Autologous extracellular Hsp70 exerts a dual role in rheumatoid arthritis
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Autologous extracellular Hsp70 exerts a dual role in rheumatoid arthritis Stefan Tukaj 1
&
Jagoda Mantej 1 & Michał Sobala 2 & Katarzyna Potrykus 2 & Krzysztof Sitko 1
Received: 24 February 2020 / Revised: 17 April 2020 / Accepted: 22 April 2020 # The Author(s) 2020
Abstract Extracellular heat shock proteins (Hsp) influence the adaptive immune response and may ameliorate pathogenesis of autoimmune diseases. While some preclinical observations suggest that highly conserved bacterial and/or murine Hsp70 peptides have potential utility in treatment of rheumatoid arthritis (RA) via induction of T regulatory cells (Treg), the role of extracellular inducible human Hsp70 in adaptive immune processes requires further investigation. The present study evaluated Hsp70 influence on inflammatory cytokine-mediated modulation of T cell immunophenotype in ways that influence RA onset and severity. Initial experiments in the present investigation revealed that serum levels of Hsp70 are approximately 2-fold higher in RA patients versus healthy control subjects. To explore the effect of extracellular Hsp70 on key processes underlying the adaptive immune system, the effects of a highly pure, substrate-, and endotoxin-free human Hsp70 on polarization of the T helper cell subpopulations, including CD4+IL-17+ (Th17), CD4+FoxP3+ (Treg), CD4+IFN-γ+ (Th1), and CD4+IL-4+ (Th2), were studied in naïve human peripheral blood mononuclear cell (PBMC) cultures stimulated with anti-CD3/28 mAb. Major findings included an observation that while Hsp70 treatment increased Th17 frequencies and Th17/Treg ratio, the frequency of Th1 cells and the Th1/ Th2 ratio were significantly decreased in the Hsp70-treated PBMC cultures. Moreover, data shown here provides preliminary suggestion that major contributing Hsp70-mediated immunomodulation includes interleukin 6 (IL-6) influence on Th17/Treg and Th1/Th2, since expression of this inflammatory cytokine is enhanced by in vitro Hsp70 treatment. These results are nevertheless preliminary and require further investigation to validate the above model. Keywords Heat shock proteins, HSP . T helper cell (Th) populations . Rheumatoid arthritis, RA . Hsp70
Introduction Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases characterized by synovial inflammation and bone erosion. This disease affects up to 1% of the worldwide population. The pathogenesis of RA is driven by an inflammatory network in which both the innate and adaptive immune systems, including the immune complex-mediated complement activation, and the pro-inflammatory cytokine networks support the disease progression (Firestein and McInnes 2017). Cells of the adaptive immune systems play * Stefan Tukaj [email protected] 1
Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
2
Department of Bacterial Molecular Genetics, Faculty of Biology, University of Gdańsk, Gdańsk, Poland
a critical role in autoimmunity. Dysregulation of this ar
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