A Role for IFN-ɛ: Type I interferons (IFNs) are critical cytokines involved in host defense against pathogens, particularly viruses. IFN-ɛ is an IFN-like gene encoded within the type I IFN locus in mice and humans whose function has not been characterized. Fung et al. (p. 1088 ) created mice with a genetic deletion in Ifn -ɛ and found that, like other type I IFNs, IFN-ɛ signals through the IFN-α receptors 1 and 2. However, unlike these other cytokines, which are primarily expressed by immune cells and are induced upon immune cell triggering, IFN-ɛ was expressed exclusively by epithelial cells of the female reproductive tract in both mice and humans and its expression was hormonally regulated. IFN-ɛ–deficient mice were more susceptible to infection with herpes simplex virus 2 and Chlamydia muridarum , two common sexually transmitted pathogens.

Following ocular infection, herpes simplex virus type 1 (HSV-1) establishes latency in trigeminal ganglion (TG) neurons. Using reverse transcription-PCR, cytokine gene expression was analyzed in the TGs of mice infected with HSV-1. IL-2, TNF-alpha, IFN-gamma, IL-10, and RANTES mRNAs were readily detected in TGs taken from mice 7 days postinoculation (PI). Likewise, IL-2, IL-6, IL-10, and IFN-gamma protein were detected by ELISA of TG homogenates. Between 5 and 45 days PI, IL-10, IFN-gamma, TNF-alpha, and RANTES mRNAs were detected in nearly 100% of latently infected TGs (latent infection was confirmed by reverse transcription-PCR detection of HSV-1 latency-associated transcripts). T cell-associated cytokine and chemokine mRNAs (IL-2, IL-10, IFN-gamma, and RANTES) were still detected in the majority of latently infected TG samples taken between 60 and 135 days PI. In contrast, these cytokine mRNA species were rarely detected in uninfected TGs. Measurement of serum Abs to HSV-1 at different times revealed that anti-HSV-1 Ab concentrations approached a plateau in mice by 30 days PI but remained at high levels 67 and 125 days PI. Although there was molecular evidence of an ongoing immune response to HSV-1 in latently infected TG, histologic analysis indicated that very few mononuclear cells remained in the ganglion 60 days PI. Collectively, the results suggest that residual lymphocytes encounter viral Ag during HSV-1 latency with sufficient frequency to remain activated. The paradox of a persistent immune response against a latent infection is discussed.

Inflammatory lymphangiogenesis plays a crucial role in the development of inflammation and transplant rejection. The mechanisms of inflammatory lymphangiogenesis during bacterial infection, toll-like receptor ligand administration, and wound healing are well characterized and depend on ligands for the vascular endothelial grow factor receptor (VEGFR) 3 that are produced by infiltrating macrophages. But inflammatory lymphangiogenesis in nonlymphoid tissues during chronic viral infection is unstudied. Herpes simplex virus 1 (HSV-1) infection of the cornea is a leading cause of blindness and depends on aberrant host immune responses to antigen within the normally immunologically privileged cornea. We report that corneal HSV-1 infection drives lymphangiogenesis and that corneal lymphatics persist past the resolution of infection. The mechanism of HSV-1–induced lymphangiogenesis was distinct from the described mechanisms of inflammatory lymphangiogenesis. HSV-1–elicited lymphangiogenesis was strictly dependent on VEGF-A/VEGFR-2 signaling but not on VEGFR-3 ligands. Macrophages played no role in the induction of lymphangiogenesis and were not a detectable source of VEGF-A. Rather, using VEGF-A reporter transgenic mice, we have identified infected epithelial cells as the primary source of VEGF-A during HSV-1 infection. Our results indicate that HSV-1 directly induces vascularization of the cornea through up-regulation of VEGF-A expression.

Objective: The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late‐stage chronic arthritis in mice with type II collagen–induced arthritis (CIA).Methods: We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin‐10 (IL‐10), IL‐4, tumor necrosis factor α (TNFα), and interferon‐γ (IFNγ) were determined.Results: Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL‐10 and IL‐4 and unchanged levels of TNFα and IFNγ compared with those from untreated animals. This indicates an immune‐stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNFα and IFNγ compared with those from nonsympathectomized controls with CIA. This indicates an immune‐depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01).Conclusion: The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.