Spontaneous Sialadenitis Like Sjögren’s Syndrome in Orphan Nuclear Receptor γt (RORγt) Transgenic Mice

Mana Iizuka¹, Hiroto Tsuboi¹, Hiromitsu Asashima¹, Yuya Kondo¹, Satoru Takahashi², Isao Matsumoto¹ and Takayuki Sumida¹, ¹Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ²Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: autoimmune diseases, sialoadenitis and transcription factor, Sjogren's syndrome, T cells

Session Information

Title: Sjögren's Syndrome - Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: The nuclear receptors retinoic-acid-receptor-related orphan receptors gt (RORγt) is required for the generation of Th17 cells expressing the proinflammatory cytokine IL-17. Th17 cells expressing IL-17 are involved in various autoimmune diseases including Sjögren’s syndrome (SS). Recent studies reported the expression of IL-17 and IL-23 in the salivary glands and serum from patients with SS. However, the pathological roles of RORγt in SS remain to be elucidated. We examined the RORγt transgenic (Tg) mice in order to clarify the role of RORγt in the pathogenesis of SS.

Methods: (1) Histological analysis of salivary glands from RORγt Tg mice and C57BL/6 mice were determined and saliva flow was measured. (2) Infiltrating cells were isolated from the salivary glands and then analyzed their character by fluorescent immunostaining and flow cytometer. (3) Cytokine expressions in salivary glands were detected by quantitative PCR. (4) CD4+ T cells from RORγt Tg mice were transferred to Rag2-/- mice (RORγt Tg→Rag2-/- mice).

Results: (1) RORγt Tg mice developed the severe sialadenitis like SS and focus score was significantly increased in RORγt Tg mice (2.33±0.88/4 mm², p<0.05, Mann-Whitney U Test), compared with C57BL/6 mice (0.22±0.38/4 mm²). Saliva flow collected from RORγt Tg mice (6.11±1.08 μl/g, p<0.05, Mann-Whitney U Test) was significantly decreased than that of C57BL/6 mice (8.63±0.76 μl/g). (2) The majority of infiltrating cells were CD4+ T cells at the early phase of sialadenitis, and B220+ cells were gradually increased at the late phase. (3) Expression of IL-17 and IL-21 mRNA was significantly increased in salivary glands of RORγt Tg mice by the side of C57BL/6 mice (p<0.05, Mann-Whitney U Test). (4) In RORγt Tg→Rag2-/- mice, cellular infiltrations were observed in salivary glands.

Conclusion: These results suggested that the overexpression of RORγt on CD4+ T cells showed play a crucial role in the development of spontaneous sialadenitis like SS.

Disclosure:

M. Iizuka,
None;

H. Tsuboi,
None;

H. Asashima,
None;

Y. Kondo,
None;

S. Takahashi,
None;

I. Matsumoto,
None;

T. Sumida,
None.

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