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K. Wu, C.–Y. Chen, M. MacVeigh, C. Ding, J. Schechter, S.F. Hamm–Alvarez; ICA69(–/–) NOD Mice Exhibit Restoration of Lacrimal Gland Endoplasmic Reticulum Morphology and Improvement in Ocular Surface Integrity Relative to NOD Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1952.
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Lymphocytic infiltration of the lacrimal gland (LG) and decreased production of tears are characteristics of the autoimmune disease, Sjögren’s syndrome (SjS). A recent report revealed that knockout of the Islet Cell Autoantigen 69 kD protein (ICA69) in NOD mice, a SjS model, was associated with substantially–decreased lymphocytic infiltration of LG (Winer et al., Lancet 360:1063, 2002), Our recent work has revealed that pathological changes in intracellular biosynthetic compartments including the endoplasmic reticulum (ER) and secretory vesicles in NOD mouse are observed at as early as 4 weeks of age, well before the detection of lymphocytic infiltration within LG. In order to understand the role of ICA69 in the development of SjS–like changes in NOD mouse LG, particularly its possible role in intracellular membrane trafficking, we have compared the function and intracellular membrane organization of the LG in ICA69(–/–) NOD mice to those from NOD and BALB/c mice.
Sections from LG from 16 week–old male BALB/c, NOD, and ICA69(–/–) NOD mice were processed for electron microscopy (EM) evaluation of intracellular membrane compartment organization. Tear flow and ocular surface integrity were evaluated in parallel by thread test and fluorescein staining, respectively.
The ER in NOD mouse LG exhibited a profound change including a loss of rough ER and swelling and vesiculation of remaining ER. The rough ER in the LG of ICA69(–/–) NOD mice displayed a remarkable restoration of rough ER and decreased vesiculation of ER, much closer to the ER in BALB/c mouse LG. The average tear flow rate (mm/5min) for BALB/c mice was 3.5 ± 0.4 (SEM) mm (n=30). Both NOD (1.8 ± 0.2 mm, n=26) and ICA69 (–/–) NOD (1.8 ± 0.2 mm, n=30) exhibited significantly (p<0.01) decreased tear flow relative to BALB/c mice but showed no difference between these two strains. For ocular surface evaluations in NOD mice, 54% of corneas exhibited positive staining; in contrast, ICA69(–/–) NOD mice exhibited 33% positive staining.
Our study suggests that the ICA69 protein is responsible for the morphological changes in ER in NOD mouse LG. Knockout of the ICA69 protein may partially restore proteins to the tear film that are necessary for preservation of the ocular surface health. CR: None
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