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S. Masli, B. Turpie, D. Dartt; Sjogren's Syndrome-Like Disease in Thrombospondin-1 Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5421.
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Thrombospondin-1 (TSP1) is a multifunctional extracellular matrix protein that binds latent TGFβ and activates it. Deficiency of TGFβ in mice leads to severe lacrimal gland inflammation as seen in autoimmune Sjogren's syndrome. We evaluated TSP1 deficient mice for the development of autoimmune Sjogren's syndrome.
Age-matched wild-type C57BL/6 mice and TSP1null mice (2-12 months) were used to determine pilocarpine-induced tear secretion. Tear content of peroxidase was measured using Amplex Red assay. Ocular surface was evaluated by fluorescein staining. Serum samples collected were tested for the presence of antibodies against muscarinic acetylcholine type 3 receptor (anti-AchM3). Lacrimal glands harvested from these mice were analyzed for the presence of inflammation by histologic examination (H&E) and presence of cytokines TNFα and IL-1β in tissue lysates by ELISA. Presence of apoptotic cleavage product of α-fodrin (120 kD) was detected by western blot analysis of lacrimal gland lysates.
Significantly increased perivascular inflammatory infiltrates were detectable in the lacrimal glands of 6 -12 month old TSP1null mice as compared to their age-matched controls. Pilocarpine-induced tears in wild-type (0.128 ±;0.023 mm/g/min, n=4) was not significantly different from those TSP1null mice (0.319 ±;0.119 mm/g/min, n=5, p>0.05). In contrast pilocarpine induced peroxidase levels in wild type tears was 69.8 ±;0.19 mU/ml (n=3) that was significantly higher than that in tears from TSP1null mice 13.88 ±;0.34 mU/ml (n=3). Increased flourescein staining was detected on the ocular surface of TSP1null mice. Antibodies against M3 receptors were detected in the sera from TSP1null mice but not wild-type mice. Increasing levels of TNFα( 119 ±;2.8, 695 ±;7.7, 2039.8 ±;65.4 pg/ml) and IL-1β (ND, 3283 ±;108, 7233 ±; 272 pg/ml) were detected with age (2, 5 and 12 months resp.) in the lacrimal gland lysates of TSP1null mice. Also increased amounts of 120 kD apoptotic cleavage product of α-fodrin was detected in the lacrimal glands of 2 month old TSP1null mice as compared to the wild-type controls.
Thrombospondin-1 deficiency results in inflammation of lacrimal gland accompanied by development of autoantibodies. These features together with the lacrimal insufficiency resemble autoimmune Sjogren's syndrome.
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