Tear proteins maintain the health of the cornea and keep the ocular surface free of infection. The major source of tear proteins is the lacrimal gland acinar cell. The major antibody present in tears is dimeric IgA (dlgA), which associates with the polymeric immunoglobulin A receptor (plgR) at epithelial cell basolateral membranes. The internalized receptor is transcytosed to the apical plasma membrane, where the ligand- binding domain is cleaved from the membrane-spanning domain and released into external fluid as the secretory component-dlgA complex termed slgA. Cleavage of the external domain of apical plgR can also occur, releasing free secretory component (SC) into external secretions. Although free SC and slgA are present in tears at concentrations among the highest in the body, almost nothing is known about the mechanisms involved in plgR trafficking and SC and/or slgA release in the lacrimal gland. Our preliminary data in rabbit lacrimal acinar cells suggests that the secretory trafficking of plgR involves additional steps beyond the simple transcytotic pathways delineated in model systems such as MDCK cells. Specifically, we have found that a component of cellular plgR in lacrimal acini is targeted to the regulated secretory (merocrine) pathway for accumulation in mature secretory vesicles. We hypothesize that this plgR pool contributes SC into tears, representing a unique pathway not seen in previously-studied models. We further propose that the merocrine effector, rabSD, plays a key role in the sorting and regulation of plgR to secretory vesicles, and that ablation of this pathway will have adverse effects on ocular surface integrity and immunity. Finally, we propose that loss of plgR will adversely affect the organization and function of the lacrimal acinar merocrine pathways, while also adversely affecting ocular surface integrity and immunity.
The aims are:
Aim 1. To test whether SC and slgA released from lacrimal gland acinar cells are derived from plgR sequestered in distinct secretory pools.
Aim 2. To test whether the exocrine secretory rab, rabSD, regulates sorting of plgR and release of SC from the merocrine pool.
Aim 3. To test whether plgR is essential for maintenance of lacrimal gland functions and corneal integrity.
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