To dampen demyelination

2 JEM Vol. 207, No. 1, 2010 Dementia’s inflammatory link Inflamed brains pose a danger to themselves, according to a report by Yin and colleagues that identifies a potential link between the immune system and neurodegenerative disease. Mutations that diminish expression of the protein progranulin cause frontotemporal dementia in humans. Progranulin is involved in various processes, including inflammation suppression, wound healing, embryonic development, and tumorigenesis. But its role in dementia has remained mysterious. Here, Yin et al. show that progranulin may prevent brain cell damage in part by promoting the expression of the anti-inflammatory cytokine IL-10. In response to Listeria infection, mice that lacked progranulin produced little IL-10 and lots of inflammatory cytokines, including the monocyte chemoattractant MCP-1. Yet despite the elevated response, fewer monocytes were deployed to infected sites, and the mice eventually succumbed to infection. Senior author Aihao Ding explains these counterintuitive results by saying that if alarms were blaring everywhere, police (i.e., monocytes and other leukocytes) wouldn’t know where to head. Two-pronged attack on HIV The antiretroviral factor A3G does more than mutate HIV, report Casartelli and colleagues. It hastens the deployment of cytotoxic T cells. A3G (short for APOBEC3G) is a restriction enzyme that inhibits HIV replication by introducing mutations into the viral genome. The team found that this editing strengthens the HIV-specific cytotoxic T lymphocyte (CTL) response. When HIV-infected cells expressed A3G, truncated viral peptides were loaded onto MHC class I machinery and were efficiently presented to HIV-specific CD8 + T cells. Wild-type HIV strains elicited a weaker response than strains missing their A3G-degrading weapon, the protein Vif. Although interferons in the innate arm of the immune system set off A3G, the authors show that the protein’s enzymatic activity is critical for optimizing adaptive immunity. To explain why imperfect viral peptides enhanced cytotoxic T cell activity, the authors invoked the controversial DRiP (defective ribosomal products) hypothesis, which predicts that most antigenic peptides originate from truncated proteins that degrade rapidly and enter into the MHC class I antigen–processing pathway. In fact, HIV made to artificially express severed Gag proteins, like those altered by A3G, enhanced CD8 + T cell activation. The control A3G has over HIV may help account for why the disease does not affect people equally. It’s possible that elite controllers—HIV-infected individuals who successfully suppress the virus—may have an A3G polymorphism to thank. However, the correlation between their polymorphisms and their CTL response has yet to be investigated. How herpes launches lymphatics Herpes simplex virus 1 (HSV-1) provokes lymph vessel overgrowth in the eye by triggering an unexpected growth factor, report Wuest and Carr. And this cascade could be blinding. Although HSV-1 infects 50–90% of people worldwide, it rarely causes substantial harm. Occasionally, however, the virus sneaks into the cornea during periods of reactivation, obscuring vision or causing blindness. The inflammatory response provoked by the infection includes new blood vessel growth, which may be partly to blame for the resulting eye damage. Clinical evidence suggests that new lymph vessels may also appear during HSV-1 eye infections. VEGF growth factors drive inflammatory lymph vessel growth in other situations, such as wound healing and bacterial infection. In these situations, infiltrating macrophages secrete VEGF-C and -D, which bind to the VEGFR-3 receptor to trigger new lymph vessels. Here, Wuest and Carr find that HSV-1 induces lymph vessel growth without help from macrophages or the usual VEGF middlemen. Instead, HSV-1–infected epithelial cells drove vessel growth by secreting VEGF-A. The new lymph vessels persisted after viral replication ceased and also remained functional, as soluble antigens drained from the cornea into the draining lymph nodes. Blossoming vessels could escalate inflammation by allowing antigens access to draining lymph nodes. Nevertheless, HSV-1 may be wise to exploit VEGF-A. The factor blocks dendritic cell maturation, perhaps helping the virus to evade the ensuing immune attack.