Immune responses of liver-infiltrating lymphocytes and peripheral blood mononuclear cells to hepatitis C virus core and NS3 antigens.

BACKGROUND AND AIM: Th1/Th2 cytokine balance is thought to play an important role in antiviral immunity and pathogenesis in viral infection. Ex vivo hepatitis C virus (HCV) antigen-specific T-cell responses were investigated. METHODS: Using enzyme-linked immunospot assay, HCV core and NS3 antigen-specific interferon-gamma-, interleukin-4- and interleukin-10-secreting cells were enumerated in peripheral blood mononuclear cells (PBMCs) from 30 chronic hepatitis C patients and 16 healthy controls, and in liver-infiltrating lymphocytes (LILs) from 17 of the 30 patients. RESULTS: IFN-gamma- and IL-10-secreting cells in response to stimulation with HCV core and NS3 antigen were detectable in both PBMCs and LILs from patients with chronic hepatitis C, although frequencies of the cytokine-secreting cells were much higher in LILs than PBMCs. They were not detectable in PBMCs of healthy controls except for IL-10-secreting cells in response to HCV NS3 antigen stimulation. IL-4-secreting cells were hardly detectable in both PBMC and LIL in both the patients and the healthy controls. Frequencies of HCV NS3 antigen-specific IFN-gamma- and IL-10-secreting cells in PBMCs correlated with those in LILs (rho=0.599, p=0.044 and rho=0.716, p=0.004, respectively). CONCLUSIONS: These data provide further evidence of the immunomodulatory role of the CD4(+)CD25(+) regulatory T lymphocytes in chronic HCV infection.

Frequencies of interferon-gamma and interleukin-10 secreting cells in peripheral blood mononuclear cells and liver infiltrating lymphocytes in chronic hepatitis B virus infection.

Cytokine balance may play an important role in effective antiviral immunity. We determined the frequencies of interferon-gamma (IFN-gamma)-, interleukin-4 (IL-4)-, and interleukin-10 (IL-10)-secreting cells in response to HBV antigens in peripheral blood mononuclear cells (PBMCs) and liver-infiltrating lymphocytes (LILs) using an enzyme-linked immuno spot (ELISpot) assay and related them to serum ALT and HBV DNA levels, and hepatic histological findings. PBMCs were obtained from 25 patients with chronic hepatitis B, from eight of whom LILs were also obtained, and 12 healthy controls. On stimulation with hepatitis B core antigen (HBcAg), the median (range) frequencies of IFN-gamma- and IL-10-secreting cells were 25 (7-71) and 54 (26-101) cells/10(4) PBMCs, respectively, in patients with chronic hepatitis B, and 4 (0-12) and 36 (7-63) cells/10(4) PBMCs, respectively, in healthy controls. The frequencies of HBcAg-specific IFN-gamma-secreting cells in PBMCs and LILs of chronic hepatitis B patients correlated with serum ALT levels. Those of LILs correlated with serum ALT levels and HAI scores. In conclusion, HBcAg-specific IFN-gamma-secreting cells may play a role in liver damage in chronic HBV infection. Excessive IL-10 production by PBMCs and LILs in response to HBcAg may suppress antiviral immune responses and contribute to persistent infection.

Delayed enhanced hepatosplenic sarcoid nodules on computed tomography in an interferon-naïve hepatitis C patient: a case report and review of the literature.

A 77-year-old woman with chronic type C hepatitis was diagnosed with hypoechoic hepatosplenic nodules on ultrasonography. These lesions showed low density on precontrast computed tomography and delayed enhancement. Judging from laboratory data and images, the nodules were considered unlikely to represent malignancies and were followed conservatively. The hepatic lesions then increased in size and number. Sarcoidosis was diagnosed following liver biopsy. All nodules disappeared spontaneously within 6 years. Although some cases of interferon-induced sarcoidosis in patients with chronic hepatitis C or hepatitis C virus (HCV)-related cirrhosis have been reported recently, interferon-naïve cases are relatively rare. Delayed enhancement on computed tomography may reflect fibrosis of hepatic sarcoid lesions that have been histologically confirmed. Gastroenterologists managing patients with chronic HCV infection need to keep such cases in mind.

Severe myelosuppression following alopecia shortly after the initiation of 6-mercaptopurine in a patient with Crohn's disease.

A 15-year-old, woman, Crohn's disease patient, who carried the TPMT *3C heterozygous mutant, complained of alopecia 3 days after starting 6-mercaptopurine (6-MP) and then developed severe myelosuppression 6 weeks after starting 6-MP. The alopecia involved scalp hair only (body hair preserved) and was dominant in the temporal region. Following these side effects, transient remission of Crohn's disease occurred. Myelosuppression due to 6-MP is a rare but life-threatening side effect that is difficult to predict despite continuous monitoring of complete blood cell counts. In the present case, 6-MP-induced alopecia preceded myelosuppression and progressed rapidly as the myelosuppression worsened.

Ventricular fibrillation during colonoscopy: a case report--colonoscopy in high-risk patients should be performed with ECG monitoring.

While ventricular premature contractions have been noted during colonoscopy (CS), ventricular fibrillation (VF) is rare. We recently had a patient who developed VF during CS and recovered without any sequelae despite severe complications after cardiopulmonary resuscitation (CPR). If electrocardiogram (ECG) monitoring had been done during CS, a direct current shock defibrillation could have been accomplished and prevented complications. CS in high-risk patients should be done with ECG monitoring.

Identification of novel hepatitis C virus-specific cytotoxic T lymphocyte epitopes by ELISpot assay using peptides with human leukocyte antigen-A*2402-binding motifs.

The human leukocyte antigen (HLA)-A*2402 is common in Asians. The authors attempted to identify epitopes for HLA-A*2402-restricted, hepatitis C virus (HCV)-specific CD8(+) T cells by an enzyme-linked immunospot (ELISpot) assay using peripheral blood CD8(+) T cells from HLA-A*2402-positive hepatitis C patients and synthetic HCV peptides based on HLA-A*2402-binding motifs and the amino acid sequence of type 1b HCV. Ten novel epitopes were identified in five of seven HLA-A*2402-positive patients with acute or short-term chronic HCV infection (<3 years), but in none of four with longer-term chronic infection (>10 years). Only one of the ten epitopes proved to be definitely HLA-A*2402-restricted. Another epitope was identified in one of two HLA-A*2402-negative acute hepatitis C patients. In two of the six patients with positive CD8(+) T cell responses, the targeted epitopes were multiple. The same epitope was targeted in two patients. When patients with unresolved acute HCV infection were treated with alpha interferon, peripheral blood HCV-specific CD8(+) T cells decreased with resolution of the hepatitis. In conclusion, CD8(+) T cell responses to HCV infection are heterogeneous. One definite HLA-A*2402-restricted and ten probably non-HLA-A*2402-restricted epitopes were identified. Patients with short-term HCV infection are suitable for searching for novel HCV epitopes, but peripheral blood HCV-specific CD8(+) T cells decrease markedly after loss of antigenic stimulation.