Sharmila Masli

Molecular Mechanisms Utilized by Ocular Antigen Presenting Cells to Induce ACAID

It is now known that various cells and molecules in the eye contribute to the unique ocular microenvironment, which directs the immune response by influencing antigen presenting cells (APCs). However, the molecular mechanisms that allow eye-derived APCs to bring about such a carefully regulated immune response are not clearly understood. In the current research project successfully employed DNA microarray technology has helped identify genes uniquely expressed (up or down regulated) when conventional APCs are exposed to molecules likely to be found in the ocular environment. This method has allowed a comprehensive analysis of the transcriptional program of cells that represent eye-derived APCs, and has provided information on expression of various genes so far not known to be directly related to anterior chamber associated immune deviation (ACAID). These include thrombospondin (TSP), TNFR2 and IkBa. Determining the significance of each of these genes in inducing the unique ocular immune response has revealed novel immunologic mechanisms utilized by eye-derived APCs. These studies contribute to our understanding of the ocular immune and inflammatory processes and further provide the basis for potential therapeutic strategies to treat ocular inflammatory diseases.

Lacrimal Gland Inflammation and Autoimmune Sjögren’s Syndrome

Our experiments addressing significance of thrombospondin in the regulation of inflammatory immune responses by eye-derived APCs have attributed an immunoregulatory role to this extracellular matrix protein-TSP. These results have broader implications for the regulation of ocular inflammatory processes by this molecule, as many ocular cells synthesize thrombospondin. The ability of thrombospondin to activate latent TGFβ extends its regulatory potential to the inflammation in the lacrimal gland as TGFβ deficiency in mice results in severe inflammatory infiltrates that lead to ocular surface inflammation and Sjögren’s syndrome. Role of thrombospondin in regulating immune responses to constitutively presented lacrimal gland autoantigens and resulting autoimmune Sjögren’s syndrome is being examined in a collaborative project to develop inducible mouse model of this disease.

Thrombospondin and Blood-Retina-Barrier

In the absence of thrombospondin mice immunized with retinal antigen developed severe inflammation in the retina that led to irreversible damage of the tissue highlighting an important role of thrombospondin in the immune privilege in the retina. The role thrombospondin plays in regulating leukocyte recruitment in the retina is being examined to understand the inflammatory responses in the retina.