In the DED draining CLN, CEC- and SCP-induced models exhibit increased Th1 and Th17 responses, accompanied by deficient Treg suppression. These findings are consistent with previous studies that combined desiccating stress (e.g., CEC) and SCP-induced DED.
5–7 However, immune responses in the draining CLN of CEC and SCP-induced models differ (
Fig. 7). SCP-induced DED demonstrated significantly lower Th17 responses and higher Treg activity than CEC-induced DED, and these alterations are attributable to the pharmacologic effects of SCP on CD4
+ T-cells. Therefore, the immune responses that occur in the CLN of SCP-induced DED mice can be considered the result of the ocular disease and drug effects. The increased Th2 responses observed in the CLN of SCP-induced DED are attributable to the pharmacologic effects of SCP, and are thought to be unrelated to the immunopathogenesis of DED. Corresponding to the relatively lower effector T-cell responses in the disease-draining lymph nodes, SCP-induced DED exhibits fewer CD11b
+ and T-cell infiltration in the ocular surface than CEC-induced DED, which can be due to the lower numbers of effector T-cells generated in the CLN, as well as the suppressive effect of mAChR blockade on monocytes and T-cell migration.
18 Although SCP induces weaker disease-promoting inflammatory immune responses, it generates comparable levels of clinical severity as the CEC, as demonstrated by comparable CFS scores. CFS is the recommended method of measuring ocular surface epithelial damage and the resultant barrier disruption,
21 which is the characteristic pathology of DED at the cellular level.
30 This most likely is due to SCP-induced lacrimal hyposecretion, which is an important factor in the pathogenesis of DED (
Fig. 7). To confirm the role of SCP further in the immunopathogenesis of DED, mice were subjected to LGE to mimic the aqueous tear deficiency induced by systemic administration of SCP. LGE has been reported to induce dry eye in rats by reducing tear secretion.
31 In our study, LGE and SCP caused tear excretory dysfunction; however, in comparison with SCP, LGE caused a more robust localized immune response without affecting systemic immunity. As a result, LGE + CEC induces more severe disease than SCP + CEC, as correlated by the higher Th17 responses measured using the LGE + CEC model (
Fig. 6).