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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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References

    1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–551. doi: 10.1056/NEJMra1104650. - DOI - PubMed
    1. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, Stone JH. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67(9):2466–2475. doi: 10.1002/art.39205. - DOI - PMC - PubMed
    1. Yamada K, Yamamoto M, Saeki T, Mizushima I, Matsui S, Fujisawa Y, Hara S, Takahashi H, Nomura H, Kawa S, Kawano M. New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases. Arthritis Res Ther. 2017;19(1):262. doi: 10.1186/s13075-017-1467-x. - DOI - PMC - PubMed
    1. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181–1192. doi: 10.1038/modpathol.2012.72. - DOI - PubMed
    1. Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, Kulikova M, Deshpande V, Pillai S, Stone JH. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. 2015;74(1):190–195. doi: 10.1136/annrheumdis-2014-205233. - DOI - PMC - PubMed