Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

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Abstract

Background

The interaction between galectin-9 (Gal-9) and its ligand, T cell immunoglobulin, and mucin-containing-molecule-3 (TIM-3), one of the coinhibitory receptors, transduce the inhibitory signaling to regulate immune responses. The dysregulated expression of checkpoint molecules has been reported under various inflammatory or autoimmune conditions. The aim of this study is to investigate the levels of these checkpoint molecules and their associations between proinflammatory markers in patients with adult Still’s disease (ASD).

Methods

Serum samples were collected from 47 patients with active ASD, 116 patients with rheumatoid arthritis (RA), and 37 healthy controls (HCs). Serum levels of Gal-9, soluble TIM-3 (sTIM-3), and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). Results were compared with the clinical features of ASD.

Results

Serum Gal-9 levels in patients with ASD (median: 21.57 ng/ml, interquartile range IQR [11.41–39.72]) were significantly higher compared to those in patients with RA (7.58 ng/ml, IQR [5.57–10.20] p < 0.001) as well as those in HCs (4.51 ng/ml, [IQR; 3.58–5.45], p < 0.001). Similarly, serum sTIM-3 levels in patients with ASD were significantly higher than those in patients with RA and HCs. Serum levels of Gal-9 or sTIM-3 showed positive correlations with IL-18 levels (Gal-9; r = 0.90, p < 0.001, sTIM-3; r = 0.78, p < 0.001) in patients with ASD. Serum levels of Gal-9 or sTIM-3 correlated with serum ferritin (Gal-9; r = 0.77, p < 0.001, sTIM-3; r = 0.71, p < 0.001) and ASD disease activity score (Pouchot’s score, Gal-9; r = 0.66, p < 0.001, sTIM-3; r = 0.59, p < 0.001), whereas there was no significant correlation between serum Gal-9 or sTIM-3 and CRP. ASD patients with chronic arthritis phenotype had a significantly higher Gal-9/ferritin and sTIM-3/ferritin ratio than those without this phenotype. After immunosuppressive treatment, Gal-9 and sTIM-3 levels showed a significant decline in parallel to the disease activity scores.

Conclusions

Serum levels of the coinhibitory checkpoint molecules were elevated and correlated with disease activity in patients with ASD. These coinhibitory checkpoint molecules may be implicated in the autoinflammatory process seen in ASD.

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Most cited references 27

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Interleukin‐18: Biological properties and role in disease pathogenesis

Gilles Kaplanski (2017)

Summary Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP.

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A comprehensive review on adult onset Still's disease

Piero Ruscitti, Yehuda Shoenfeld, Roberto Giacomelli (2018)

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology usually affecting young adults; spiking fever, arthritis and evanescent rash are commonly observed during the disease. Other frequently observed clinical features include sore throat, hepatomegaly, splenomegaly, lymphadenopathy and serositis. Furthermore, AOSD patients may experience different life-threating complications. Macrophage activation syndrome (MAS) has been reported up to 15% of AOSD patients and it is considered to be the most severe complication of the disease being characterised by high mortality rate. During AOSD, laboratory tests reflect the systemic inflammatory process showing high levels of erythrocyte sedimentation rate and C-reactive protein. In addition, the ferritin levels are typically higher than those observed in other autoimmune, inflammatory, infectious, or neoplastic diseases. Analysing AOSD disease course, 3 different clinical patterns of AOSD have been identified: i. monocyclic pattern, characterised by a systemic single episode; ii. polycyclic pattern, characterised by multiple, ≤ 1 year lasting, flares, alternating with remissions; iii. chronic pattern, related to a persistently active disease with associated polyarthritis. At present, AOSD therapeutic strategy is aimed at targeting pro-inflammatory signs and symptoms, preventing organ damage and life-threating complications and minimising adverse effects of treatment. However, the treatment of AOSD remains largely empirical, lacking controlled clinical trials. High dosages of corticosteroids are usually the first line therapy when the systemic symptoms predominate. Despite this treatment, a large percentage of patients experiences several flares with an evolution toward the chronic disease course and up to 16% of patients die during the follow up, due to AOSD-related complications. On these bases, in the last years, biological agents have been successfully used in refractory cases. Finally, multiple recent lines of evidence have suggested new insights in AOSD pathogenesis unmasking further therapeutic targets. In fact, small molecules, used in experimental MAS models, might represent new therapeutic options.

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Mechanisms, biomarkers and targets for adult-onset Still’s disease

Eugen Feist, Stéphane Mitrovic, Bruno Fautrel (2018)

Adult-onset Still’s disease (AoSD) is a rare but clinically well-known, polygenic, systemic autoinflammatory disease. Owing to its sporadic appearance in all adult age groups with potentially severe inflammatory onset accompanied by a broad spectrum of disease manifestation and complications, AoSD is an unsolved challenge for clinicians with limited therapeutic options. This Review provides a comprehensive insight into the complex and heterogeneous nature of AoSD, describing biomarkers of the disease and its progression and the cytokine signalling pathways that contribute to disease. The efficacy and safety of biologic therapeutic options are also discussed, and guidance for treatment decisions is provided. Improving the approach to AoSD in the future will require much closer cooperation between paediatric and adult rheumatologists to establish common diagnostic strategies, treatment targets and goals.

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Author and article information

Contributors

Yuya Fujita: fujita31@fmu.ac.jp

Tomoyuki Asano: asanovic@fmu.ac.jp

Haruki Matsumoto: haruki91@fmu.ac.jp

Naoki Matsuoka: naoki-11@fmu.ac.jp

Jumpei Temmoku: temmoku@fmu.ac.jp

Shuzo Sato: shuzo@fmu.ac.jp

Makiko Yashiro Furuya: myashiro@fmu.ac.jp

Eiji Suzuki: azsuzuki@ohta-hp.or.jp

Hiroshi Watanabe: chiehiro@fmu.ac.jp

Tomohiro Koga: tkoga@nagasaki-u.ac.jp

Atsushi Kawakami: atsushik@nagasaki-u.ac.jp

Kiyoshi Migita: migita@fmu.ac.jp

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 22 July 2020

Publication date PMC-release: 22 July 2020

Publication date (Print): 2020

Volume: 22

Electronic Location Identifier: 174

Affiliations

[1 ]GRID grid.411582.b, ISNI 0000 0001 1017 9540, Department of Rheumatology, , Fukushima Medical University School of Medicine, ; 1 Hikarigaoka, Fukushima, Fukushima 960-1295 Japan

[2 ]GRID grid.174567.6, ISNI 0000 0000 8902 2273, Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, , Nagasaki University Graduate School of Biomedical Sciences, ; Sakamoto1-7-1, Nagasaki, 852-8501 Japan

Article

Publisher ID: 2263

DOI: 10.1186/s13075-020-02263-3

PMC ID: 7374897

SO-VID: 79683506-7ce9-423c-b8b3-e8985318a3c9

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

History

Date received : 29 April 2020

Date accepted : 6 July 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;

Award ID: 20182231

Award Recipient : Kiyoshi Migita

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: adult still’s disease,checkpoint molecules,galectin-9,interleukin-18,t cell immunoglobulin and mucin domain-3

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ScienceOpen disciplines: Orthopedics

Keywords: adult still’s disease, checkpoint molecules, galectin-9, interleukin-18, t cell immunoglobulin and mucin domain-3

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Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

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Abstract

Background

Methods

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Related collections

Orthopedics

Most cited references 27

Interleukin‐18: Biological properties and role in disease pathogenesis

A comprehensive review on adult onset Still's disease

Mechanisms, biomarkers and targets for adult-onset Still’s disease

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Cited by 9

Most referenced authors 382