Published online before print August 21, 2009

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(American Journal of Pathology. 2009;175:1136-1147.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081058

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

From the Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts

Correspondence: Address correspondence to Sharmila Masli, Ph.D., Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. E-mail: sharmila.masli{at}schepens.harvard.edu

Thrombospondin-1 (TSP-1) is a major activator of latent transforming growth factor-β in vitro as well as in vivo. Mice deficient in TSP-1, despite appearing normal at birth, develop a chronic form of ocular surface disease that is marked by increased apoptosis and deterioration in the lacrimal gland, associated dysfunction, and development of inflammatory infiltrates that result in abnormal tears. The increase in CD4⁺ T cells in the inflammatory infiltrates of the lacrimal gland, and the presence of anti-Sjögren’s syndrome antigen A and anti-Sjögren’s syndrome antigen B antibodies in the serum resemble autoimmune Sjögren’s syndrome. These mice develop an ocular surface disorder dry eye that includes disruption of the corneal epithelial layer, corneal edema, and a significant decline in conjuctival goblet cells. Externally, several mice develop dry crusty eyes that eventually close. The inflammatory CD4⁺ T cells detected in the lacrimal gland, as well as those in the periphery of older TSP-1 null mice, secrete interleukin-17A, a cytokine associated with chronic inflammatory diseases. Antigen-presenting cells, derived from TSP-1 null, but not from wild-type mice, activate T cells to promote the Th17 response. Together, these results indicate that TSP-1 deficiency results in a spontaneous form of chronic dry eye and aberrant histopathology associated with Sjögren’s syndrome.