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The disturbance of the distribution of T helper cell subsets in the mantle area surrounding germinal centers in immunoglobulin G4–related sclerosing sialadenitis

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Abstract

The function of germinal centers (GCs) is an important factor in the pathogenesis of immunoglobulin G4 (IgG4)–related disease, in which inflammatory and fibrotic processes are controlled by type 2 helper T (Th) cells and regulatory T cells. T follicular helper cells (Tfh), which are present in GCs, regulate GC development, and they consist of Tfh1, Tfh2, and Tfh17 subsets. This study examined the association of Th cell subsets in IgG4-RD and pathogenesis of the disease using whole-slide image analysis for immunohistochemistry. IgG4-related sclerosing sialadenitis (IgG4-SS, n = 19) was characterized by higher numbers of Tfh2 and Tfh17 cells than Tfh1 cells compared to the findings in patients with chronic sialadenitis (n = 18) or Sjögren syndrome (n = 17). The number of Tfh2 cells was significantly associated with all parameters of GC structures and the number of IgG4 + plasmacytes, whereas the number of Tfh1 cells was inversely associated with the aforementioned parameters. Concerning extrafollicular helper T (Teh) cells, among three groups, the Tfh2/Teh2 ratio was highest and the Tfh1/Teh1 ratio was lowest in the IgG4-SS group, which exhibited a characteristically regional distribution of Tfh and Teh subsets, especially higher numbers of Teh2 cells and lower numbers of Teh1 cells in the mantle areas surrounding GCs. Mantle Teh2 cells and central Tfh17 cells were significantly correlated with morphological abnormalities of GCs. Our results indicated that the peculiar regional distribution and altered balance of Tfh and Teh subsets are novel hallmarks of IgG4-SS that are associated with GC formation in IgG4-SS.

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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.

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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.

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Correspondence to Satomi Kasashima.

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Kasashima, S., Kawashima, A., Kurose, N. et al. The disturbance of the distribution of T helper cell subsets in the mantle area surrounding germinal centers in immunoglobulin G4–related sclerosing sialadenitis. Virchows Arch 481, 767–777 (2022). https://doi.org/10.1007/s00428-022-03384-7

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