Age-related macular degeneration (AMD) is a highly prevalent, multifactorial, polygenic complex disease. It is now widely accepted that inflammation and the immune system play a direct role in the pathogenesis of AMD. As inflammation builds up in aging and, much more so, in AMD, we hypothesize that a vicious cycle is set in motion that exposes macular tissues to an increasing amount of inflammatory and immune-mediated damage. We propose that this mechanism is critical to AMD development and progression. We have strong evidence that patients with early and advanced AMD express auto-antibodies (auto-Abs) against macular human tissue antigens significantly more commonly and more intensely than elderly controls. However, having shown this does not prove that the auto-Abs have a direct role in contributing to disease development and/or progression. To understand the role of auto-Abs in AMD, it is essential to discover the identity of their targets, and provide prof of a causal link between disease and presence of auto-Abs. To tackle these critically important questions, we propose the following series of Aims: 1) To discover the identity of all statisticall significant macular antigens identified in our preliminary investigations and test the hypothesis that wild-type (WT) mice immunized against these antigens develop auto-Abs towards them and changes consistent with an AMD phenotype. 2) To test the hypothesis that auto-Abs that develop in an early-onset murine model of AMD can be used to accelerate disease appearance and increase its severity in a late-onset model via adoptive transfer of serum IgG. 3) To test the hypothesis that similar autoimmune reactivity patterns occur not only across species but also across animal models of AMD, and to establish a relationship between time course of auto-Ab development and time of onset of phenotypes. These studies will allow us to discover targets of autoreactivity in AMD, investigate commonalities (and differences) across species and models, test the causality of the autoimmune hypothesis in AMD, define an "autoreactivity sequence", identify early disease markers and progression risk markers, and develop a much more refined pathogenic framework for the role of autoimmunity in AMD. We predict that these studies will ultimately pave the way toward using the existing AMD models and those that we plan to induce to investigate and develop new treatments for the manifestations of AMD, and that it will be possible to translate these treatments back to bedside in human clinical trials.
The role of inflammation has recently emerged as a key pathogenic factor in age-related macular degeneration (AMD). We have documented that AMD patients have autoantibodies (auto-Abs) against macular tissue antigens significantly more commonly and more intensely than controls. We now propose to: (1) identify the antigens recognized by these auto-Abs with immunoprecipitation and mass spectrometry experiments;(2) test the hypothesis that these auto-Abs are pathogenic and that a) by immunizing mice against the antigens that they recognize mice will develop AMD-like fundus lesions and b) that passive (adoptive) transfer of the auto-Abs developed by these mice to naive mice will lead to disease development also in these mice;(3) test the hypothesis that, like human beings, existing mouse models of AMD also develop autoreactivities against ocular tissue antigens;(4) to test the hypothesis that late-onset mouse models of AMD can have their disease appearance be sped up or its severity made worse by passive transfer of auto-Abs from other models in which disease also is present;and (5) to investigate mouse models of AMD prospectively to characterize the sequence of events leading up to auto-Ab formation and development of fundus lesions. This series of studies will allow us to define the role that autoimmunity has in AMD and, ultimately, to pave the way toward using the existing AMD models and those that we plan to induce to explore treatments of the manifestations of AMD.
|Iannaccone, Alessandro; Giorgianni, Francesco; New, David D et al. (2015) Circulating Autoantibodies in Age-Related Macular Degeneration Recognize Human Macular Tissue Antigens Implicated in Autophagy, Immunomodulation, and Protection from Oxidative Stress and Apoptosis. PLoS One 10:e0145323|