Skip to main content
SpringerLink
Log in

Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Stone JH, Zen Y, Deshpande V (2012) IgG4-related disease. N Engl J Med 366:539–551. https://doi.org/10.1056/NEJMra1104650

    Article  CAS  Google Scholar 

  2. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T et al (2012) Consensus statement on the pathology of IgG4-related disease. Mod Pathol 25:1181–1192. https://doi.org/10.1038/modpathol.2012.72

    Article  Google Scholar 

  3. Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Jean-Francois Dicaire J, American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group et al (2020) The 2019 American College of Rheumatology/European League Against Rheumatism Classification criteria for IgG4-related disease. Arthritis Rheumatol 72(1):7–19. https://doi.org/10.1002/art.41120

    Article  PubMed  Google Scholar 

  4. Neyt K, Perros F, GeurtsvanKessel CH, Hammad H, Lambrecht BN (2012) Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol 33:297–305. https://doi.org/10.1016/j.it.2012.04.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Weih F, Gräbner R, Hu D, Beer M, Habenicht AJ (2012) Control of dichotomic innate and adaptive immune responses by artery tertiary lymphoid organs in atherosclerosis. Front Physiol 6(3):226. https://doi.org/10.3389/fphys.2012.00226

    Article  CAS  Google Scholar 

  6. Mochizuki Y, Omura K, Kayamori K, Sakamoto K, Shimamoto H, Yamaguchi A (2011) Kuttner’s tumor of the sub-mandibular gland associated with fibrosclerosis and follicular hyperplasia of regional lymph nodes: a case report. J Med Case Rep 29(5):121. https://doi.org/10.1186/1752-1947-5-121

    Article  Google Scholar 

  7. Vizcaino MA, Joseph SS, Eberhart CG (2018) Orbital progressive transformation of germinal centers as part of the spectrum of IgG4-related ophthalmic disease: Clinicopathologic features of three cases. Saudi J Ophthalmol 32(1):56–61. https://doi.org/10.1016/j.sjopt.2018.02.017

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kasashima S, Kawashima A, Kasashima F, Matsumoto Y, Yamamoto Y, Ozaki S, Takemura H (2020) Adventitial matrix metalloproteinase production and distribution of immunoglobulin G4-related abdominal aortic aneurysms. JVS Vascular Science 1:151–165

    Article  Google Scholar 

  9. Vinuesa CG, Linterman MA, Yu D, MacLennan IC (2016) Follicular helper T cells. Ann Rev Immunol 20(34):335–368. https://doi.org/10.1146/annurev-immunol-041015-055605

    Article  CAS  Google Scholar 

  10. Crotty S (2014) T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529–542. https://doi.org/10.1016/j.immuni.2014.10.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wollenberg I, Agua-Doce A, Hernandez A, Almeida C, Oliveira VG, Faro J, Graca L (2011) Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol 187:4553–4560. https://doi.org/10.4049/jimmunol.1101328

    Article  PubMed  CAS  Google Scholar 

  12. Sage PT, Sharpe AH (2015) T follicular regulatory cells in the regulation of B cell responses. Trends Immunol 36:410–418. https://doi.org/10.1016/j.it.2015.05.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Laidlaw BJ, Lu Y, Amezquita RA, Weinstein JS, Vander Heiden JA, Gupta NT, Kleinstein SH, Kaech SM, Craft J (2017) Interleukin-10 from CD4(+) follicular regulatory T cells promotes the germinal center response. Sci Immunol 2(16):eaan4767. https://doi.org/10.1126/sciimmunol.aan4767

    Article  PubMed  PubMed Central  Google Scholar 

  14. Xu B, Wang S, Zhou M, Huang Y, Fu R, Guo C, Chen J, Zhao J, Gaskin F, Fu SM, Yang N (2017) The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. Clin Immunol 183:46–53. https://doi.org/10.1016/j.clim.2017.07.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Deng J, Wei Y, Fonseca VR, Graca L, Yu D (2019) T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol 15(8):475–490. https://doi.org/10.1038/s41584-019-0254-2

    Article  PubMed  CAS  Google Scholar 

  16. Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY (1998) IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 160:3555–3561

    PubMed  CAS  Google Scholar 

  17. Tsuboi H, Matsuo N, Iizuka M, Tsuzuki S, Kondo Y, Tanaka A, Moriyama M, Matsumoto I, Nakamura S, Sumida T (2012) Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther 14:R171. https://doi.org/10.1186/ar3924

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Yoshikawa T, Watanabe T, Minaga K, Kamata K, Kudo M (2019) Cytokines produced by innate immune cells in IgG4-related disease. Mod Rheumatol 29(2):219–225. https://doi.org/10.1080/14397595.2018.1536364

    Article  PubMed  CAS  Google Scholar 

  19. Kasashima S, Kawashima A, Zen Y, Ozaki S, Kasashima F, Endo M, Matsumoto M, Kawakami K (2018) Upregulated interleukins (IL-6, IL-10, and IL-13) in Immunoglobulin G4-related aortic aneurysm patients. J Vasc Surg 67(4):1248–1262. https://doi.org/10.1016/j.jvs.2016.12.140

    Article  PubMed  Google Scholar 

  20. Kamekura R, Takano K, Yamamoto M, Kawata K, Shigehara K, Jitsukawa S, Nagaya T, Ito F, Sato K, Ogasawara N, Tsubomatsu C, Takahashi H, Nakasa H, Himi T, Ichimiya S (2017) Cutting edge: a critical role of regional T follicular helper cells in the pathogenesis of IgG4-related disease. J Immunol 199:2624–2629. https://doi.org/10.4049/jimmunol.1601507

    Article  PubMed  CAS  Google Scholar 

  21. Akiyama M, Suzuki K, Yasuoka H, Kaneko Y, Yamaoka K, Takeuchi T (2018) Follicular helper T cells in the pathogenesis of IgG4-related disease. Rheumatology (Oxford) 57:236–245. https://doi.org/10.1093/rheumatology/kex171

    Article  CAS  Google Scholar 

  22. Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S (2019) IL-10(+) T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease. Immunol Lett 207:56–63. https://doi.org/10.1016/j.imlet.2019.01.008

    Article  PubMed  CAS  Google Scholar 

  23. Gars E, Butzmann A, Ohgami R, Balakrishna JP, O’Malley DP (2020) The life and death of the germinal center. Ann Diagn Pathol 44:151421. https://doi.org/10.1016/j.anndiagpath.2019.151421

    Article  PubMed  Google Scholar 

  24. Satyanarayanan M, Goode A, Gilbert B, Harkes J, Jukic D (2013) OpenSlide: a vendor-neutral software foundation for digital pathology. J Pathol Inform 4:27. https://doi.org/10.4103/2153-3539.119005

    Article  PubMed  PubMed Central  Google Scholar 

  25. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to Image J: 25 years of image analysis. Nat Methods 9:671–675. https://doi.org/10.1038/nmeth.2089

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Osborne BM, Butler JJ (1984) Clinical implications of progressive transformation of germinal centers. Am J Surg Pathol 8:725–733

    Article  CAS  Google Scholar 

  27. Chang CC, Osipov V, Wheaton S, Tripp S, Perkins SL (2003) Follicular hyperplasia, follicular lysis, and progressive transformation of germinal centers. A sequential spectrum of morphologic evolution in lymphoid hyperplasia. J Clin Pathol 120(3):322–326. https://doi.org/10.1309/UUEP-LF2P-HYXQ-DJNQ

    Article  Google Scholar 

  28. Amin S, Ramsay A (2012) Orbital and lacrimal gland progressive transformation of germinal centers- an underdiagnosed entity? Br J Ophthalmol 96(9):1242–1245. https://doi.org/10.1136/bjophthalmol-2012-301574

    Article  PubMed  Google Scholar 

  29. Kojima M, Nakamura N, Sakamoto K, Sakurai S, Tsukamoto N, Itoh H, Itoka H, Enomoto Y, Shimizu K, Mototori T, Hoshi K, Igarashi T, Masawa N, Nakamine H (2010) Progressive transformation of the germinal center of extranodal organs: a clinicopathological, immunohistochemical, and genotypic study of 14 cases. Pathol Res Pract 206(4):235–240. https://doi.org/10.1016/j.prp.2009.12.001

    Article  PubMed  CAS  Google Scholar 

  30. Grimm KE, Barry TS, Chizhevsky V, Hii A, Weiss LM, Siddiqi IN, Brynes RK, O’Malley DP (2012) Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol 25(3):480–491. https://doi.org/10.1038/modpathol.2011.177

    Article  PubMed  CAS  Google Scholar 

  31. Sato Y, Inoue D, Asano N, Takata K, Asaoku H, Maeda Y, Morito T, Okumura H, Ishizawa S, Matsui S, Miyazono T, Takeuchi T, Kuroda N, Orita Y, Takagawa K, Kojima M, Yoshino T (2012) Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes. Mod Pathol 25(7):956–967. https://doi.org/10.1038/modpathol.2012.54

    Article  PubMed  CAS  Google Scholar 

  32. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, Wang Y, Lim H, Reynolds JM, Zhou X, Fan H, Liu Z, Neelapu SS, Dong C (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17(8):983–988. https://doi.org/10.1038/nm.2426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TFrivastava M, Divekar DP, Beaton L, Hogan JL, Fagarasan S, Liston A, Smith KGC, Vinuesa CG, (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17:975–982. https://doi.org/10.1038/nm.2425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Fahlquist Hagert C, Degn SE (2020) T follicular regulatory cells: guardians of the germinal center? Scand J Immunol 92:e12942. https://doi.org/10.1111/sji.12942

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to sincerely thank Ms. Hiromi Kojima, Ms. Youko Umehara, and Mr. Kenji Takahashi for their special technical assistance.

Funding

This work was supported by Grant-in AUC for Scientific Research (C) (JSPS KAKENHI) Grant Number 20K9142.

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory Science, Graduate School of Health Science, Kanazawa University, Kanazawa, Japan

    Satomi Kasashima & Satoru Ozaki

  2. Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan

    Satomi Kasashima, Atsuhiro Kawashima & Nozomu Kurose

  3. Department of Clinical Laboratory, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan

    Satomi Kasashima, Atsuhiro Kawashima & Nozomu Kurose

  4. Department of Pathology, Kanazawa University Hospital, Kanazawa, Japan

    Hiroko Ikeda

  5. Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan

    Ken-Ichi Harada

Authors
  1. Satomi Kasashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsuhiro Kawashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nozomu Kurose
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoru Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroko Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ken-Ichi Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SK performed data selection, experiments, data analysis, and manuscript writing. NK and HI participated in the selection of cases. AK and KH supervised the work and were involved in setting up the experimental design. All authors reviewed the manuscript and agreed with its contents.

Corresponding author

Correspondence to Satomi Kasashima.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kasashima, S., Kawashima, A., Kurose, N. et al. Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis. Virchows Arch 479, 1221–1232 (2021). https://doi.org/10.1007/s00428-021-03187-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-021-03187-2

Keywords

Search

Navigation