sq-23377 and Hepatitis-E

Hepatitis E virus (HEV) infection is endemic in several developing countries. Clinical manifestations of this infection vary widely from asymptomatic infection to uncomplicated acute viral hepatitis and fulminant hepatic failure. The pathogenesis of this disease and the reason of varying disease severity remain unknown. In viral infections, tissue injury can be caused either by virus itself or by host immune responses directed against infected cells. We therefore studied adaptive immune responses to HEV antigens in patients with hepatitis E of varying disease severity and healthy controls.. Cytokine secreting CD4+ T cells and antibody-producing B cells specific for HEV were enumerated through intracellular cytokine staining and enzyme-linked immunosorbent spot assay, respectively.. Patients with fulminant hepatitis E had a less marked expansion of HEV-specific interferon-γ or tumor necrosis factor-a secreting CD4+ T cells than patients with uncomplicated hepatitis E and healthy controls. These patients also had fewer CD4+ T cells that produce γ-interferon or tumor necrosis factor-a upon in vitro polyclonal stimulation. In addition, patients with fulminant disease had a more marked expansion of B cells that can secrete immunoglobulin G anti-HEV than patients with uncomplicated infection and control patients.. These findings suggest that less-marked antiviral cellular immune responses and heightened antiviral humoral responses are associated with a more severe disease during HEV infection.

Topics: Acute Disease; Adaptive Immunity; Adolescent; Adult; B-Lymphocytes; Case-Control Studies; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis Antibodies; Hepatitis E; Hepatitis E virus; Humans; Immunity, Cellular; Immunity, Humoral; Immunoglobulin G; Interferon-gamma; Ionomycin; Male; Middle Aged; Recombinant Proteins; Severity of Illness Index; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Viral Proteins; Young Adult

Hepatitis E virus (HEV) causes acute viral hepatitis and is endemic in the developing world. Few data are available on cellular immune responses in HEV infection. Using flow cytometry, we studied the frequencies of peripheral blood CD4(+) /CD8(+) T cells secreting interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-4 in 21 patients with acute hepatitis E and 18 healthy controls, after stimulation with the HEV capsid (ORF2) protein. Cytokine levels in serum specimens and culture supernatants of ORF2-stimulated peripheral blood mononuclear cells (PBMCs) were estimated in enzyme-linked immunosorbent assays. In addition, cytokine mRNA transcripts were measured in PBMCs by reverse transcription-polymerase chain reaction. In patients with acute hepatitis E, although the total CD4(+) population was expanded, the proportions of CD4(+)/CD69(+) and CD8(+) /CD69(+) cells producing IFN-gamma, TNF-alpha, and IL-4 in response to HEV ORF2 stimulation were unchanged. However, IFN-gamma levels in the supernatants and IFN-gamma mRNA transcripts in cells were elevated in ORF2-stimulated PBMCs in acute hepatitis E; levels of IL-2 or TNF-alpha were unchanged. Our findings suggest that CD4(+) IFN-gamma-secreting cells, which do not belong either to the helper T cell type 1 or type 2 phenotype, as is the case with natural killer T cells, may be involved in the pathogenesis of hepatitis E. Further, the limited immune reactivity we detected in peripheral blood cells may be related to the sequestration of immune events to the intrahepatic compartment, which is the major disease site.

Topics: Acute Disease; Cytokines; Female; Hepatitis E; Humans; Ionomycin; Male; RNA, Messenger; T-Lymphocytes; Tetradecanoylphorbol Acetate; Viral Proteins