No abstract

Hepatitis B virus (HBV) infection has a low rate of chronicity compared to HCV infection, but chronic liver inflammation can evolve to life threatening complications. Experimental data from HBV infected chimpanzees and HBV transgenic mice have indicated that cytotoxic T cells are the main cell type responsible for inhibition of viral replication, but also for hepatocyte lysis during chronic HBV infection. Their lower activation and impaired function in later stages of infection was suggested as a possible mechanism that allowed for low levels of viral replication. The lack of an interferon response in these models also indicated the importance of adaptive immunity in clearing the infection. Increased knowledge of the signalling pathways and pathogen associated molecular patterns that govern activation of innate immunity in the early stages of viral infections in general has led to a re-evaluation of the innate immune system in HBV infection. Numerous studies have shown that HBV employs active strategies to evade innate immune responses and induce immunosuppression. Some of the immune components targeted by HBV include dendritic cells, natural killer cells, T regulatory cells and signalling pathways of the interferon response. This review will present the current understanding of innate immunity in HBV infection and of the challenges associated with clearing of the HBV infection.

Monocytic cells survive HIV replication and consequent cytopathic effects because of their decreased sensitivity to HIV-induced apoptosis. However, the mechanism underlying this resistance to apoptosis remains poorly understood. Lymphocytic cells are exposed to microbial products because of their translocation from the gut in persons with chronic HIV infections or following coinfections. We hypothesized that activation of monocytic cells by such microbial products through interaction with corresponding TLRs may confer antiapoptotic signals. Using HIV-viral protein R (Vpr)(52–96) peptide as a model apoptosis-inducing agent, we demonstrated that unlike monocyte-derived macrophages, undifferentiated primary human monocytes and promonocytic THP-1 cells are highly susceptible to Vpr(52–96)-induced apoptosis. Interestingly, monocytes and THP-1 cells stimulated with TLR9 agonist CpG induced almost complete resistance to Vpr(52–96)-induced apoptosis, albeit through a TLR9-independent signaling pathway. Moreover, CpG selectively induced the antiapoptotic cellular inhibitor of apoptosis (c-IAP)-2 protein and inhibition of the c-IAP-2 gene by either specific small interfering RNA or synthetic second mitochondrial activator of caspases mimetic reversed CpG-induced resistance against Vpr(52–96)-mediated apoptosis. We demonstrated that c-IAP-2 is regulated by the JNK and calcium signaling pathway, in particular calmodulin-dependent protein kinase-II. Furthermore, inhibition of JNK and the calcium signaling including the calmodulin-dependent protein kinase-II by either pharmacological inhibitors or their specific small interfering RNAs reversed CpG-induced protection against Vpr(52–96)-mediated apoptosis. We also show that CpG induced JNK phosphorylation through activation of the calcium signaling pathway. Taken together, our results suggest that CpG-induced protection may be mediated by c-IAP-2 through the calcium-activated JNK pathway via what appeared to be TLR9-independent signaling pathways.

AimsGrading of primary ovarian mucinous carcinoma (OMC) is inconsistent among practices. The International Collaboration on Cancer Reporting recommends grading OMC using the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, when needed. The growth pattern (expansile versus infiltrative), a known prognostic variable in OMC, is not considered in any grading system. We herein analysed the prognostic value of various grading methods in a well‐annotated cohort of OMC.Methods and resultsInstitutional OMCs underwent review and grading by the Silverberg and FIGO schemes and a novel system, growth‐based grading (GBG), defined as G1 (expansile growth or infiltrative invasion in ≤10%) and G2 (infiltrative growth >10% of tumour). Of 46 OMCs included, 80% were FIGO stage I, 11% stage II and 9% stage III. On follow‐up (mean = 52 months, range = 1–190), five patients (11%) had adverse events (three recurrences and four deaths). On univariate analysis, stage (P = 0.01, Cox proportional analysis), Silverberg grade (P = 0.01), GBG grade (P = 0.001) and percentage of infiltrative growth (P < 0.001), but not FIGO grade, correlated with disease‐free survival. Log‐rank analysis showed increased survival in patients with Silverberg grade 1 versus 2 (P < 0.001) and those with GBG G1 versus G2 (P < 0.001). None of the parameters evaluated was significant on multivariate analysis (restricted due to the low number of adverse events).ConclusionsSilverberg and the new GBG system appear to be prognostically significant in OMC. Pattern‐based grading allows for a binary stratification into low‐ and high‐grade categories, which may be more appropriate for patient risk stratification. Despite current practices and recommendations to utilise FIGO grading in OMC, our study shows no prognostic significance of this system and we advise against its use.