatory response extending into lesion-adjacent clinically non-lesional skin. Overall IL19 upregulation was not detected, and lower lesional expression was observed in severe-to-very severe AD. However, these exploratory observations do not establish cytokine function or validate either transcript as a stand-alone biomarker.