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S. Masli, A. Gulati, B. Turpie, J.D. Rios, D. Dartt; Thrombospondin Deficiency Predisposes Mice To Dacroadenitis–A Model For Autoimmune Sjogren's Syndrome . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4527.
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© ARVO (1962-2015); The Authors (2016-present)
Autoimmune Sjogren's syndrome is characterized by dacroadenitis (inflammation in the lacrimal gland) that leads to loss of secretory function resulting in ocular surface disease that clinically manifests as dry eye. Absence of immunomodulatory TGFß is known to contribute to the lacrimal gland inflammation. Thrombospondin (TSP–1) is a major activator of latent TGFß. Therefore we examined the susceptibility of TSP–1 deficient mice to develop dacroadenitis spontaneously or upon immunization with α– fodrin and determined whether these mice could serve as experimental mouse model of autoimmune Sjogren's syndrome.
C57BL/6 wild–type or TSP–1 null mice were immunized with α–fodrin derived peptide –JS–1 (50 ng) in complete Freund's adjuvant. At d12 and 21 post–immunization, lacrimal glands were analyzed for the presence of inflammation by (a) histologic examination (H&E), (b) flowcytometric analysis and (c) real–time PCR analysis of cytokines (d) western blot analysis for 120 kD α–fodrin. Secretory function of lacrimal glands was assessed using peroxidase assay (measures peroxidase secretion in response to stimulation with high KCl buffer).
Detectable inflammatory infiltrates appeared spontaneously in the lacrimal glands of TSP–1 null mice between the ages of 3 to 5 months. Similar infiltrates were detected in JS–1 immunized C57BL/6 mice (d21) and TSP–1 null mice (d12). These infiltrates included CD4 and CD8 T cells. Increased expression of pro–inflammatory cytokines IL–1ß, IL–6, TNFα, was detectable in the lacrimal glands of immunized mice (d12). Increased expression of IL–2, IFNγ, IL–4 and IL–10 was also detected. By d21 most cytokine message levels in the lacrimal glands of immunized and un–immunized mice were comparable except for IL–10 message which remained elevated in immunized mice. Secretory function of lacrimal glands was spontaneously lost in TSP–1 null mice by 2 months of age and in immunized wild–type mice by 15 days post–immunization. Increased apoptotic cells were detected in immunized mice as compared to control mice. Apoptotic cleavage product of α–fodrin (120 kD) was detectable in the lacrimal glands of immunized mice. but not in those of control mice. This cleavage product was also detectable in TSP–1 null mice.
Thrombospondin deficiency induces a local microenvironment that promotes lacrimal gland inflammation and predisposes TSP–1null mice to dacroadenitis resembling that observed in autoimmune Sjogren's syndrome.
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