Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome
Abstract Objective Primary Sjögren syndrome (pSS) is characterized by T and B cell infiltration of exocrine glands. The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T cell stimulation, and elevated levels have been found in patients with RA, psoriasis and pSS. H...
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doaj-7f8394541fc0457b90bba1612c018e6c2020-11-25T03:51:41ZengBMCArthritis Research & Therapy1478-63622019-07-0121111110.1186/s13075-019-1955-2Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndromePatrick Hargreaves0Douglas Daoudlarian1Michel Theron2Fabrice A. Kolb3Marianne Manchester Young4Bernhard Reis5Andre Tiaden6Bettina Bannert7Diego Kyburz8Tobias Manigold9Department of Rheumatology, University Hospital BaselDepartment of Rheumatology, University Hospital BaselRoche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La RocheRoche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La RocheRoche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La RocheRoche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La RocheDepartment of Rheumatology, University Hospital BaselDepartment of Rheumatology, University Hospital BaselDepartment of Rheumatology, University Hospital BaselDepartment of Rheumatology, University Hospital BaselAbstract Objective Primary Sjögren syndrome (pSS) is characterized by T and B cell infiltration of exocrine glands. The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T cell stimulation, and elevated levels have been found in patients with RA, psoriasis and pSS. However, little is known about the functional characteristics and mechanisms of SS-A- and SS-B-specific T cells in pSS patients. We herein investigated the inhibition of CatS activity in different biocompartments of pSS patients including antigen-specific T cell responses. Methods Ex vivo CatS activity was assessed in tears, plasma and saliva of 15 pSS patients and 13 healthy controls (HC) and in the presence or absence of the specific CatS inhibitor RO5459072. In addition, antigen (SS-A (60kD), SS-B, influenza H3N2, tetanus toxoid and SEB)-specific T cell responses were examined using ex vivo IFN-γ/IL-17 Dual ELISPOT and Bromdesoxyuridin (BrdU) proliferation assays in the presence or absence of RO5459072. Supernatants were analysed for IL-1β, IL-6, IL-10, TNF-α, IL-21, IL-22 and IL-23, using conventional ELISA. Results CatS activity was significantly elevated in tear fluid, but not other biocompartments, was inversely associated with exocrinic function in pSS patients and could significantly be suppressed by RO5459072. Moreover, CatS inhibition by RO5459072 led to strong and dose-dependent suppression of SS-A/SS-B-specific T cell effector functions and cytokine secretion by CD14+ monocytes. However, RO5459072 was incapable of suppressing SS-A/SS-B-induced secretion of cytokines in CD14+ monocytes when T cells were absent, confirming a CatS/MHCII-mediated mechanism of suppression. Conclusion CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. Conversely, CatS inhibition diminishes T cell and associated monokine responses towards relevant autoantigens in pSS. Thus, CatS inhibition may represent a promising novel treatment strategy in pSS.http://link.springer.com/article/10.1186/s13075-019-1955-2Primary Sjögren syndromeCathepsin STear fluidT cell responsesRO5459072 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patrick Hargreaves Douglas Daoudlarian Michel Theron Fabrice A. Kolb Marianne Manchester Young Bernhard Reis Andre Tiaden Bettina Bannert Diego Kyburz Tobias Manigold |
spellingShingle |
Patrick Hargreaves Douglas Daoudlarian Michel Theron Fabrice A. Kolb Marianne Manchester Young Bernhard Reis Andre Tiaden Bettina Bannert Diego Kyburz Tobias Manigold Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome Arthritis Research & Therapy Primary Sjögren syndrome Cathepsin S Tear fluid T cell responses RO5459072 |
author_facet |
Patrick Hargreaves Douglas Daoudlarian Michel Theron Fabrice A. Kolb Marianne Manchester Young Bernhard Reis Andre Tiaden Bettina Bannert Diego Kyburz Tobias Manigold |
author_sort |
Patrick Hargreaves |
title |
Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome |
title_short |
Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome |
title_full |
Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome |
title_fullStr |
Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome |
title_full_unstemmed |
Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome |
title_sort |
differential effects of specific cathepsin s inhibition in biocompartments from patients with primary sjögren syndrome |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2019-07-01 |
description |
Abstract Objective Primary Sjögren syndrome (pSS) is characterized by T and B cell infiltration of exocrine glands. The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T cell stimulation, and elevated levels have been found in patients with RA, psoriasis and pSS. However, little is known about the functional characteristics and mechanisms of SS-A- and SS-B-specific T cells in pSS patients. We herein investigated the inhibition of CatS activity in different biocompartments of pSS patients including antigen-specific T cell responses. Methods Ex vivo CatS activity was assessed in tears, plasma and saliva of 15 pSS patients and 13 healthy controls (HC) and in the presence or absence of the specific CatS inhibitor RO5459072. In addition, antigen (SS-A (60kD), SS-B, influenza H3N2, tetanus toxoid and SEB)-specific T cell responses were examined using ex vivo IFN-γ/IL-17 Dual ELISPOT and Bromdesoxyuridin (BrdU) proliferation assays in the presence or absence of RO5459072. Supernatants were analysed for IL-1β, IL-6, IL-10, TNF-α, IL-21, IL-22 and IL-23, using conventional ELISA. Results CatS activity was significantly elevated in tear fluid, but not other biocompartments, was inversely associated with exocrinic function in pSS patients and could significantly be suppressed by RO5459072. Moreover, CatS inhibition by RO5459072 led to strong and dose-dependent suppression of SS-A/SS-B-specific T cell effector functions and cytokine secretion by CD14+ monocytes. However, RO5459072 was incapable of suppressing SS-A/SS-B-induced secretion of cytokines in CD14+ monocytes when T cells were absent, confirming a CatS/MHCII-mediated mechanism of suppression. Conclusion CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. Conversely, CatS inhibition diminishes T cell and associated monokine responses towards relevant autoantigens in pSS. Thus, CatS inhibition may represent a promising novel treatment strategy in pSS. |
topic |
Primary Sjögren syndrome Cathepsin S Tear fluid T cell responses RO5459072 |
url |
http://link.springer.com/article/10.1186/s13075-019-1955-2 |
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