Background: Lymphocyte-specific protein 1 (LSP1), associated with actin remodeling, is known to negatively regulate T cell migration in autoimmune diseases such as rheumatoid arthritis [1]. However, its pathophysiological role in the development of autoimmune diseases, particularly in T cell activation, remains to be clarified. Primary Sjögren’s syndrome (pSS) is characterized by chronic inflammation and tissue damage in the exocrine glands, along with the extensive infiltration of proinflammatory immune cells [2]. Recent studies suggest that Th17 cells contribute to the aggravation of pSS development in inflamed tissues, making them a potential therapeutic target for pSS [3, 4].

Objectives: We aimed to explore the immunological role of LSP1 in T cells under a Th17 cell-mediated pSS context, using an experimental Sjögren’s syndrome (ESS)-induced murine model and peripheral blood T cells derived from pSS patients.

Methods: LSP1 expression was determined in the ESS-induced SG T cells and peripheral blood T cells of patients with pSS, by flow cytometry. The disease severity of ESS-induced mice was compared in wild-type (WT) and Lsp1 ^{-/ -} mice, based on saliva flow rate and histological analysis. The frequency and number of IL-17A- or interferon-gamma (IFNγ)-expressing T cells from SG and cervical lymph nodes in ESS-induced WT and Lsp1 ^{-/ -} mice, as well as from peripheral blood T cells of patients with pSS, were analyzed using flow cytometry and immunohistochemistry. Additionally, LSP1 expression in human T cells was detected in the presence or absence of hydroxychloroquine (HCQ), by flow cytometry.

Results: We found that LSP1 expression was substantially decreased in T cells, accompanied by increased infiltration of leukocytes in the SG of ESS-induced WT mice. Next, we found that Lsp1 deficiency aggravated the severity of ESS, compared to WT mice. Furthermore, Lsp1 ^{-/ -} mice showed the increased numbers and frequencies of IL-17A- or IFNγ-expressing T cells in cervical lymph nodes with the increased the number of infiltrated cells and foci in the SG of ESS models. Along with the results of ESS-induced murine model, we demonstrated that LSP1 expression in T cells was dramatically decreased in the peripheral bloods of patients with pSS, compared to healthy donors. In particular, T cells of pSS patients showed an increased percentage of IL-17A-expressing T cells, which inversely correlated with LSP1 expression. Moreover, LSP1 expression levels in T cells were higher in pSS patients who had been treated with HCQ for more than 3 months than in those without. This was further corroborated by an in vitro culture system treated with 50 μM HCQ for 72 hours.

Conclusion: These findings indicate that LSP1 deficiency promotes the development of IL-17-producing T cells, leading to exacerbating the pathogenesis of pSS. Therefore, we suggest that LSP1 may be a potential therapeutic target to treat autoimmune diseases like pSS via regulating IL-17-producing T cells.

REFERENCES: [1] SH. Hwang, SH. Jung, S. Lee, S. Choi, SA. Yoo, JH. Park et al., Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis, Proc. Natl. Acad. Sci. U S A. 112 (2015) E6535-E6543, https://doi.org/10.1073/pnas.1514152112 .

[2] SS. Kassan, HM. Moutsopoulos, Clinical manifestations and early diagnosis of Sjögren syndrome, Arch. Intern. Med. 164 (2004) 1275-1284, https://doi.org/10.1001/archinte.164.12.1275 .

[3] Y. Fei, W. Zhang, D. Lin, C. Wu, M. Li, Y. Zhao, et al., Clinical parameter and Th17 related to lymphocytes infiltrating degree of labial salivary gland in primary Sjögren’s syndrome, Clin. Rheumatol. 33 (2014) 523-529, https://doi.org/10.1007/s10067-013-2476-z .

[4] X. Lin, K. Rui, J. Deng, J. Tian, X. Wang, S. Wang, et al., Th17 cells play a critical role in the development of experimental Sjögren’s syndrome, Ann. Rheum. Dis. 74 (2015) 1302-1310, https://doi.org/10.1136/annrheumdis-2013-204584 .

Acknowledgements: This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2015R1A3A2032927 and RS-2024-00442793 to W.U.K.).

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.