Many of the drusen proteins were covalently modified with adducts, including advanced glycation end products (AGE) and pyrrole adducts generated from the oxidative damage of docosahexaenoic acid (DHA)

Many of the drusen proteins were covalently modified with adducts, including advanced glycation end products (AGE) and pyrrole adducts generated from the oxidative damage of docosahexaenoic acid (DHA). blinding end-stage condition characteristic of the dry form of AMD. Inflammatory cells are present in the region of lesions and may be actively involved in the pathology observed. We conclude that early immunization of mice with CEP-adducted MSA sensitizes these animals to the ongoing production of CEP-adducts in the outer retina where DHA is usually abundant and the conditions for oxidative damage are permissive. In response to this early sensitization, the immune system mounts a complement mediated attack around the cells of the outer retina where CEP-adducts are formed. This animal model for AMD is the first developed from an inflammatory signal discovered in eye tissue and blood from AMD patients. JDTic It provides a JDTic novel opportunity for dissecting the early pathology of AMD and the immune response contributing to this disorder. The availability of a mouse with a mechanistically based AMD-like disease that progresses rapidly is usually highly desirable. Such a model will allow for the efficient preclinical testing of much needed therapeutics quickly and inexpensively. Age-related macular degeneration (AMD) is the most common cause of legal blindness in developed countries and constitutes a major health problem. Millions of the elderly are blind from AMD in Europe and North America with over 300,000 new AMD cases being diagnosed annually (1,2). During aging many individuals accumulate material in JDTic Bruchs membrane causing this acellular lamina below the retinal pigment epithelium (RPE) to thicken (3C5), while in others focal deposits of debris accumulate below the RPE along Bruchs membrane and are recognized in an eye exam as drusen. Clinicians have long recognized that drusen in the macula of the eye, their density and the area covered by these deposits are early stages in the AMD disease process. Individuals with drusen are considered at risk for developing the advanced blinding forms of AMD (6C8). Advanced AMD is usually subdivided into two forms: (a) geographic atrophy and (b), choroidal neovascularization. Geographic atrophy (also referred to as the dry form of AMD) develops slowly but results in blindness by the focal degeneration of the RPE below the fovea (9). Without the RPE, the foveal photoreceptors lose function and foveal blindness ensues. Choroidal neovascularization (also called the wet form of AMD) is usually characterized by new blood vessels that break through Bruchs membrane and the RPE. When these new blood vessels hemorrhage, a blood clot accumulates between the RPE and foveal photoreceptors causing immediate blindness (6,7). Our initial studies on AMD focused on understanding the composition and distribution of proteins in drusen (10C15). Over 120 different proteins were identified in isolated drusen. A number of other laboratories have made significant contributions to the understanding of drusen composition in recent years and a consistent finding in their reports is usually that proteins in JDTic the complement attack pathway and its regulators are present in drusen (11,16C20). The older literature, primarily from twin studies, pointed to the likelihood that genetic factors played a role in AMD (21C24). Recent genetic studies also establish that mutations/polymorphisms in genes coding for complement pathway proteins (complement component C2 and factor B) and its regulators (factor H and factor H-related proteins) are present in approximately 50% of AMD patients. Collectively these studies strongly indicate that AMD is usually a genetic disease and that inflammation is usually a likely participant in the AMD pathology (25C29). The complement system plays an essential role in inflammation and immune responses. Soluble complement proteins are present in the blood in precursor forms and require activation to fulfill their specific physiological roles. Activated complement has diverse functions, including the initiation of inflammation, recruitment of leukocytes, clearance of immune complexes, neutralization of pathogens, regulation of antibody responses, and disruption of cell membranes. The complement cascade can be activated by three initiating pathways. The classical activation pathway depends on assembly of complement factors at sites of antigen-antibody complexes. Activation of the alternative pathway is usually triggered by a variety of pathogen surfaces and requires the conversation of the third complement component (C3), factor B, and factor D. The lectin pathway is initiated by mannan-binding lectin bound to pathogen surfaces. Regardless of the pathway, activation leads to the cleavage of C3. Mmp2 This generates the smaller, proinflammatory C3a fragment and the larger C3b fragment. C3b together with other activated proteins form the important convertases required for the terminal part of the complement cascade, culminating in the assembly of the membrane attack complex (MAC) and.

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