Immune Responses in Age-Related Macular Degeneration and a Possible Long-term Therapeutic Strategy for Prevention

Abstract

Purpose To describe the immune alterations associated with, age related macular degeneration (AMD). Based on these findings, to offer an approach to possibly prevent the expression of late disease. Design Perspective Methods Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients. Results Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin-17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occurs throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed immunotherapy has been shown to affect the late stages of AMD. Conclusion Immune dysregulation appears to be an underlying alteration in AMD as in other diseases thought to be degenerative and due to aging. Parainflammation and immunosensescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin-17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression.

The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells

“…For instance, regarding AMD, there remains enough clinical and experimental support of the concept of immune engagement that goes far beyond the role of FH as complement inhibitor. Indeed, evidence supporting the adaptive immune system is directly implicated in both mouse and human (56). Thus, several FH mutations affecting its immunomodulatory activity might lead to loss of local control of many aspects of the immune system, and the release of inflammatory factors would lead to injury and loss of retinal pigment epithelium cells.…”

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

“…RPE cells are critical for retinal homoeostasis and essential for the visual cycle (Strauss, 2005). Critical functions include outer blood–retinal barrier (oBRB) properties; transport of oxygen and nutrients from the choroid to the outer layers of the retina and removal of metabolic waste from the outer retina to choroid [reviewed in (Strauss, 2005)]; and maintenance of an immune‐regulatory microenvironment within the subretinal space (Nussenblatt et al ., 2014; Ozaki et al ., 2014). Some aspects of RPE cell biology have been reviewed recently (Pfeffer & Philp, 2014).…”

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…The consequence is a switch to a more 'classical' chronic inflammatory responses propagating tissue destruction and angiogenesis and as 'frame-shots' of evidence in man supports. 3,[85][86][87] The cause of change from parainflammation to chronic inflammation remains unknown. We can however make inroads and unwrap possible mechanisms for AMD by comparing with immunemediated uveitis and the role of innate immunity and, in particular, macrophages.…”