Blockage of complement regulators in the conjunctiva and within the eye leads to massive inflammation and iritis

Abstract

SUMMARYThe open environment of the eye is continuously subject to an in¯ux of foreign agents that can activate complement. Decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 are regulators that protect self-cells from autologous complement activation on their surfaces. They are expressed in the eye at unusually high levels but their physiological importance in this site is unstudied. In the rat, a structural analogue termed 5I2 antigen (5I2 Ag) has actions overlapping DAF and MCP. In this investigation, we injected F(abk ) 2 fragments of 5I2 mAb into the conjunctiva and aqueous humor, in the latter case with and without concomitant blockage of CD59. Massive neutrophilic in®ltration of the stroma and iris resulted upon blocking 5I2 Ag activity. Frank necrosis of the iris occurred upon concomitant intraocular blockage of CD59. C3b was identi®ed immunohistochemically, and minimal effects were seen in complement-depleted animals and in those treated with non-relevant antibody. The ®nding that blockage of 5I2 Ag function in periocular tissues and within the eye causes intense conjunctival in¯ammation and iritis demonstrates the importance of intrinsic complement regulators in protecting ocular tissues from spontaneous or bystander attack by autologous complement.

The complement anaphylatoxin receptors are not required for the development of experimental autoimmune uveitis

“…Animals subsequently develop posterior segment inflammation, with evidence of retinal vasculitis, vitreitis, and retinal and subretinal inflammatory infiltrates (Caspi et al, 1988). Activation of the complement system is involved in the pathogenesis of EAU (Bardenstein et al, 2001, Marak et al, 1979, Read et al, 2005, Sohn et al, 2000) as evidenced by the marked reduction in severity of disease when C3, the central component of the complement cascade, is deleted or inhibited by treatment with the soluble regulatory protein sCrry (Read, Szalai, 2005). However, which of the complement anaphylatoxin receptors mediates the pro-inflammatory effects of complement during EAU remains unknown.…”

In vitro effects of preserved or preservative-free antiglaucoma medications on human complement system

“…21 Activation of complement can lead to the formation of a membrane attack complex responsible for complement cytolytic activity against cells that do not express the adequate regulatory proteins. Unregulated complement activation has been involved in the pathogenesis of conjunctival inflammation, 22 ocular infections, 23 anterior uveitis, 24,25 iris necrosis, 22 diabetic retinopathy, 26 proliferative vitreoretinopathy, 27 as well as in drusen formation and age-related macular degeneration. 28,29 Additionally, proteolytic cleavage of native complement proteins generates anaphylatoxins that bind to specific receptors on nearby cells and induce the release of pro-inflammatory mediators.…”

Differential gene expression in anatomical compartments of the human eye

“…In support of this theory, Bardenstein et al . [31] showed that blocking the complement regulator CD59 in the rat eye precipitated massive inflammation in the anterior eye, including intense conjunctival inflammation and iritis. Our evidence that complement pathway components and regulators are highly expressed in anterior segment tissues provides further impetus for investigating their links to ocular disease.…”