Pathobiology of autoimmune Meibomian gland dysfunction

Dry eye disease (DED) is a chronic condition affecting millions worldwide, with approximately 21 million patients affected in the US. Symptoms of DED vary from mild irritation to severe ocular pain, and, if left untreated, can lead to the loss of vision. The pathogenesis of DED is a subject of intense research efforts, but its etiology

is still unknown. It can be classified as evaporative dry eye (which includes Meibomian Gland Dysfunction [MGD]) and aqueous-tear-deficient DED (which includes lacrimal gland deficiencies, such as Sjögren Syndrome [SS]). Meibomian glands (MGs) secrete lipids (meibum) onto the ocular surface to stabilize the tear film. Changes in

MG function (MGD) lead to altered quality and quantity of meibum, causing increased tear film evaporation, and leading to evaporative DED. Clinical studies suggest that 85% of all DED cases are caused by some form of MGD. Despite the high prevalence of MGD, its etiology has not been fully investigated. SS is an autoimmune

DED characterized by over-reactive CD4+T cell-mediated inflammatory response in various tissues. Studies have demonstrated that a high prevalence of SS patients present MGD. However, the pathobiology of MGD in SS patients remains unknown. Our innovative hypothesis is that SS patients also present an autoimmune

response in the MG that leads to an autoimmune form of MGD. This hypothesis is supported by our preliminary studies showing that CD25KO mice, a mouse model of SS rich in autoreactive T cells and no regulatory T cells (Tregs), present CD4+T cell infiltration in the MG area, which is associated with MG atrophy and drop-out.

Further, the co-adoptive transfer of CD4+T cells from CD25KO mice into immune-deficient mice leads to immune cell infiltration into the MG, causing MGD. Interestingly, the co-adoptive transfer of wild-type Tregs with CD4+T cells from CD25KO mice is enough to prevent immune cell infiltration in the MG and MGD. Based on this

preliminary data, we hypothesize that autoreactive CD4+T cell infiltration into the MG area drives MG damage, causing MGD. Taken together, this proposal will characterize the inflammatory cell infiltration into the MG area in two well-established murine models of SS, and thereafter establish how autoimmune CD4+T cells are able to

lead to MG damage, causing an autoimmune form of MGD. This will be accomplished with the following specific aims: Specific Aim 1: To characterize the MG inflammatory cell infiltration in the MG of CD25KO mice and how it contributes to MGD; and Specific Aim 2: Investigate if autoimmune CD4+ T cells can cause MGD

and whether this can be prevented by Tregs. Currently, the etiology of MGD remains elusive, and, thus, it is difficult to design preventative therapies and treatments. Understanding and characterizing a potential role for inflammation (particularly CD4+T cell) in MGD will open new research avenues for developing new treatments.

This work is significant because it will develop and characterize for the first time an autoimmune model of MGD which will shed light on the etiology of MGD, a great public health problem that affects millions of people.