Because of the small samples size in these studies and because environmental and host factors such as HLA and CFH polymorphisms are also involved in AMD, it will be difficult to definitely link one pathogen to AMD

Because of the small samples size in these studies and because environmental and host factors such as HLA and CFH polymorphisms are also involved in AMD, it will be difficult to definitely link one pathogen to AMD. this date however, the exact roles (if any) of autoantibodies and T cells in AMD remain unknown. In this review we discuss the potential effects of adaptive immune responses in AMD pathogenesis. 1. Introduction Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world [1]. There are two clinical forms of late AMD: the fast developing exudative form (wet AMD) defined by choroidal neovascularization (CNV) and the more slowly developing atrophic form known as geographic atrophy (GA or dry AMD). Wet AMD is characterized by subretinal extravasations of neovessels and hemorrhage under and into the photoreceptor cell layer which Rabbit Polyclonal to HNRCL induces photoreceptor cell loss [2]. Dry AMD is characterized by retinal pigment epithelium (RPE) atrophy and photoreceptor degeneration [2]. Both wet AMD and dry AMD are complex multifactorial events. Aging [3, 4] and environmental factors such as smoking history [5], oxidative stress [6C9], and more recently low grade inflammation [8, 10, 11] are clearly involved in both CNV and dry AMD pathogenesis. First evidence that innate immunity was at play during AMD came from genetic studies showing that people with polymorphisms in the complement factor H (CfH) [12C15] had an increased prevalence of AMD. Since then, polymorphisms in C3 [16, 17] and complement factors B (CfB) [17, 18] and I (CfI) [19] have been linked to AMD. Moreover, polymorphisms in the CX3CR1 gene, which, in the eye, is specifically expressed on microglia, have also been associated with AMD [20C22]. The exact role of polymorphisms in the CX3CR1 gene during AMD remains however unknown [23]. In CX3CR1 deficient mice, accumulation of microglia and macrophages (M) Indoramin D5 in the subretinal space has been observed. Similarly, in humans it has been proposed that mutations in the CX3CR1 gene would induce recruitment of monocytes/microglia into the subretinal space in the eyes of patients with AMD [22, 24C26]. It has also been shown that, in mice deficient in the CX3CR1 gene, phagocytosis of cellular debris and lipids by monocytes in the subretinal space [22, 24C26] is important in drusen formation and photoreceptors degeneration. Finally in mouse models of CNV the release of VEGF by monocytes recruited to the subretinal space plays a crucial role in choroidal blood vessel growth [22, 27C29]. Therefore CX3CR1-dependent regulation of monocytes/ M recruitment in the subretinal space appears to be involved in the development of both wet and dry AMD [22, 26C30]. The role of innate immunity in AMD has been further demonstrated by the elevated plasma levels of activated complement factor 3 (C3a) [31] and C-reactive protein (CRP), a marker of inflammation [32, 33]. Recently, human and animal studies indicated that adaptive immunity directed towards the retina and/or the RPE is also involved in wet and dry AMD [34C37]. In this review we will discuss the potential sources and roles of adaptive immune responses in the various processes leading to the exudative and atrophic forms of AMD. 2. Role of Antiretinal and Anti-RPE Autoantibodies Found in the Serum and Drusen of AMD Patients As early as 1990, autoantibodies to retinal astrocytes were detected in serum of patients with AMD [38], suggesting that antiretinal autoantibodies could play a role in this disease. Accordingly, using indirect immunohistochemistry, Patel and colleagues showed that serum from people with age-related maculopathy (ARM) exhibited higher levels of retinal autoantibodies than serum of controls. These autoantibodies were specific for all layers of the retina [39]. Autoantibodies present in AMD patient’s serum have been mostly associated with the exudative form of AMD. Multiple retinal autoantigens have been described. These antiretinal antibodies from AMD patients partly react with unknown retinal proteins of varying Indoramin D5 molecular weight [40] including a 68?kDa neurofilament protein found in photoreceptors outer segments [41]. A more recent study showed that antiretinal antibodies recognizing glial fibrillary protein (GFAP, expressed by Mller cells and astrocytes in the retina) and in vivo[58]. Moreover they have demonstrated that adoptive transfer of antiretinal autoantibodies obtained from Royal College of Surgeons’ (RCS) rats (a model of inherited retinal degeneration) induced disruption of the blood retinal barrier (BRB), upregulated CCL2, attracted macrophages in the retina, and increased the level of photoreceptors Indoramin D5 apoptosis.

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