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VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs
BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235212/ https://www.ncbi.nlm.nih.gov/pubmed/30413189 http://dx.doi.org/10.1186/s13075-018-1742-5 |
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author | Schub, David Assmann, Gunter Sester, Urban Sester, Martina Schmidt, Tina |
author_facet | Schub, David Assmann, Gunter Sester, Urban Sester, Martina Schmidt, Tina |
author_sort | Schub, David |
collection | PubMed |
description | BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells. METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro. RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05). CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13075-018-1742-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6235212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62352122018-11-20 VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs Schub, David Assmann, Gunter Sester, Urban Sester, Martina Schmidt, Tina Arthritis Res Ther Research Article BACKGROUND: Varicella zoster virus (VZV)-specific cellular immunity is essential for viral control, and the incidence of VZV reactivation is increased in patients with rheumatic diseases. Because knowledge of the influence of antirheumatic drugs on specific cellular immunity is limited, we analyzed VZV-specific T cells in patients with rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA), and we assessed how their levels and functionality were impacted by disease-modifying antirheumatic drugs (DMARDs). A polyclonal stimulation was carried out to analyze effects on general effector T cells. METHODS: CD4 T cells in 98 blood samples of patients with RA (n = 78) or SpA (n = 20) were quantified by flow cytometry after stimulation with VZV antigen and the polyclonal stimulus Staphylococcus aureus enterotoxin B (SEB), and they were characterized for expression of cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-2) and markers for activation (CD69), differentiation (CD127), or functional anergy programmed death 1 molecule [PD-1], cytotoxic T-lymphocyte antigen 4 [CTLA-4]. Results of patients with RA were stratified into subgroups receiving different antirheumatic drugs and compared with samples of 39 healthy control subjects. Moreover, direct effects of biological DMARDs on cytokine expression and proliferation of specific T cells were analyzed in vitro. RESULTS: Unlike patients with SpA, patients with RA showed significantly lower percentages of VZV-specific CD4 T cells (median 0.03%, IQR 0.05%) than control subjects (median 0.09%, IQR 0.16%; p < 0.001). Likewise, SEB-reactive CD4 T-cell levels were lower in patients (median 2.35%, IQR 2.85%) than in control subjects (median 3.96%, IQR 4.38%; p < 0.05); however, expression of cytokines and cell surface markers of VZV-specific T cells did not differ in patients and control subjects, whereas SEB-reactive effector T cells of patients showed signs of functional impairment. Among antirheumatic drugs, biological DMARDs had the most pronounced impact on cellular immunity. Specifically, VZV-specific CD4 T-cell levels were significantly reduced in patients receiving TNF-α antagonists or IL-6 receptor-blocking therapy (p < 0.05 and p < 0.01, respectively), whereas SEB-reactive T-cell levels were reduced in patients receiving B-cell-depleting or IL-6 receptor-blocking drugs (both p < 0.05). CONCLUSIONS: Despite absence of clinical symptoms, patients with RA showed signs of impaired cellular immunity that affected both VZV-specific and general effector T cells. Strongest effects on cellular immunity were observed in patients treated with biological DMARDs. These findings may contribute to the increased susceptibility of patients with RA to VZV reactivation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13075-018-1742-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-09 2018 /pmc/articles/PMC6235212/ /pubmed/30413189 http://dx.doi.org/10.1186/s13075-018-1742-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Schub, David Assmann, Gunter Sester, Urban Sester, Martina Schmidt, Tina VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title | VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title_full | VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title_fullStr | VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title_full_unstemmed | VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title_short | VZV-specific T-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
title_sort | vzv-specific t-cell levels in patients with rheumatic diseases are reduced and differentially influenced by antirheumatic drugs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235212/ https://www.ncbi.nlm.nih.gov/pubmed/30413189 http://dx.doi.org/10.1186/s13075-018-1742-5 |
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