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. 2021 May 24;23(1):148.
doi: 10.1186/s13075-021-02527-6.

Serum checkpoint molecules in patients with IgG4-related disease (IgG4-RD)

Haruki Matsumoto  1 , Yuya Fujita  2 , Naoki Matsuoka  1 , Jumpei Temmoku  1 , Makiko Yashiro-Furuya  1 , Tomoyuki Asano  1 , Shuzo Sato  1 , Hiroshi Watanabe  1 , Eiji Suzuki  3 , Sosuke Tsuji  4 , Shoichi Fukui  4 , Masataka Umeda  4 , Naoki Iwamoto  4 , Atsushi Kawakami  4 , Kiyoshi Migita  1
Affiliations

Serum checkpoint molecules in patients with IgG4-related disease (IgG4-RD)

Haruki Matsumoto et al. Arthritis Res Ther. .

Abstract

Background: Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4+ plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements.

Methods: Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD.

Results: In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy.

Conclusion: Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.

Keywords: Galectin-9; IgG4-related disease; Immune checkpoint molecules; T cell immunoglobulin and mucin-containing-molecule-3.

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Conflict of interest statement

KM has received research grants from Chugai, Pfizer, and AbbVie. The rest of the authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Serum levels of Gal-9 and sTIM-3 in IgG4-RD. The comparison of serum levels of Gal-9 and sTIM-3 among IgG4-RD patients (n = 59), RA patients (n = 13), and healthy controls (n = 37). a Serum levels of Gal-9 in IgG4-RD and RA patients were significantly higher compared to those in healthy controls. b Serum levels of sTIM-3 in IgG4-RD patients and RA patients were significantly higher compared to HCs. The Kruskal-Wallis test was used for continuous variables for comparisons among the three groups. Post hoc pairwise analyses between the two groups were performed by the Games-Howell test
Fig. 2
Fig. 2
Relationships among the serum sTIM-3, Gal-9, and BAFF in patients with IgG4-RD. a Serum Gal-9 was positively correlated with serum sTIM-3. b, c The serum levels of BAFF were positive in correlation with the serum levels of sTIM-3 and Gal-9. All correlations were determined using Spearman’s rank correlation test. The lines shown are based on simple linear regression
Fig. 3
Fig. 3
Relationships between the serum levels of checkpoint molecules and IgG subclass in IgG4-RD. a, b The serum levels of Gal-9 showed a positive correlation with IgG whereas not a significant correlation with IgG4. c, d The serum levels of sTIM-3 showed a positive correlation with IgG whereas not a significant correlation with IgG4. All correlations were determined using Spearman’s rank correlation test. The lines shown are based on simple linear regression
Fig. 4
Fig. 4
Serum levels of Gal-9 and sTIM-3 with or without visceral organ involvement in IgG4-RD. a Serum levels of Gal-9 were not significantly different in the presence of visceral organ involvement. b Serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral organ lesions compared to those without visceral organ lesions. Statistical significance was determined by the Mann-Whitney U test
Fig. 5
Fig. 5
Relationship between IgG4-RD responder index and kidney involvement. IgG4-responder index of IgG4-RD patients with kidney involvement was not significantly higher than that of IgG4-RD patients without kidney involvement. Statistical significance was determined by the Mann-Whitney U test
Fig. 6
Fig. 6
Longitudinal changes of serum Gal-9 or sTIM-3 concentrations in 7 patients with IgG4-RD before and after glucocorticoid therapy. a–c Gal-9, sTIM-3, and IgG4 concentrations in IgG4-RD patients were not significantly different between before and after treatment. d IgG4 responder index was significantly decreased after glucocorticoid therapy. Paired samples from the same subjects were compared by the Wilcoxon signed-rank test
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