Alterations in Extracellular Matrix/Bruch's Membrane Can Cause the Activation of the Alternative Complement Pathway via Tick-Over.

Given the complex etiology of age-related macular degeneration (AMD), treatments are developed to target intermediate/late stages of the disease. Unfortunately, the design of therapies for early stages of the disease is limited by our understanding of the mechanisms involved in the formation of basal deposits and drusen, the first clinical signs of AMD. During the last decade, the identification of common and rare alleles in complement genes as risk AMD variants in addition to the presence of active complement components in basal deposits and drusen has provided compelling evidence that the complement system plays a key role in the pathobiology of AMD. However, the mechanisms for complement activation in AMD are unknown. Here we propose that the activation of the complement system is a consequence of alterations in the aged extracellular matrix (ECM) of the retinal pigment epithelium (RPE)/Bruch's membrane (BrM), which favors the anchoring of complement C3b generated by convertase-independent cleavage of C3 via tick-over and produces a chronic activation of the alternative complement pathway.

Chemokine CXCL-1: activity in the vitreous during proliferative vitreoretinopathy.

The aim of this study was to investigate CXCL-1 chemokine levels in the vitreous during rhegmatogenous retinal detachment (RRD) with and without proliferative vitreoretinopathy (PVR) and identify possible correlations with clinical parameters (extent and duration or RRD and PVR grade). Vitreous samples from patients with primary RRD with or without PVR were collected and assayed using a double antibody enzyme-linked immunosorbent assay (ELISA). Eleven vitreous samples from organ donors were employed as a control group. CXCL-1 levels were measured in 35 vitreous samples from 35 RRD patients. Mean CXCL-1 levels (64·82 ± 6·47 pg/ml) were significantly higher (P = 0·048) compared to controls. There was a significant positive correlation between CXCL-1 levels and the extent of the detachment (r = 0·794, P = 0·006). Peak CXCL-1 levels coincided with 3+ quadrant RRD, an interim of 29-60 days' duration and PVR grade B. Increased CXCL-1 levels may be indicative of mild inflammation in the detached retina and the adjacent vitreous. The results of the present study may provide novel insight into the complex interactions taking place during the early and late stages of RRD complicated by PVR.

The immunological basis of degenerative diseases of the eye.

It has become clear that disorders that were once considered "degenerative" have complex mechanisms, with many having been shown to have immune mediation as part of the disease process. These include arteriosclerotic heart disease and Alzheimer's disease. Indeed, several ocular disorders that once fell into the "degenerative" category meet this criterion as well. Immune mediation has been shown to be a part of many of the most common ocular disorders, and not just that of uveitis, or ocular inflammatory disease.

Loss of anterior chamber-associated immune deviation (ACAID) in aged retinal degeneration (rd) mice.

PURPOSE: To determine whether the capacity to induce ACAID by antigen injection into the anterior chamber is altered in animals with genetically determined retinal degeneration and increased age. METHODS: Anterior chamber-associated immune deviation (ACAID) induced by injection of ovalbumin into the anterior chamber of the eye was studied in three rodent strains with different forms of hereditary retinal degeneration (Royal College of Surgeon [RCS] rats, retinal degeneration [rd] mice, and Norrie-Disease [ND] mice) and in different age groups (age range, 1-23 months). The data were compared with those of age-matched controls. Aqueous humors of rd mice, RCS rats, and age-matched congenic controls were investigated for concentrations of transforming growth factor-beta2 (TGF-beta2) using enzyme-linked immunosorbent assay. RESULTS: ACAID was readily induced in RCS rats and ND mice irrespective of amount of retinal degeneration or aging. In rd mice ACAID could be induced in young animals but not in animals more than 12 months of age. In old rd mice, loss of ACAID was accompanied by a marked reduction in total TGF-beta2 levels in aqueous humor. CONCLUSIONS: Rd mice more than 1 year of age lose the capacity of the anterior chamber to support the induction of ACAID by intracameral injection of soluble protein antigen. Because loss of ACAID correlated with a decrease in TGF-beta2 concentration in aqueous humor, it is proposed that eyes of rd mice are unable to maintain an immunosuppressive microenvironment necessary for ACAID.