Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30 -50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.angiogenesis ͉ inflammation ͉ injury A ge-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries (1). The majority of vision loss due to AMD is a result of pathologic new blood vessels, termed choroidal neovascularization (CNV), invading the retina from the underlying choroid through fractures in Bruch membrane, the extracellular matrix between the choroid and the retinal pigmented epithelium (RPE). The earliest clinical hallmark of AMD is the appearance of drusen (2), localized lipoproteinaceous deposits between the RPE and Bruch membrane. Although their presence is an epidemiological risk factor for the development of CNV (3, 4), the mechanism of how, or whether, drusen provoke CNV remains undefined. Some investigators have suggested that drusen are epiphenomena, whereas others have claimed that drusen constituents act as a focal stimulus for inflammatory cells that secrete angiogenic molecules such as VEGF, and still others have suggested that drusen disturb RPE homeostasis by impairing transport across Bruch membrane (reviewed in ref. 5).Recent work has demonstrated that complement components C3 and C5 are constituents of drusen in patients with AMD (6-9). Their presence, as well as that of the membrane-attack-complex (MAC) C5b-9 and other acute-phase reactant proteins in RPE cells overlying drusen, ha...

In the CNS, the transcription factor NF-κB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-κB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-κB (glial fibrillary acidic protein-IκBα-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8+CD122+ T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuro-protective mechanisms. Our data indicate that inhibiting NF-κB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.

Keywords: Blood-brain barrier r CD4 + effector/memory T (T EM ) cells r Diapedesis r EAE r ICAM-1Additional supporting information may be found in the online version of this article at the publisher's web-site

The complement cascade has long been recognized to play a key role in inflammatory and degenerative diseases. It is a ‘double edged’ sword as it is necessary to maintain health, yet can have adverse effects when unregulated, often exacerbating disease. The contrasting effects of complement, depending on whether in a setting of health or disease, is the price paid to achieve flexibility in scope and degree of a protective response for the host from infection and injury. Loss or even decreased efficiency of critical regulatory control mechanisms can result in aggravated inflammation and destruction of self-tissue. The role of the complement cascade is poorly understood in the nervous system and neurological disorders. Novel studies have demonstrated that the expression of complement proteins in brain varies in different cell types and the effects of complement activation in various disease settings appear to differ. Understanding the functioning of this cascade is essential, as it has therapeutic implications. In this review, we will attempt to provide insight into how this complex cascade functions and to identify potential strategic targets for therapeutic intervention in chronic diseases as well as acute injury in the CNS.

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, immunological synapse formation and, numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane bound and soluble ICAM-1 isoforms which arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types is poorly understood. In the generation of ICAM-1-deficient mice, two isoform-deficient ICAM-1 mutants were inadvertently produced due to alternative splicing. These mice along with true ICAM-1-deficient mice and newly generated ICAM-1 transgenic mice have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis.