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

Abstract

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.

Dual role of autoantibodies to heat shock proteins in autoimmune diseases

“…The latter interactions may stimulate a humoral (auto)immune response and lead to the production of anti-Hsp (auto)antibodies. Although levels of anti-Hsp autoantibodies are elevated in patients suffering from numerous inflammatory and autoimmune diseases, including rheumatoid arthritis (RA) ( 37 – 40 ), juvenile idiopathic arthritis ( 41 ), autoimmune myasthenia gravis ( 42 ), dermatitis herpetiformis (DH) ( 43 ), psoriasis ( 44 ), systemic lupus erythematosus (SLE) ( 45 ), epidermolysis bullosa acquisita (EBA) ( 46 ), celiac disease (CD) ( 47 ), atopic dermatitis ( 48 ) and other (auto)inflammatory diseases, their pathological role is not fully understood ( Table 1 ). The mechanism of anti-Hsp antibody formation also remains to be clarified.…”

“…Animals treated with Hsp70, or anti-Hsp70 IgG showed more intense clinical and histological disease activity. Mechanistically, anti-Hsp70 IgG enhanced neutrophil infiltration into the skin and activation of the NF-κB signaling pathway ( 22 , 46 , 59 ).…”

Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases

“…Circulating anti-Hsp70 IgG autoantibodies were significantly elevated in EBA patients as compared to healthy individuals and positively correlated with IFN-γ in patients. The importance of these newly discovered, pathologically relevant autoantibodies has been proven in vivo, since anti-Hsp70 IgG-treated EBA mice had a more intense clinical and histological disease activity [ 52 ]. The above outcomes suggest that both autologous Hsp70 and autoantibodies to Hsp70 display proinflammatory activities in the context of EBA development [ 51 , 52 ].…”

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

“…Compared to Hsp90, the role of Hsp70 in AIBDs has been overall less studied ( 9 ). Two recent studies indicated that both extracellular Hsp70 and autoantibodies to Hsp70 display pro-inflammatory activities in the context of EBA development ( 16 , 17 ). In the first study, the in vivo pathophysiological relevance of extracellular Hsp70 was demonstrated in mice with experimental EBA in which elevated blood levels of this chaperone were recorded.…”

“…In addition, cell culture experiments using human naive peripheral blood mononuclear cells revealed that extracellular Hsp70 stimulated the secretion of the T-cell-derived pro-inflammatory cytokines IL-6 and IL-8 ( 16 ). In the second study, it was demonstrated that autoantibodies to Hsp70 may contribute to EBA development via enhanced neutrophil infiltration to the skin and activation of the NF-κB signalling pathway in an IFN-γ-associated manner ( 17 ).…”