4.1.2. Th2 Cells

Th2 cells mediate humoral immunity and are involved in allergic immune responses in the body [123]. Th2 cells play a critical role in sustaining B cell function and conversely, B cells regulate the maintenance and expansion of both IL-4 producing cell lineages [124]. Hyperactivity of B cells, specifically overproduction of autoantibodies is observed in SS patients. This activity is attributed by cytokines secreted by Th2 cells. Th2 cells are generated following priming of CD4<sup>+</sup> T cells by IL-4, resulting in the induction of the Th2 transcription factor GATA3. Th2 cells express a range of cytokines that influence B cell differentiation, eosinophil recruitment, and mucus production [125]. The signature cytokines produced by Th2 cells are IL-4, IL-5, and IL-13 but they can also produce IL-9, IL-10, IL-25, and amphiregulin [126]. Genetic ablation of IL-4 in NOD mice was able to restore normal levels of secretory function however, leukocytic infiltration and pathophysiological abnormalities in gland pathology persisted [127,128]. IL-4 has also been found to play a crucial function during the clinical manifestation of SS while having limited effect on the pathology associated with the preclinical disease. *Il4* KO mice do not produce IgG1 isotypic autoantibodies against the muscarinic acetylcholine receptor (M3R), a known autoantibody target in SS, indicating a critical role of IgG1 isotype switching in SS. Other antibodies such as IgG2a, IgG2b, IgG3, IgM, and IgA are produced against M3R [108] in both the *Il4* KO and NOD.B10-*H2<sup>b</sup>* mouse models. The NOD.B10-*H2b* mouse model has the *Stat6* gene knocked out that impairs the capability of IgG1 production against M3R [129]. Purified IgG fractions from NOD.B10-*H2b* mice were capable of reducing saliva secretions in normal C57BL/6 mice as opposed to fractions isolated from sera of NOD.B10-H2b. Stat6−/<sup>−</sup> mice that inhibited saliva flow rates when infused into naive C57BL/6 mice [129]. Thus, it is essential to note that IL-4, the primary cytokine produced by Th2 cells, plays a part in the isotype class switching to produce pathogenic IgG1 auto-antibodies highlighting the significance of the IL-4/Stat6 pathway.
