Researchers at the National Eye Institute, Bethesda, MD, have demonstrated that C3 and CR3 proteins – components of the human innate immune system – have immunological activity to protect photoreceptor cells in retinitis pigmentosa. The new study shows that the “complement system” (a key biological process for managing normal activity for homeostasis) provides a protective role to slow retinal degeneration in a mouse model of retinitis pigmentosa (called rd10). According to the research, published by the Journal of Experimental Medicine (http://doi.org/10.1084/ jem.20190009), the authors stated that “genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia–photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP”.
As highlighted, the complement cascade is an innate part of the immune defence system, consisting of over 30 serum proteins. In general, substances on the surface of microbes or other infectious agents can trigger the complement cascade, which then activates a series of biochemical steps leading to the lysis of invading cells. However, certain complement proteins may also help trigger inflammation. Several components of the complement cascade have been found in drusen deposits which have led to the hypothesis that AMD may result from dysfunctional inflammation which incorporates inappropriate complement activation. A series of seminal papers over 12 years ago established an association between variants in complement genes and increased risk of AMD, findings which attracted significant attention in the search for a clinical target. The complement pathway contains three arms – classical, alternative and lectin – all of which converge on C3, potentially making the molecule a key therapeutic target. While this has been focused on the AMD biology triggering of the pathology, the current research in retinitis pigmentosa indicates that there may be a double-edge sword of the complement activity. According to one of the authors of the study “the current study involving retinitis pigmentosa underscores the notion that the complement system may in fact exacerbate or curb retinal degeneration depending on the context. Appreciating this complexity is important for guiding the development of therapies that target the complement immune system to treat degenerative diseases of the retina”.