Jonathan Liu

Introduction: Primary Sjögren’s syndrome (pSS) is an autoimmune disease that presents with dry eyes, mouth and often other systemic manifestations such as cough, fatigue, and chronic fibromyalgia. While Th1, Th2, Th17, various T cell subsets are present in pSS, follicular helper T cells (Tfh) are the main subset responsible for activating B cells in lymphoid organs, which is crucial to pathogenesis of symptoms¹. Several novel developing therapies including abatacept, B cell depletion, and mesenchymal stem cell therapy, have been shown to be effective through targeting Tfh activity. Methods: Salivary gland epithelial cells (SGECs) were co-cultured in-vitro with naïve CD4+ T cells and surface expression of cytokines was surveyed to measure the role of SGECs in Tfh differentiation². Paired blood and salivary gland biopsy samples between 16 pSS and 16 control patients were analyzed to study blood Tfh and T follicular regulatory cell levels (Tfr)³. 24 patients with pSS were treated with rituximab (RTX) B cell depletion therapy and effects on CD4+ T cell subsets were examined by flow cytometry⁴. 15 patients with pSS were treated with abatacept (CTLA-4lg), which limits T cell activation, and CD4+ T cell subsets were also analyzed with flow cytometry⁵. In vitro, mesenchymal stem cells (MSCs) were derived from transgene-free human induced pluripotent stem cells (iPSC) and introduced to mouse models to investigate effects on lymphocyte infiltration of salivary glands⁶. Results: SGECs were shown to secrete significant amounts of IL-6 which promotes Tfh differentiation². Additionally, SGECs were shown to increase Tfh IL-21 secretion, which is associated with increased systemic disease activity as assessed by EULAR Sjögren’s syndrome disease activity index (ESSDAI)². Blood Tfr:Tfh level was shown to be a powerful marker of pSS, ectopic lymphoid neogenesis and focal sialadenitis³. After ritiuximab treatment, Tfh levels were normalized with little effect on other T cell subsets and in-vitro production of IL-21 was significantly decreased⁴. Abatacept therapy also specifically reduced the levels of circulating Tfh and Treg cell numbers in peripheral blood and consequently, acute and systemic symptoms of pSS⁵. iPSC-MSCs introduced in pSS mouse models resulted in diminished lymphocyte infiltration of salivary glands⁶. Conclusion: Research shows that Tfh cells have a powerful role in the pathogenesis and prognosis of pSS symptoms. The efficacy of novel therapies that specifically target Tfh cells suggests a need for more clinical trials and further investigation of Tfh interactions in autoimmunity.

1. Both T, Dalm V, van Hagen P, van Daele P. Reviewing primary Sjögren’s syndrome: beyond the dryness – From pathophysiology to diagnosis and treatment. Int J Med Sci. 2017;14(3):191-200. doi:10.7150/ijms.17718.
2. Gong Y, Nititham J, Taylor K et al. Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren’s syndrome. J Autoimmun. 2014;51:57-66. doi:10.1016/j.jaut.2013.11.003.
3. Fonseca V, Romão V, Agua-Doce A et al. The Ratio of Blood T Follicular Regulatory Cells to T Follicular Helper Cells Marks Ectopic Lymphoid Structure Formation While Activated Follicular Helper T Cells Indicate Disease Activity in Primary Sjögren’s Syndrome. Arthritis & Rheumatology. 2018. doi:10.1002/art.40424.
4. Verstappen G, Kroese F, Meiners P et al. B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome. J Rheumatol. 2016;44(1):49-58. doi:10.3899/jrheum.160313.
5. Verstappen G, Meiners P, Corneth O et al. Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjögren’s Syndrome. Arthritis & Rheumatology. 2017;69(9):1850-1861. doi:10.1002/art.40165.
6. Hai B, Shigemoto-Kuroda T, Zhao Q, Lee R, Liu F. Inhibitory Effects of iPSC-MSCs and Their Extracellular Vesicles on the Onset of Sialadenitis in a Mouse Model of Sjögren’s Syndrome. Stem Cells Int. 2018;2018:1-10. doi:10.1155/2018/2092315.