Physiology & Biophysics, Ophthalmology
Keck School of Medicine
- Cell Structure & Organization
- Membranes & Transport
Research OverviewThis laboratory focuses most of its efforts on exocrine gland secretory cells, with acinar cells from rabbit lacrimal glands as the primary model. The motivation for this work comes in part from the high incidence of ocular morbidity associated with insufficient lacrimal gland function; after the need for refractive correction, dry eye is the most common problem seen by eye care specialists. Many of the diseases that impair lacrimal gland function, such as Sj�gren's syndrome, graft-versus-host disease, and HIV infection, are characterized by increased lymphocytic infiltration of the lacrimal glands. There is also evidence that increased lymphocytic infiltration may also contribute to the lacrimal insufficiency that typically accompanies ageing. Therefore, we are attempting to understand the mechanisms which cause lymphocytes to accumulate in the lacrimal glands.
One of our starting points is the working hypothesis that cells which aberrantly express major histocompatibility complex Class II molecules (MHC II, or, in humans, HLA II) provoke autoimmune responses by proteolytically processing and presenting certain of their own proteins with mechanisms that mimic those used by the professional antigen presenting cells. One of our approaches to testing this hypothesis has been to develop novel methods for biochemically dissecting cells and using these methods to map the endomembrane system within which potential autoantigens are processed and resulting peptides associate with MHC II. We have begun identifying changes in intracellular compartmentation which are induced by sustained secretomotor stimulation and which are likely to alter the spectrum of autoantigens the cells display. Such changes are of interest because the may over-ride peripheral tolerance mechanisms that normally work to restrain autoimmune responses.
We believe that this work will lead to insights into the mechanisms that initiate autoimmune processes in a variety of tissues. We also believe that the understanding we are gaining will enable us to propose new therapeutic and preventive strategies. In addition to these possible clinical implications, this work is contributing to the understanding mechanisms of sorting and targeting that underlie the development of epithelial polarity, intracellular compartmentation, and rapid responses to regulatory signals.