Stefan Tukaj

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

Frontiers in Immunology

Stress-induced heat shock protein 70 (Hsp70) is a key intra- and extracellular molecular chaperon... more 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 ser...

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Commentary: Bullous pemphigoid associated with COVID-19 vaccines: An Italian multicenter study

Frontiers in Medicine

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Dosage Compensation in Females with X-Linked Metabolic Disorders

International Journal of Molecular Sciences

Through the use of new genomic and metabolomic technologies, our comprehension of the molecular a... more Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders.

format_quoteThe timing of complete X chromosome inactivation varies between cell lineages, complicating the assessment of its impact.format_quote

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Case Report: Circulating Anti-SARS-CoV-2 Antibodies Do Not Cross-React With Pemphigus or Pemphigoid Autoantigens

Frontiers in Medicine, 2021

It is hypothesized that SARS-CoV-2 has the potential to elicit autoimmunity due to molecular mimi... more It is hypothesized that SARS-CoV-2 has the potential to elicit autoimmunity due to molecular mimicry between immunogenic proteins of the virus and human extracellular molecules. While in silico and in vitro evaluation of such immune cross-reactivity of human antibodies to SARS-CoV-2 proteins with several different tissue antigens has been described, there is limited information specifically pertaining to the immunological effects of COVID-19 and vaccines against SARS-CoV-2 on the development of autoimmune bullous diseases (AIBDs). Twelve seropositive post-COVID-19 individuals and 12 seropositive healthy volunteers who received two doses of the mRNA COVID-19 vaccine from Pfizer-BioNTech have been included in this case series investigation. Serum samples of these blood donors were tested for autoantibodies to the main immunobullous autoantigens, i.e., desmoglein 1, desmoglein 3, envoplakin, BP180, BP230, and type VII collagen. Our study revealed that none of the 24 anti-SARS-CoV-2 IgG...

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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

Cell Stress and Chaperones, 2021

Highly conserved heat shock proteins (Hsps) are localized in the cytoplasm and cellular organelle... more 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, a...

format_quoteHumoral immune response to SARS-CoV-2 lacks production of related anti-Hsp antibodies, supporting the non-activation of autoimmunity.format_quote

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

Cell Stress and Chaperones, 2021

Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses characterized by... more 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). ...

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Autoantibodies to heat shock proteins 60, 70, and 90 in patients with rheumatoid arthritis

Cell Stress and Chaperones, 2018

Heat shock proteins (HSP) have been reported to impact immune responses and to be associated with... more 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.

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Analysis of serum markers of cellular immune activation in patients with bullous pemphigoid

Experimental Dermatology, 2017

Experimental models of bullous pemphigoid (BP), the most frequent subepidermal autoimmune bullous... more Experimental models of bullous pemphigoid (BP), the most frequent subepidermal autoimmune bullous disease, revealed that the immune response leading to blister formation represents an incompletely understood complex process involving different inflammatory cells. In contrast to previous reports commonly focusing on limited molecular and cellular phenotypes of the disease, the aim of this study was to investigate a broad spectrum of markers of cellular immune activation in patients with BP. We found that serum levels of soluble CD4, myeloperoxidase, S100A12, eosinophil cationic protein and soluble P‐selectin were significantly elevated in patients with active BP compared with normal controls. Mast cell tryptase and neopterin serum levels significantly decreased at the time of clinical remission of the patients. Additionally, serum concentrations of soluble IL‐2 receptor, mast cell tryptase and soluble P‐selectin were significantly associated with levels of circulating anti‐BP180 auto...

format_quoteBP patients exhibited significantly higher levels of immune markers sCD4, MPO, S100A12, ECP, and sP-selectin compared to healthy controls, indicating active disease.format_quote

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Autoimmunity to heat shock proteins and vitamin D status in patients with celiac disease without associated dermatitis herpetiformis

The Journal of Steroid Biochemistry and Molecular Biology, 2017

Inflammation-induced heat shock proteins (HSPs) and hypovitaminosis D have been reported to impac... more Inflammation-induced heat shock proteins (HSPs) and hypovitaminosis D have been reported to impact immune responses and to be associated with autoimmune diseases including celiac disease (CD), a gluten-sensitive enteropathy mediated by autoantibodies against tissue transglutaminase (TG2). Recently, we provided evidence for a role of autoantibodies to HSPs in patients with dermatitis herpetiformis (DH), an inflammatory skin disease induced by underlying latent CD. In this study, we aimed at investigating the humoral autoimmune response to HSPs and vitamin D status in CD patients (n = 15) presenting without the cutaneous disease manifestation. In comparison with healthy controls (n = 15), circulating autoantibodies against HSP40, HSP60, and HSP90 were increased in these patients, and these autoantibodies, including anti-HSP70, correlated with serum anti-TG2 autoantibodies. Deficient and insufficient vitamin D serum levels were found in 8 out of 15 CD patients and 11 out of 15 healthy controls, and the vitamin D status showed no relationship with levels of circulating anti-TG2 or anti-HSP autoantibodies in the patients. Our results preliminarily suggest a pronounced anti-HSP autoimmune response in CD that is linked to pathophysiological processes in the gut independently of both a potential concomitant disease-related extra-intestinal inflammatory manifestation in the skin and the vitamin D status. Future studies on larger groups of patients are needed to confirm the present data and to further clarify whether autoimmunity towards HSPs is primarily related to underlying CD or skin inflammation in DH patients.

format_quoteA pronounced anti-HSP autoimmune response in CD may signal underlying gut pathophysiology, necessitating further research on patient groups.format_quote

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Calcitriol Treatment Ameliorates Inflammation and Blistering in Mouse Models of Epidermolysis Bullosa Acquisita

Journal of Investigative Dermatology, 2017

A link between hypovitaminosis D and development of autoimmune bullous disorders has been suggest... more A link between hypovitaminosis D and development of autoimmune bullous disorders has been suggested recently, but this association has not been elaborated experimentally. Here, the role of vitamin D was investigated in epidermolysis bullosa acquisita (EBA), an antiÀtype VII collagen autoantibody-induced blistering skin disease. Oral administration of the hormonally active vitamin D metabolite calcitriol ameliorated clinical disease severity and dermal neutrophil infiltration in both an antibody transfer-and immunization-induced EBA mouse model. Mechanistically, calcitriol hindered immune effector cell activation as evidenced by increased L-selectin expression on Gr-1 þ cells in calcitriol-treated mice with antibody transfer-induced EBA, as well as suppressed in vitro immune complexÀinduced reactive oxygen species production in calcitriol-treated murine neutrophils. Additionally, calcitriol administration was associated with an increase of regulatory cells as well as reduction of pro-inflammatory T helper 17 (CD4 þ IL-17 þ ) cells in mice with immunization-induced EBA. In line, levels of circulating antiÀtype VII collagen autoantibodies were lower in mice that received calcitriol compared to solvent-treated animals. Together with the observed state of hypovitaminosis D in most cases of an analyzed EBA patient cohort, the results of this study support the use of vitamin D derivatives or analogs for patients with EBA and related diseases.

format_quoteCalcitriol significantly reduced EBA skin lesion severity from 8.35% to 1.8% body surface area affected in treated mice.format_quote

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

Experimental Dermatology, 2015

The chaperone heat shock protein 90 (Hsp90), a cell stress‐inducible molecule that regulates acti... more 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 ...

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Heat shock protein 90 is required for ex vivo neutrophil-driven autoantibody-induced tissue damage in experimental epidermolysis bullosa acquisita

Experimental dermatology, Jan 5, 2015

A broad range of immunosuppressive and immunomodulatory effects of heat shock protein 90 (Hsp90) ... more A broad range of immunosuppressive and immunomodulatory effects of heat shock protein 90 (Hsp90) blockade has been described in models of autoimmune bullous diseases, but the direct contribution of this chaperone to neutrophil effector pathways in the context of autoantibody-driven blistering is generally unknown. Therefore, this has been addressed in the current study on the basis of the subepidermal blistering disease epidermolysis bullosa acquisita (EBA) characterized by autoantibodies against type VII collagen, in which a crucial role of neutrophils and both their reactive oxygen species and matrix metalloproteinases in mediating tissue injury has been established. First, the Hsp90 antagonist 17-DMAG dose-dependently inhibited dermal-epidermal separation ex vivo in cryosections of human skin induced by co-incubation of EBA patient autoantibodies with neutrophils from healthy blood donors. Next, 17-DMAG dose-dependently suppressed production and release of reactive oxygen species...

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Immunomodulatory effects of heat shock protein 90 inhibition on humoral immune responses

Experimental Dermatology, 2014

Heat shock protein 90 (Hsp90) inhibition blocks T‐cell‐linked inflammatory disease pathways and e... more Heat shock protein 90 (Hsp90) inhibition blocks T‐cell‐linked inflammatory disease pathways and exhibits therapeutic activity in autoimmune disease mouse models, including the blistering disease epidermolysis bullosa acquisita. Although we previously showed that preformed autoreactive plasma cells do not seem to be directly affected by anti‐Hsp90 treatment, immunomodulatory effects of Hsp90 inhibition on (auto‐)antibody responses are not yet fully understood. In this study, the Hsp90 blocker 17‐DMAG inhibited proliferation of activated total B cells and their IgG secretion in cultures of human peripheral B cells from healthy subjects, but IgG production was no longer affected when these activated B cells were allowed to differentiate prior to a deferred application of the inhibitor. 17‐DMAG treatment was associated with induction of nuclear and cytoplasmic heat shock factor 1 and Hsp70 in stimulated human B cells, respectively. Type VII collagen (epidermolysis bullosa acquisita)‐imm...

format_quote17-DMAG inhibited autoantibody production in immunized mice, enhancing regulatory B cell function, highlighting its potential for treating autoantibody-mediated disorders.format_quote

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