H epatitis B, caused by hepatitis B virus (HBV) infection, is very common in Asia, Africa, and the Middle East. It is estimated that there are 280 million carriers worldwide, representing more than 5% of the global population. Chronic infection with HBV is a major risk factor for the development of hepatocellular carcinoma (HCC); however, the mechanism by which HBV induces events leading to HCC has not been clearly elucidated. The HBV genome consists of four overlapping open reading frames encoding DNA polymerase, surface antigen, core protein, and a regulatory X protein [hepatitis B virus X protein (HBx)].

Experimental autoimmune encephalomyelitis (EAE) is mediated by Th1 and Th17 cells. Invariant NKT (iNKT) cells prevent EAE in an IL-4–, IL-10–, and IFN-γ–dependent manner. However, which of the iNKT cell-produced cytokines regulates the Th1 or Th17 response in EAE remains unclear. Wild-type B6 and Jα18−/− mice were immunized with MOG35–55 peptide to address this issue. Clinical scores for EAE, IL-17, and IFN-γ transcript levels, and IL-17– or IFN-γ–expressing CD4+ T cell percentages in the CNS and draining lymph nodes were higher in Jα18−/− than in B6 mice, but all of these parameters in the CNS were reduced by the adoptive transfer of wild-type or IFN-γ–deficient iNKT cells into the Jα18−/− mice before immunization. In contrast, adoptive transfer of IL-4– or IL-10–deficient iNKT cells into Jα18−/− mice decreased IL-17 transcript levels and the percentage of IL-17–expressing CD4+ T cells in the CNS but did not affect clinical scores, IFN-γ transcript levels, or the percentage of IFN-γ–expressing CD4+ T cells in the CNS. Taken together, IL-4– and IL-10–producing iNKT cells inhibit the Th1 cell response, but not the Th17 cell response, although wild-type iNKT cells suppress both the Th1 and Th17 responses in the CNS during EAE. Moreover, IFN-γ–producing iNKT cells have a minimal role in the regulation of the Th1 and Th17 responses in EAE.

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Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic protein that plays a defensive role in bacterial infection by sensing peptidoglycans. C5a, which has harmful effects in sepsis, interacts with innate proteins. However, whether NOD2 regulates C5a generation during sepsis remains to be determined. To address this issue, cecal ligation & puncture (CLP)-induced sepsis was compared in wild type and Nod2−/− mice. Nod2−/− mice showed lower levels of C5a, IL-10, and IL-1β in serum and peritoneum, but higher survival rate during CLP-induced sepsis compared to wild type mice. Injection of recombinant C5a decreased survival rates of Nod2−/− mice rate during sepsis, whereas it did not alter those in wild type mice. These findings suggest a novel provocative role for NOD2 in sepsis, in contrast to its protective role during bacterial infection. Furthermore, we found that NOD2-mediated IL-10 production by neutrophils enhanced C5a generation by suppressing CD55 expression on neutrophils in IL-1β-dependent and/or IL-1β-independent manners, thereby aggravating CLP-induced sepsis. SB203580, a receptor-interacting protein 2 (RIP2) inhibitor downstream of NOD2, reduced C5a generation by enhancing CD55 expression on neutrophils, resulting in attenuation of polymicrobial sepsis. Therefore, we propose a novel NOD2-mediated complement cascade regulatory pathway in sepsis, which may be a useful therapeutic target.

HP results from the repeated inhalation of environmental antigens; however, the roles of CD4(+)CD25(+) T(reg) cells in HP are unknown. Therefore, we investigated the functions of CD4(+)CD25(+) T(reg) cells in SR-induced murine HP. More severe HP was observed in CD4(+)CD25(+) T(reg) cell-depleted mice than in control mice in terms of histological alterations, inflammatory cell numbers in BALF, and the serum level of SR-specific IgG, which were restored by the adoptive transfer of CD4(+)CD25(+) T(reg) cells. The CD4(+)CD25(+) T(reg) cell-depleted mice also showed elevated levels of IFN-gamma, TGF-beta, and reduced IL-4 production in the lungs. Moreover, IL-10 production of CD4(+)CD25(+) T(reg) cells and direct contact between CD4(+)CD25(+) T(reg) cells and CD4(+) or CD8(+) T cells in BALF resulted in reduced IFN-gamma production. Taken together, CD4(+)CD25(+) T(reg) cells play a protective role in SR-induced HP by suppressing IFN-gamma production by T cells.