Gregerson Research

	What's Immunology Got To Do With Eye Disease? Eye and Immune System Coordination What We Do How to Help

Dale Gregerson, Ph.D.
Professor
Department of Ophthalmology
grege001@umn.edu

Research Interests:

Ocular Immunology; Autoimmunity and Tolerance in the Retina

A central problem in immunology is that the strategy used to generate a large variety of antigen receptors also results in the production of receptors with specificity for self. The potential for self-reactivity is balanced by compensatory/regulatory mechanisms, collectively called tolerance. Tolerance is an operational definition which refers to the lack of, inhibition of, or alteration of an immune response. There are several types of tolerance including: clonal deletion, anergy, suppression, and immunological ignorance (lack of sufficient antigen to achieve levels of receptor binding required for signaling). Some tolerance results from the "fail-safe" manner in which the immune system operates; a minimum of two signals between two cells is required for activation.

One way to study tolerance is to use examples of the loss of tolerance, such as autoimmune disease. Our lab works with an autoimmune disease, experimental autoimmune uveoretinitis (EAU), in which the target autoantigen is a protein expressed in retinal photoreceptor cells. EAU resembles several clinical diseases of the retina with possible autoimmune origins. Nervous system autoantigens provide unique challenges to tolerance. Some of these autoantigens are tissue-specific, no antigen is available to drive negative selection in the thymus. Some appear for the first time well after the immune system has started to generate mature T lymphocytes, so that these lymphocytes have escaped usual selective mechanisms. Furthermore, the nervous system is isolated behind physiological barriers, whose effect on immune function is not well understood.

Our lab concentrates on studies of the role of the nervous system environment in immune tolerance, primarily by study of the retina. The nervous system is a complex and somewhat fragile collection of tissues. Since bystander damage due to severe inflammation can do great harm, mechanisms to minimize the potential for such damage have developed. These mechanisms are collectively termed immune privilege. As new mechanisms of immune privilege continue to be revealed, the relevance of old theories comes into question. Our lab has a particular interest in the immune privilege of retina, and we wonder how much of immune privilege is due to newly-described active mechanisms of tolerance, and how much is due to older hypotheses based on the anatomy and physiology of the retina; i.e., mechanisms such as sequestration, which depend on its relative isolation. Sequestration refers to the barrier function played by the tight junctions of the retinal vascular endothelium and the RPE. The idea is that together, these features of the eye protect it from inflammation by reducing the access of inflammatory cells, and promoting immunological tolerance to existing antigens in retina.

For several years, our lab studied a retinal antigen called S-Ag (or "arrestin") to learn about retinal immunology. While this has allowed considerable progress, there are complications. Arrestin is now known to belong to an extensive family of highly related proteins that show widespread expression and cross-reactivity. There is also evidence for thymic expression of arrestin and arrestin-like molecules. As a result, we recognized a few years ago that the complications of this model system would hinder progress.

Consequently, we recently undertook a strategy that would allow direct testing of our hypotheses based on studying immune responses in transgenic mice. These mice express an antigen, beta-galactosidase (beta-gal), without homology to any known mammalian sequence. Depending on the promoters used, the tissue site and amount of bgal expression can be manipulated. We are presently using several different strains of Tg mice; one gives systemic beta-gal expression, one gives retinal expression, and one has brain and retinal expression. Non-transgenic littermates and normal mice are used as controls. Collectively, these mice are used to compare the effects of retina-restricted expression to systemic or CNS expression on tolerance. A beta-gal-specific CD4 T cell receptor transgenic mouse has been made to provide a clonal population of naive T cells with specificity for this antigen.

This strategy has yielded important preliminary results about the difference in the immune recognition of a protein in the retina as compared to the recognition of that same protein expressed elsewhere, addressing fundamental questions about immune privilege. Some of the recent specifics of this research can be found at http://www.micab.umn.edu/faculty/Gregerson.html.