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Zhiyuan Yu, Jehan Alam, Rodrigo G. de Souza, Cintia S De Paiva, Stephen C Pflugfelder; Low humidity plus anti-cholinergic-induced dry eye skews toward a Th1 response. Invest. Ophthalmol. Vis. Sci. 2019;60(9):275.
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Mouse dry eye models have been created with low humidity (LH) plus anti-cholinergic suppression of tear secretion or LH alone. We investigated the ocular surface immune response to these different dry eye-inducing conditions, with particular attention to their effects on Th1 (CD4+IFN-γ+) and Th17 (CD4+IL-17A+) polarization.
6-to-8 week old C57BL/6J mice were housed under normal humidity and left untreated or subjected to LH or LH and scopolamine SC (LH+Scop) for 1 day (D1) and 10 days (D10), respectively. Populations of Th1 and Th17 cells were analyzed in the cervical lymph nodes (CLNs) by flow cytometry. Expression of Th1 genes (IFN-γ, CXCL10 and Sprr2f, Sprr2g) and Th17 genes (IL-17A, CCL20 and MMP9) in the conjunctiva and cornea was evaluated by real-time PCR.
Compared to naïve mice, greater frequency of Th1 cells at D10 in the LH+Scop group, and elevated frequency of Th17 cells was detected at D10 in LH and LH+Scop groups in the CLNs (P<0.0001). Expression of Th1 genes in the conjunctiva showed IFN-γ unchanged at D1 and significantly higher at D10 in the LH+Scop group (2 fold, P<0.0001). CXCL10 was higher at D10 in the conjunctiva of the LH group compared to LH+Scop (1.9 fold, P<0.001). Sprr2f and Sprr2g, two IFN-γ induced cornified envelope genes, were higher in cornea in LH+Scop compared to LH (Sprr2f: 2.9 vs. 0.45 (D1) and 18.6 vs. 14.3 (D10); Sprr2g: 5 vs. 2.5 fold (D1) and 3 vs. 1.3 fold (D10); respectively, P<0.0001 for both). Expression of IL-17 genes showed early upregulation of IL-17A (2.70 fold, P<0.0001) in the LH group. In the cornea, IL-17A was significantly higher at D1 and and undetected at D10 in both LH and LH+Scop groups (~20 and 5 fold, respectively, P<0.0001 for both). CCL20 peaked at D1 in the cornea (~12 fold) and in the conjunctiva (2.37 fold) in the LH group, while it was significantly elevated in cornea at D1 and D10 in the LH+Scop groups (4.6 and 4.2fold, D1 and D10, respectively, P<0.0001). MMP9 increased 2 fold at 1 day (P <0.0001) only in the LH group.
These findings indicate that different dry eye inducing conditions in mice show a different pattern of T helper immune response. LH+Scop skews toward a Th1 response; whereas LH alone promotes a Th17 biased response. These finding suggest that secreted tear factors suppress Th1 induction and IFN-γ+ expression. They suggest that therapy of aqueous tear deficiency should include agents that suppress Th1.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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