Manifestations of viral infections can differ between women and men 1 , and significant sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral load levels early in HIV-1 infection, but progress faster to AIDS for a given viral load than men 2-7 . Here we demonstrate substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce significantly more interferon-α (IFN-α) in response to HIV-1-encoded TLR7 ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naïve chronically HIV-1-infected women had significantly higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs can account for higher immune activation in women compared to men at a given HIV-1 viral load, and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a novel approach to reduce HIV-1-associated pathology. According to UNAIDS, almost half of all HIV-1-infected individuals worldwide are women. Studies comparing the course of HIV-1 infection between women and men have demonstrated significant sex differences in the manifestations of HIV-1 disease. While HIV-1-infected women present with lower viral load early in HIV-1 infection, women with the same HIV-1 viral load as men have a 1.6-fold higher risk of developing AIDS 2-7 . The mechanisms underlying these significant sex differences in the manifestation of HIV-1 disease are not understood. NIH Public AccessThere is increasing consensus that the level of immune activation in HIV-1-infected subjects is a strong independent predictor for HIV-1 disease progression [8][9][10][11][12][13][14][15][16] . Plasmacytoid dendritic cells (pDCs) play a central role in this HIV-1-induced activation of the immune system, as they can sense HIV-1 ssRNA via Toll-like receptor (TLR)7 [17][18][19][20] . Interestingly, PBMCs derived from women have been shown to produce significantly more IFN-α in response to the synthetic TLR7 ligand Imiquimod than PBMCs derived from men 21 . We therefore reasoned that sex differences in HIV-1-induced immune activation might be responsible for the observed differences in HIV-1 disease, and investigated differences in cytokine production by PBMC in response to HIV-1 between men and women, and their consequences for T cell activation.Intracellular cytokine staining (ICS) using multiparameter flow cytometry was performed to quantify the percentage of pDCs producing IFN-α or TNF-α after stimulation with HIV-1-derived TLR7/8 ligands, TLR9 ligand ODN2216 (CpG-A), or inactivated HIV-1 virus (AT-2 virus) (Fig. 1). A significantly higher percentage of pDCs derived from women produced IFN-α in response to HIV-1-derived TLR ligands or AT-2 viru...

Corneal neovascularization (NV) is a sight-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface. It has been shown in the field of cancer angiogenesis research that a balance exists between angiogenic factors (such as fibroblast growth factor and vascular endothelial growth factor) and anti-angiogenic molecules (such as angiostatin, endostatin, or pigment epithelium derived factor) in the cornea. Several inflammatory, infectious, degenerative, and traumatic disorders are associated with corneal NV, in which the balance is tilted towards angiogenesis. The pathogenesis of corneal NV may be influenced by matrix metalloproteinases and other proteolytic enzymes. New medical and surgical treatments, including angiostatic steroids, nonsteroidal inflammatory agents, argon laser photocoagulation, and photodynamic therapy have been effective in animal models to inhibit corneal NV and transiently restore corneal "angiogenic privilege."

Corneal neovascularization is a serious condition that can lead to a profound decline in vision. The abnormal vessels block light, cause corneal scarring, compromise visual acuity, and may lead to inflammation and edema. Corneal neovascularization occurs when the balance between angiogenic and antiangiogenic factors is tipped toward angiogenic molecules. Vascular endothelial growth factor (VEGF), one of the most important mediators of angiogenesis, is upregulated during neovascularization. In fact, anti-VEGF agents have efficacy in the treatment of neovascular age-related macular degeneration, diabetic retinopathy, macular edema, neovascular glaucoma, and other neovascular diseases. These same agents have great potential for the treatment of corneal neovascularization. We review some of the most promising anti-VEGF therapies, including bevacizumab, VEGF trap, siRNA, and tyrosine kinase inhibitors.

Increased IFNα production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFNα upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. Here, we show that basal levels of interferon regulatory factor 5 (IRF5) in pDCs were significantly higher in females compared to males and positively correlated with the percentage of IFNα-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFNα secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced IRF5 mRNA expression in pDCs and IFNα production. IRF5 mRNA levels furthermore correlated with Esr1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by Esr1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFNα production upon TLR7 stimulation in females, and provide novel targets for the modulation of immune responses and inflammation.

Background Angiogenesis is the process of neovascularization from pre-existing vasculature and is involved in various physiological and pathological processes. Inhibitors of angiogenesis, administered either as individual drugs or in combination with other chemotherapy, have been shown to benefit patients with various cancers. Endostatin, a 20-kDa C-terminal fragment of type XVIII collagen, is one of the most potent inhibitors of angiogenesis. Scope of review We discuss the biology behind endostatin in the context of its endogenous production, the various receptors to which it binds, and the mechanisms by which it acts. We focus on its inhibitory role in angiogenesis, lymphangiogenesis, and cancer metastasis. We also present emerging clinical applications for endostatin and its potential as a therapeutic agent in the form a short peptide. Major conclusions The delicate balance between pro- and anti-angiogenic factors can be modulated to result in physiological wound healing or pathological tumor metastasis. Research in the last decade has emphasized an emerging clinical potential for endostatin as a biomarker and as a therapeutic short peptide. Moreover, elevated or depressed endostatin levels in diseased states may help explain the pathophysiological mechanisms of the particular disease. General significance Endostatin was once sought after as the ‘be all and end all’ for cancer treatment; however, research throughout the last decade has made it apparent that endostatin’s effects are complex and involve multiple mechanisms. A better understanding of newly discovered mechanisms and clinical applications still has the potential to lead to future advances in the use of endostatin in the clinic.

PURPOSE. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro.METHODS. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Widefield stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth.RESULTS. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001).CONCLUSION. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production. (Invest Ophthalmol Vis Sci.

Hepatitis B virus (HBV) infection is a non-cytopathic hepatotropic virus that can lead to severe liver disease including acute hepatitis, cirrhosis and hepatocellular carcinoma. Successful clearance of the virus as well as the establishment of liver disease is largely driven by a complex interaction between the virus and the host immune response. In this review, the immunological events, including both the innate and adaptive immune response are discussed in the setting of both acute and chronic HBV infection and liver disease.

Engagement of the T cell antigen receptor (TCR) leads to rapid activation of protein tyrosine kinases, which in turn phosphorylate downstream enzymes and adapter proteins. Some adapter proteins, such as SLP-76, Vav, and LAT, positively regulate TCR-mediated signal transduction, whereas others, such as Cbl, play an inhibitory role. SLAP (Src-like adapter protein), an adapter protein containing a Src homology 3 and a Src homology 2 domain, was isolated from a yeast interacting screen by using N-terminal Cbl as bait. N-terminal Cbl interacts with SLAP in vivo and in vitro in a tyrosine phosphorylation-independent manner. We observed that SLAP is expressed in T cells, and upon TCR activation, SLAP interacts with ZAP-70, Syk, LAT, and TCR chain in Jurkat T cells. In transiently transfected COS-7 cells, SLAP forms separate complexes with ZAP-70, Syk, and LAT through its Src homology 2 domain. Overexpression of a C-terminal-truncated SLAP mutant down-regulates nuclear factor of activated T cells-AP1 activity. We have evidence that SLAP forms homodimers through its C-terminal region. Serial truncations and mutations in the C terminus of SLAP demonstrate that there is a correlation between the loss of dimerization and the inhibition of nuclear factor of activated T cells-AP1 activity. The in vivo association of SLAP with key signaling molecules and its inhibition of T cell activation suggests that SLAP plays an important role in TCR-mediated signal transduction.