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A. K. Mircheff, Y. Wang, D. W. Warren, J. E. Schechter; Environmental Influences Promoting Possible Prodromes of Alternative Chronic Inflammatory Processes in Rabbit Lacrimal Gland. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5196.
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© ARVO (1962-2015); The Authors (2016-present)
Several mouse strains model Sjögren’s dacryoadenitis. However, infiltrates in aging rodent lacrimal glands (LG) contain as many mast cells as lymphocytes, and thus appear to not model age-related dacryoadenitis in humans. We now report that environmental factors influence the immune response-related gene expression profile and immunoarchitecture of the rabbit LG, and that different adverse environments may promote pathogenesis of different immunopathologies.
Rabbits were raised at Irish Farms (Norco, CA). Weather data for 30 d prior to arrival at USC vivaria were obtained retrospectively. The mean ratio of daily high temperature to daily low humidity was used to express adverseness to the ocular surface. Abundances of target mRNAs relative to GAPDH mRNA in each sample were determined by real time RT-PCR . Correlations were tested by Spearman and nonlinear regression analyses.
mRNAs for caspase-1, CCL2, CCL4, IL-1α, IL-1β, IL-6, IL-10, TGF-β2, and CD8 correlated (ρ > 0.73, P < 0.0001) with number of days of above average adverseness. mRNAs for IL-2, IL-4, and BAFF correlated somewhat less strongly (0.64 > ρ > 0.62), but still significantly (0.005 < P < 0.004). Relationships were described by exponential increases (1.00 > R2 > 0.91). The discrepancy between the two groups of parameters suggests an additional influence of elevated temperature. mRNAs for prolactin (PRL), MMP9, CCL21, CCL28, CXCL8, CXCL13, APRIL, and IL-18 were uniquely abundant in the group that was exposed to the highest temperatures, and H&E sections revealed that periductal / perivenular lymphocyte aggregates were larger and more frequent in this group.
The correlations for mRNAs for the chemokines, CCL2 and CCL4; for the regulatory cytokines, IL-10 and TGF-β; and for CD8 suggest that increasing exposure to adverse environments is associated with a trajectory of increasingly robust CD8+ cell-mediated immunoregulation that might evolve into the histopathology of chronic, age-related dacryoadenitis. The temperature-related divergence toward increasing abundances of mRNAs for the inflammatory cytokines, PRL and IL-18; the B cell activation and proliferation mediators, IL-2, IL-4, IL-6, BAFF, APRIL, and the B cell chemokine, CXCL13, suggest a possible prodrome of Sjögren’s immunopathology, which is characterized by ectopic autoantibody production. Since PRL is elevated in the physiologic heat stress response, we conjecture that PRL may be an environmentally-induced systemic signal that promotes Sjögren’s pathogenesis.
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