Background/Purpose: Accumulating data showed that Glucocorticoid-induced Tumor Necrosis Factor Receptor Family-related Protein (GITR), with its ligand (GITRL), plays an important role in promoting T-cell-mediated immunity and exacerbating autoimmunity in animal models. But its pathogenesis role in primary sjögren syndrome (pSS) remains unclear. Our study aimed to evaluate whether GITRL is related to disease severity and organ involvement in pSS patients and explore the possible mechanisms.

Methods:  78 pSS patients and 44 healthy controls were recruited, and the serum level of GITRL was measured by ELISA, and the serum levels of interleukin (IL) -17A, IL-17E, IL-17F, IL-6, IL-22 and IL-23 were determined by multiplex cytokine assays. CD4⁺ T lymphocytes were isolated from PBMCs of 5 healthy donors by CD4⁺ T Cell isolation kit and cultured in TexMACS™ GMP medium with anti-CD3 monoantibody (mAb), anti-CD28 mAb and rhIL-2. For Th1/Th17 cell differentiation and the pathway exploration of pS6 and pSTAT5, CD4⁺T cells were treated either with recombinant human GITRL protein or with the medium control for 5 days. Surface marker, intracellular cytokine and phosphorylated signal protein were evaluated by flow cytometry. Clinical and laboratory data were collected and the clinical relevance of GITRL in pSS was analyzed

Results:  Serum levels of GITRL were significantly higher in pSS patients than those in HC. There is a negative correlation between elevated levels of serum GITRL and WBC, Neutrophils, PLT, C₃ and C₄, and a positive correlation with Lymphocytes, IgG and RF. Interestingly, pSS patients with overt hypothyroidism showed higher level of serum GITRL comparing to pSS patients with subclinical hypothyroidism and normal thyroid function. Patients with pulmonary involvement had higher serum GITRL level, and pSS patients of moderate to high disease activity (ESSDAI≥5) showed higher serum level of GITRL. Moreover, Serum GITRL level was positively correlated with the Th17 related cytokine profile including IL-17A, IL-17E, IL-17F, IL-1β, IL-22 and IL-23, some of which had been shown to be the causal agents increasing autoimmunity and organ involvement in pSS. After GITRL treatment, we found the expansion of Th1, Th17 and Th1/17cells in vitro and there was a dose-dependent effect. We also found that the increased activaton of mTOR (S6 and STAT3) signaling in Th cells after GITRL ligation.

Conclusion:  Our results identified the clinical significance of GITRL in exacerbating disease activity in pSS patients, and its pathogenic roles in enhancing the differentiation of Th1, Th17 and Th1/17 cells and the possible involved signaling pathways.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-gitrl-is-associated-with-multi-organ-involvement-and-increased-disease-activity-of-primarty-sjogrens-syndrome-and-promotes-pathogenic-th117-differentiation/