4.1.1. Th1 Cells

Th1 cells produce the inflammatory cytokines IFN-γ and TNF-α, and both of these cytokines regulate cell mediated immunity and activate macrophages, NK, and CD8+T cells [105]. SS was originally considered a Th1 dominated autoimmune disorder, but it has gradually been observed that both Th1 and Th2 cells are drivers of the disease depending on the stage. Deciphering the specific roles of the Th1 subpopulation in the disease progression in SS has been a primary goal in understanding the disease [106]. IFN-γ has a significant effect on the organ development of SGs. *Ifn*γ−/<sup>−</sup> and NOD.*IfncR*−/<sup>−</sup> mice have been shown to be clinically asymptomatic for SS and indicate normal acinar cell proliferation and maturation [107,108]. It has been established that IFN-γ induces expression of glandular adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), α4β1 integrin, peripheral node addressin, L-selectin and LFA-1, which facilitate the influx of inflammatory cells into glands [108–110]. Further transcription signature analysis of the Th1 cell type suggests that the IFN-γ regulated cytokines CCL5, CCL8, CXCL9, CXCL13, and CXCL16 (an IFN-γ regulated chemokine) attract both NK and memory T cells [109]. IFN-γ plays an important role in the perpetuation of inflammation of SS as labial salivary gland primary cell cultures from patients indicate epithelial HLA-DR expression in 80% of cultures. IFN-γ can alter tight junction function and causes an increase of permeability across the epithelium [111]. The in-vitro exposure of acinar cells to IFN-γ causes alterations in tight junction components as observed in the SGs of patients with pSS [112]. It can induce Fas mediated apoptosis in SGEC cultures, ultimately contributing to epithelial cell damage and diminished saliva secretion [113]. Other proteins like IFN inducible guanylate binding protein 1 and CD45<sup>+</sup> cell infiltration are corelated and may be analyzed by the degree of CD45<sup>+</sup> infiltration in the major SGs of pSS patients [107]. CCL9 and CCL19 expression is up-regulated in the salivary (SG) and LGs (LG) of NOD and C57BL/6.NOD-*Aec1Aec2* mice during disease onset, inducing other potentially disease relevant genes such as *Epsti1* and *Ubd* that show enhanced activity in the LGs of male mice [109,114]. IL-7, known to cause increased production of IFN-γ and CXCR3 via upregulation of Th1 cells, has been shown to accelerate the development of SS [115]. Okamoto et al. have shown that IκB-ζ induction is necessary for Th17 cell differentiation and is important in experimental autoimmune encephalomyelitis [116]. Similarly, Okuma et al. have determined that the STAT3-IκB-ζ signaling pathway is essential for the development of SS-like disease, as the genetic deletion of the STAT3-IκB-ζ signaling pathway is sufficient for the development of SS-like disease, as enhanced apoptosis is observed after deletion of the pathway in SG tissue [117]. The epithelial cell-specific STAT3-deficient mice develop SS-like inflammation with impaired IκB-ζ expression in the LGs, activating Th1 cells [117]. The disruption of STAT3-mediated IκB-ζ induction elicits the activation of self-reactive lymphocytes that causes the spontaneous development of SS. The IκB-ζ-deficient epithelial cells accelerate apoptosis even without the involvement of lymphocytes [117]. STAT3 is widely expressed in different cells and is activated by an array of cytokines and growth factors [118,119]. It controls RORγt expression and Th17 development, but alternatively it has been found that epithelial deletion of STAT3 induced SS-like symptoms. IκB-ζ expression is significantly reduced in the LGs of STAT3-deficient mice, proving that STAT3 is required for the expression of IκB-ζ [117].

IL-18, another Th1 cytokine, has been detected in CD68<sup>+</sup> macrophages, ductal, and acinar cells of SGs of SS mice and is secreted at a significantly higher level in sera and the saliva of patients with SS and NOD mice [59,120,121]. It has been established that IL-18 produced by activated macrophages and T cells stimulates the inflammatory pathway within the glands [122].
