nach oben

Virchows Archiv

Erschienen in:

20.08.2021 | Original Article

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

verfasst von: Satomi Kasashima, Atsuhiro Kawashima, Nozomu Kurose, Satoru Ozaki, Hiroko Ikeda, Ken-Ichi Harada

Erschienen in: Virchows Archiv | Ausgabe 6/2021

Einloggen, um Zugang zu erhalten

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.

Stone JH, Zen Y, Deshpande V (2012) IgG4-related disease. N Engl J Med 366:539–551. https://doi.org/10.1056/NEJMra1104650CrossRef

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.2012.72CrossRef

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.41120CrossRefPubMed

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.2012.04.006CrossRefPubMedPubMedCentral

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.2012.00226CrossRef

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/10.1186/1752-1947-5-121CrossRef

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.2018.02.017CrossRefPubMedPubMedCentral

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 1:151–165CrossRef

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-041015-055605CrossRef

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.2014.10.004CrossRefPubMedPubMedCentral

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.1101328CrossRefPubMed

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.2015.05.005CrossRefPubMedPubMedCentral

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.aan4767CrossRefPubMedPubMedCentral

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.2017.07.004CrossRefPubMedPubMedCentral

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/s41584-019-0254-2CrossRefPubMed

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 160:3555–3561PubMed

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/ar3924CrossRefPubMedPubMedCentral

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/10.1080/14397595.2018.1536364CrossRefPubMed

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.2016.12.140CrossRefPubMed

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.1601507CrossRefPubMed

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/kex171CrossRef

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.2019.01.008CrossRefPubMed

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.2019.151421CrossRefPubMed

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/10.4103/2153-3539.119005CrossRefPubMedPubMedCentral

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.2089CrossRefPubMedPubMedCentral

26.

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

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-DJNQCrossRef

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-2012-301574CrossRefPubMed

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.2009.12.001CrossRefPubMed

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.2011.177CrossRefPubMed

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.2012.54CrossRefPubMed

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.2426CrossRefPubMedPubMedCentral

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.2425CrossRefPubMedPubMedCentral

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.12942CrossRefPubMedPubMedCentral

Titel: Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis
verfasst von: Satomi Kasashima
Atsuhiro Kawashima
Nozomu Kurose
Satoru Ozaki
Hiroko Ikeda
Ken-Ichi Harada
Publikationsdatum: 20.08.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Virchows Archiv / Ausgabe 6/2021
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-021-03187-2

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

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

Abstract

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2021

The histopathologist is essential in molecular pathology quality assurance for solid tumours

LRIG1 is a positive prognostic marker in Merkel cell carcinoma and Merkel cell carcinoma expresses epithelial stem cell markers

Localized ALK-positive histiocytosis in a Chinese woman: report of a case in the lung with a novel EML4-ALK rearrangement

Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis

Rudolf Virchow: 200th birth anniversary

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie