MedicalResearch.com Interview with:
Kip Connor, Ph.D.
Harvard Medical School
Associate Professor of Ophthalmology
Department of Ophthalmology
Massachusetts Eye and Ear
MGH ECOR Ophthalmology Representative
MedicalResearch.com: What is the background for this study?
Response: Classically, the retina and the central nervous system (CNS) have long been considered immunoprivileged sites within the body. This is not to say that these sites lack immunity; rather, they are capable of exhibiting a contained yet modifiable form of immunological response. Indeed, an intricate immune surveillance system exists within the retina that can interact with the retinal cellular milieu both during development and in response to injury or disease. While activation of this surveillance system can help protect and repair the delicate neural tissue of the retina in certain disease states, over-activation of this system can exacerbate disease pathology, thereby worsening vision loss.
Microglia are the resident immune cells of the central nervous system, including the retina, and are thought to function acutely in the homeostatic maintenance of the neuro-retinal microenvironment. However in chronic conditions, like autoimmune uveitis, we hypothesized that microglia become neurodegenerative.
In our current study we show for the first time a role for microglia in directing the initiation of this autoimmune disease by orchestrating the inflammatory response within the retina through the retinal vessels.
MedicalResearch.com: What are the main findings?
Response: Normally, the blood brain barrier serves as an impediment and prevents the immune response from going into tissues of the central nervous system, including the retina. However, our results provide clear evidence, that in the context of uveitis, microglia can facilitate entry of inflammatory immune cells into the retina, and enable the host immune responses to attack cells that are not normally recognized by the immune system. Until now, the role of microglia in retinal disease has not been fully understood, but our research shows—for the first time—that these cells serve as gatekeepers from the immune system to the central nervous system. This gateway not only has implications for treating uveitis, but may provide future avenues for drug delivery across the blood brain barrier for other diseases of the central nervous system.
MedicalResearch.com: In lay terms how did you conduct the experiment(s)?
Response: We first examined if autoimmune uveitis developed in animals without microglia, and found that without microglia disease induction did not occur. Interestingly, the inhibitor that was used for microglia depletion did not alter systemic immune activity. This indicated to us that development of uveitis was blocked locally in the retina due to an lack of microglia, thus in the context of autoimmune uveitis microglia functions promote disease. We then closely observed the morphological changes of microglia in response to the induction of uveitis. We found that microglia were activated very quickly after induction of uveitis and that microglia became morphologically closely associated with retinal vessels in the early stage of uveitis before clinically evident inflammation was observed in the retina. We then observed association of microglia with surrounding cells and components of the retina. Interestingly, we found that microglia interact with circulating leukocytes in the retinal vessels, and seem to facilitate these cells into the retinal where they target photoreceptors and induce active uveitis.
MedicalResearch.com: What are the clinical implications of your finding(s)?
Response: Uveitis, or intraocular inflammation, is one of the leading causes of blindness, accounting for approximately 10% of significant visual impairment worldwide. Uveitis is characterized as inflammation of the retina as well as the uveal tissues, optic nerve and vitreous, whereby a large influx of immune cells into the eye are coincident with elevated production of pro-inflammatory cytokines. Uveitis with autoimmune etiology, defined by autoreactive inflammation against the retina, occurs in a variety of diseases including Bechet’s disease, sarcoidosis, and Vogt-Koyanagi-Harada disease. Patients with autoimmune uveitis often suffer serious visual loss after persistent inflammation due to immune mediated damage in the neuronal cells of the retina. Despite significant advances in research and therapeutics, the prevalence of autoimmune uveitis has not been reduced in the past 30 years.
The current standard care of autoimmune uveitis involves systemic administration of corticosteroids and immunosuppressive drugs which elicit their functions by suppressing systemic immune activity. Patients often have to terminate or switch treatment methods due to serious systemic side effects. Although topical use of corticosteroids have been used for long time, its application is limited to mild cases. In addition, no specific treatment has been developed so far that focuses on local immune mechanisms within the eye, which could be used as a supplement of systemic treatment or by itself. While this work was carried out in an preclinical model, it is our hope that in the future therapeutics targeting microglia will be possible, hopefully thereby reducing or shortening systemic treatment period, which will be great benefit.
MedicalResearch.com: What should readers take away from your report?
Response: Our findings begin to identify microglia as a gatekeeper regulating entry into the neuro-retina of systemic inflammatory immune cells. These findings provide the first insights into how microglia respond and function during a systemic autoimmune disease targeting the eye. It is our hope that future studies will allow us to develop specific therapeutics that control microglial function, resulting in a greater visual outcome and quality of life for patients suffering from this sight threatening disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Since microglia have multiple phenotypes and/or different stages of activation that can be associated with either harmful or beneficial effects in disease pathogenesis, their role and function in disease progression is not well defined. Researchers across all fields of medicine have recently begun to elucidate the function of microglial cells in various conditions. For example, in Alzheimer’s, Parkinson’s and other neurodegenerative diseases of the brain, microglia are thought to be harmful. In ophthalmology, it is known that microglial cells are activated in response to a number of developmental and disease indications and their roles in disease are thought to be context dependent, where they can be either beneficial or harmful. It is our hope that in the future we and others will continue to identify new roles and targeted therapeutics for microglia for any number of disease conditions.
MedicalResearch.com: Is there anything else you would like to add?
Response: This research was supported by the National Eye Institute of the National Institutes of Health under grant R01EY027303, the Massachusetts Lions Eye Research Fund, and by an American Macular Degeneration Foundation Prevention Award.
Yoko Okunuki el al., “Retinal microglia initiate neuroinflammation in ocular autoimmunity,” PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1820387116
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