Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1 mice, a model of dry eye.

The purpose of this study was to investigate the changes that occur in the lacrimal glands (LGs) in female thrombospondin 1 knockout (TSP1) mice, a mouse model of the autoimmune disease Sjogren's syndrome. The LGs of 4, 12, and 24 week-old female TSP1 and C57BL/6J (wild type, WT) mice were used. qPCR was performed to measure cytokine expression.

Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090.

Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome.

Sjögren's syndrome-like ocular surface disease in thrombospondin-1 deficient mice.

Thrombospondin-1 (TSP-1) is a major activator of latent transforming growth factor-beta 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.

Thrombospondin-1-mediated regulation of microglia activation after retinal injury.

Purpose: Thrombospondin (TSP)-1 has been demonstrated to play a vital role in immune privilege. The functional phenotype of ocular antigen-presenting cells that contributes to the immune privilege status of the eye is dependent on their expression of TSP-1. Microglia, the local antigen-presenting cells in the retina, undergo rapid activation in response to injury and have the ability to produce both proinflammatory and regenerative neurotrophic factors.

Increased IkappaB alpha expression is essential for the tolerogenic property of TGF-beta-exposed APCs.

IkappaB alpha is an inhibitor of the transcriptional factor NF-kappaB, and it is an essential component of the signaling pathways that lead to expression of inflammatory molecules. These include cytokines and costimulatory molecules associated with antigen presentation in an inflammatory immune response. In this study, we report that antigen-presenting cells exposed to TGF-beta induce peripheral tolerance by increasing IkappaB alpha expression.

Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells.

Exposure of macrophages to transforming growth factor (TGF)-beta is known to alter their functional phenotype such that antigen presentation by these cells leads to tolerance rather than an inflammatory immune response. Typically, eye-derived antigen-presenting cells (APCs) exposed to TGF-beta in the local environment are known to induce a form of peripheral tolerance and protect the eye from inflammatory immune effector-mediated damage. In response to TGF-beta, APCs increase their expression of tumour necrosis factor (TNF)-alpha and TNF receptor 2 (TNF-R2).

Thrombospondin orchestrates the tolerance-promoting properties of TGFbeta-treated antigen-presenting cells.

Eye-derived antigen-presenting cells (APCs) are known to contribute to the immune privilege status of the eye by inducing a form of peripheral tolerance that deviates T(h)1 type of pro-inflammatory immune responses. Similar systemic tolerance can also be induced by non-ocular APCs exposed to transforming growth factor beta (TGFbeta) in vitro. Such APCs were found to express enhanced levels of thrombospondin (TSP)-1, an extracellular matrix (ECM) protein.

Expression of thrombospondin in TGFbeta-treated APCs and its relevance to their immune deviation-promoting properties.

APCs deployed within iris/ciliary body are responsible for promoting anterior chamber-associated immune deviation following injection of Ag into the eye. TGFbeta-2, a constituent of the ocular microenvironment, converts conventional APCs that are pulsed with Ag into cells that induce immune deviation when injected into naive mice. TGFbeta-2-treated APCs under-express IL-12 and CD40, and over-express active TGFbeta.