Gastroenterol. are probably related to the severity or symptoms of the disease [54, 55]. In this context, Tfh cells play an important role in the B-cell autoimmune responses. The presence of peripheral Tfh cells is one of the biomarkers of autoimmune diseases, such as myasthenia gravis, autoimmune thyroiditis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, inflammatory bowel disease, and SS in both humans and animal models [17, 56-63]. The ectopic GC formation is observed in the salivary gland tissues of SS patients by histological analysis (Fig. ?2a2a). CD3+ T cells including Tfh cells infiltrate within GC in addition to the accumulation out side GC in salivary gland tissue from SS patients (Fig. ?2b2b). Ectopic GC formation has been associated with development and outcome of B cell lymphoma [64-66]. In addition, a previous study demonstrated that a large number of Tfh cells were detected in the peripheral blood of SS patients at the time of disease onset, with aberrations of serum anti-Ro/SSA and anti-La/SSB levels. Moreover, CD4+CXCR5+Tfh cells are significantly elevated in the salivary gland tissues and peripheral blood of SS patients, together with aberrant B cells and plasma cells. This suggests that CD4+CXCR5+Tfh cells contribute to the pathogenesis of SS by promoting the maturation of B cells . Open in a separate window Fig. (2) Ectopic GC formation in the salivary gland tissue from SS patients. (a) Inflammatory lesions including CG in the lip biopsy tissue from a SS patient ERK-IN-1 is shown by histological staining with hematoxylin and eosin. A lot of lymphocytes infiltrate extensively in the salivary gland tissue with destruction of ERK-IN-1 acinar cells. (b) CD3+ T cells in lip biopsy tissue from a SS patient are shown by immunohistochemistry. Scale bar: 200 m. IL-21 is a key regulator of B-cell ERK-IN-1 activation and is primarily secreted by Tfh cells. Previous reports have indicated that the number of Tfh cells is significantly increased in the peripheral blood and that the expression of the IL-21/IL-21 receptor is elevated in the salivary glands of SS patients [17, 67]. Other studies have also suggested that IL-21 plays a pathogenic CR6 role in the onset or development of other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis [68-70]. On the other hand, salivary gland epithelial cells are capable of promoting Tfh-cell differentiation and IL-21 secretion through the production of IL-6 and inducible T cell co-stimulator ligand expression . Increased serum IL-21 levels in SS patients are associated with systemic disease activity . Furthermore, and gene polymorphisms are associated with an increased susceptibility to several autoimmune diseases [73-76]. expression in T cells has been reported to be essential for the formation of Tfh and GC B cells [14, 49]. Recent studies have described the mRNA expression levels of to be significantly higher in ectopic GC of the salivary gland tissues from SS patients . In addition to CXCR5, CD84 and PD-1 expression were also detected on infiltrating lymphocytes in the salivary gland tissues of SS patients . 4.?TREG CELLS IN SS Treg cells are a unique subset of T cells that play an important role in the maintenance of immune tolerance [78, 79]. The expression of the transcription factor forkhead box p3 (Foxp3) is the genetic hallmark of Treg cells.