Levels of some cytokines and antibodies to hepatitis C virus in patients with chronic hepatitis C

The comparison of the levels of some cytokines (tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-2, IL-4) in the blood serum of patients with chronic hepatitis C (CHC) having different antibody spectrum was carried out. In CHC patients increased levels of the serum cytokines IL-1beta, TNF-alpha under study in comparison with cytokine levels in donor sera was noted. In patients with detected antiNS5 and antiHCV IgM and antiNS5 HCV the level of IL-1beta was significantly higher than that in CHC patients without antibodies in sera. A change in the levels of proinflammatory and anti-inflammatory cytokines in the blood sera of CHC patients may be of significant diagnostic and prognostic importance.     

Antibody to hepatitis B core antigen in chronic active hepatitis.

Antibody to hepatitis B core antigen (anti-HBc), which has been assumed to be a more sensitive indicator of hepatitis B virus replication than hepatitis B surface antigen (HBsAg), was detected in the sera of 26 of our 65 patients with HBsAg-negative chronic active hepatitis. Thus despite the absence of HBsAg the liver disease could be the consequence of chronic infection with hepatitis B virus in these patients. They differed, however, from a group of 35 patients with HBsAg-positive hepatitis in being older on average and having less active liver lesions. The two groups could represent either two stages of chronic infection with hepatitis B virus or two types of response to it.     

Role of haemodialysis and hepatitis c virus infection in spontaneous and induced cytokine production of patients with chronic renal disease

Cytokines modulate general and virus infection-related host immune responses. We have investigated cytokine responses in chronic renal disease patients with regard to haemodialysis and hepatitis C virus (HCV) infection. Compared with healthy subjects with normal renal function (n=15), non-dialyzed/renal disease individuals without HCV infection (n=11) showed increased production of tumour necrosis factor (TNF)-alpha, interleukin (IL-)6, IL-10, interferon (IFN-)gamma and IL-12 by blood mononuclear cells (P<0.05). These inflammatory cytokine responses were abolished in haemodialysis patients (n=37;P<0.05), except for IL-12. This hyporesponsiveness in haemodialysis patients was more evident in stimulatory conditions, as shown by the consistent inhibition of IFN-gamma production, and the failure of exogenous IFN-gamma to prime for IL-12 inducibility (P<0.01). The disturbed cytokine response appeared to focus in the T-helper lymphocyte phenotype 1 (Th(1)) because the stimulation of IL-6 and IL-10 (Th(2)phenotype cytokines) was not impaired. The pattern of response was similar among haemodialysis patients with (n=24) or without (n=13) HCV infection. However, HCV-positive haemodialysis patients had a blunted TNF-alpha response (P<0.05) and failed to increase the stimulated IFN-gamma and IL-12 production (P<0.01) compared with chronic hepatitis C patients without renal disease (n=25). On the contrary, IL-10 stimulation was higher in HCV-positive haemodialysis patients (P<0.01). These results disclose the presence in haemodialysis patients of markedly abnormal general and HCV infection-related cytokine responses; the inhibitory alterations appear to affect predominantly the stimulated responses via the Th(1)subset and its relationship with monocyte response with possible pathogenic and therapeutic implications.     

Level of serum tumor necrosis factor-alpha and the degree of liver fibrosis in children with chronic viral hepatitis B,C and B+C,treated with interferon-alpha

Children with chronic virus hepatitis B and C, as well as combined chronic virus hepatitis B + C, were found to have a higher level of tumor necrosis factor-alpha (TNF-alpha) in their serum than healthy children. Complete clinical and virological response to treatment with interferon-alpha is accompanied by a decreased inflammation and fibrosis of the liver, as well as by a decreased level of TNF-alpha, in comparison with nonresponsive patients. Positive correlation between the level of TNF-alpha and the degree of liver fibrosis in sick children was noted.     

Antibodies to the RNase H domain of hepatitis B virus P protein are associated with ongoing viral replication.

Antibodies against the RNase H domain of human hepatitis B virus P protein(s) are frequent markers of acute and chronic virus infection (T. Weimer, K. Weimer, Z.-X. Tu, M.-C. Jung, G. R. Pape, and H. Will, J. Immunol. 143:3750-3756, 1989). In the present study, these antibodies were determined in serial serum samples of experimentally infected chimpanzees and naturally infected human patients with acute and chronic hepatitis B virus infection. Anti-P antibodies were found in the sera of both chimpanzees and humans early in infection shortly after the immunoglobulin M anti-HBc response; they persisted in chronic carriers with ongoing viral replication but declined and disappeared at the time of virus clearance from the sera. These data demonstrate that antibodies to the RNase H domain of the hepatitis B virus P protein are early markers of infection and a signal of ongoing virus replication. Falling titers indicate the decline or end of active virus production and may therefore be a prognostic sign of virus elimination in natural infection and after antiviral therapy.     

Level of Tx1- and Tx2-type cytokines in blood sera of hepatitis C patients

The content of cytokines of type Tx1 (IL-2 and IFN-gamma) and type Tx2 (IL-4) in blood sera of 132 patients with hepatitis C and the combined form of hepatitis B + C was studied. For control, blood sera taken from healthy donors were used. A significant increase, in comparison with the control, in the content of IL-4 in all subgroups of the patients was registered. The content of IFN-gamma reached the maximum level in patients with acute hepatitis C with the positive result of the polymerase chain reaction (PCR) for the virus (216.4 and 46.4 pg/ml respectively) and was somewhat lower in acute hepatitis C with the negative PCR-result (77.7 and 9.6 pg/ml), mean while in the chronic course of hepatitis C these data were within the limits of control values irrespective of the results of PCR. In case of mixed infection in the acute clinical form a significant increase in the concentration of IFN-gamma (34.4 pg/ml) in comparison with the control (25.3 pg/ml) was observed. The content of IFN-gamma in patients with acute hepatitis C and the positive result of the test for NS antibodies also reached the maximum level (207.3 and 42.7 pg/mg respectively). But in contrast to hepatitis C in the acute form with the negative results of PCR in patients with hepatitis C in the acute form and the negative results of the NS test these data were within the limits of control values, as well as in the chronic course of hepatitis C irrespective of the results of the NS antibodies serum test. In case of mixed infection a significant increase in the concentration of IFN-gamma was registered in the subgroup of patients with the acute form of NS+ (39.9 pg/ml). The data obtained in this study were indicative of significant changes in the serum profile of serum cytokines of types Tx1 and Tx2 in different forms and courses of virus hepatitis. This makes it possible to believe that the chronization of the process was associated with the prevalence of the Tx2 function.     

Kinetics of cytokine profile during intraperitoneal inoculation of Japanese encephalitis virus in BALB/c mice model

Infection with Japanese encephalitis virus (JEV) is mostly asymptomatic/subclinical in 90% of the individuals. Host immune response during subclinical JEV infection is poorly understood. We assessed iNOS, IFN-gamma, TNF-alpha, IL-10 and IL-4 production in spleen, brain and sera of intraperitoneally challenged BALB/c mice by RT-PCR and ELISA along with brain histopathology at different days post inoculation (d.p.i.). In spleen of virus infected mice, expression of all cytokines including iNOS mRNA were upregulated till 5d.p.i. followed by decline. At 5d.p.i., IL-10 expression outcompeted TNF-alpha, IFN-gamma and IL-4. However, in the virus infected mice sera, IL-4 production predominated over TNF-alpha and IL-10 at 5d.p.i. Conversely, cytokines expression and iNOS mRNA remained unchanged in the brain of virus infected mice from 1 to 7d.p.i. A significant increase in the cytokine expression was observed at 11d.p.i. (P<0.05) in virus infected mice brain, with the predominance of IL-10 along with the presence of meningeal inflammation and viral RNA by histology and RT-PCR, respectively. We report a biased pattern of cytokine production in sera, brain and spleen of mice intraperitoneally challenged with JEV. IL-10 exerts neuroprotective function during JEV and regulates deleterious effects of proinflammatory cytokines; however, its mechanism needs further investigation.     

Serum levels of interleukin-12 in various clinical states with hepatitis B virus infection

Hepatitis B virus (HBV) infection involves various clinical states. Interleukin-12 (IL-12) has been identified as a crucial cytokine in the development of cellular immunity. But the association between HBV infection clinical states and cellular immunity response remains unclear. The aim was to explore the association by investigating serum levels of IL-12. Observed in acute hepatitis B, the highest serum levels of IL-12 was accompanied by HBeAg seroconversion. Serum levels of IL-12 was associated with alanine transaminase (ALT) levels and significant more in chronic hepatitis B patients with ALT over five times upper limit of normal and a minority of immune-tolerance patients than controls. Serum levels of IL-12 may be an available marker to evaluate cellular immunity for HBV infection. Elevation in IL-12 levels may be a factor to promote HBeAg seroconversion and an opportunity to be given antivirus treatment for immune-tolerance carriers.     

Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation

Antiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-alpha production in monocytes. Degradation of I-kappa B alpha suggested involvement of NF-kappa B activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-alpha and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients' DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.     

病毒性肝炎患者抗—HBcIgA 、IgE 、IgG 、IgM 平行检测的临床意义

目的：通过对乙肝病人血清抗-HBcIgA、HBcIgE、HbcIgc、HbcIgM平行检测进一步地探讨其临床应用价值。方法：收集216份乙肝病人血清（均为我院住院病人的血清）,采用ELISA法对病人血清抗-HBcIgA、HBcIgE、HBcIgc、HBcIgM平行检测,并对检测结果作统计学分析。结果：检测结果表明：抗-HBcIgA是HBV感染后肝脏损害的明显标志,抗-HBdgE是HBV感染后乙型肝炎慢性化的标志,抗-HBcIgG持续存在则是以往感染的标志,抗-HBcIgM是HBV感染后病毒持续复制的标志。结论：在急慢性乙型肝炎、慢活肝与慢迁肝鉴别诊断中,平行检测病人血清抗-HBcIgA、HBcIgE、HbcIgG、HbcIgM对乙型肝炎慢性化及其预后估价均有重要临床意义。     

长效干扰素对CHB患者CD4^＋T细胞ICOS表达及血清IFN-γ、IL-4水平的影响

目的探讨长效干扰素对慢性乙型肝炎患者外周血CD4^＋T细胞上ICOS表达及血清IFN-γ、IL-4水平的影响。方法慢性乙型肝炎患者52例,其中聚乙二醇干扰素α2a治疗28例,常规治疗24例,另征集健康志愿者20例为正常对照组。采集治疗前及治疗后24、48周的患者外周血,以FCM检测ICOS^＋CD4^＋T细胞在PBMC中的频数变化;以ELISA检测治疗前后患者血清中IFN-γ、IL-4的水平变化;以Realtime—PCR检测患者HBV—DNA载量变化。结果慢性乙肝患者CD4^＋T细胞ICOS表达水平明显高于正常对照者（P〈0．001）,干扰素治疗者48周时ICOS表达水平低于常规治疗者,差异有统计学意义（P〈0．01）。经干扰素治疗后,患者Th1细胞因子IFN-γ水平升高,与常规治疗者相比有差异有统计学意义（P〈0．001）;而Th2细胞因子IL-4水平逐渐降低,与常规治疗者相比差异有统计学意义（P〈0．001）。干扰素治疗者ICOS、HBV-DNA载量变化值同IFN-γ水平的变化值呈负相关（P〈0．001）,而与IL4水平的变化值则为正相关（P〈0．001）。结论慢性乙肝患者存在着细胞免疫紊乱,干扰素治疗可以在一定程度纠正患者体内的Th2偏移,降低CD4^＋T细胞上ICOS的表达,促进IFN-γ表达,发挥抗病毒作用。     

Alcohol as a pathological factor for patients with acute and chronic viral hepatitis and liver cirrhosis

The investigations have shown presence of HBsAg in the blood sera of 4% of alcohol abusers and in 17.7% of chronic alcoholics. Among 274 patients with acute viral hepatitis A, more than 50% abuse alcohol. The study has revealed that the lipid spectrum has its specific features in hepatitis patients abusing alcohol and chronically addicted to it. Among patients with chronic persistent hepatitis and cirrhosis of the liver, the combined effects of hepatitis B virus and alcohol have been revealed in 50%.     

Detection of hantaviral antibodies among patients with hepatitis of unknown etiology in Japan

Hantaviral antibodies were detected in the sera from patients with hepatic disease of unknown etiology in Japan by several different serological diagnostic methods. A total of 105 sera from diseased patients which were negative to A-G hepatitis virus infections in the Tokyo area were tested. Among them, 3 out of 73 sera from patients with chronic hepatic disease were positive to hantaviral antibody by enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescent antibody assay (IFA) and Western blot analysis (WB). Neutralizing antibody titers of the 3 sera to Seoul virus (SEO) were 4 to 8 times higher than those to Hantaan virus (HTN). However, all of the 32 sera from patients with acute hepatitis were negative for hantaviral antibody. Among the 60 patients with chronic hepatitis in Hokkaido which were serologically negative to B and C hepatitis virus infection, one was positive for hantaviral antibody by ELISA and WB. In contrast, the sera from healthy adults in Japan, 550 from the Honshu and Kyushu regions, and 1,000 from the Hokkaido region, were negative for hantavirus antibody. These results show that hantaviral antibodies are more frequently detected in patients with hepatic disease than in healthy adults. However, the observation that no positive sera were detected from patients with acute hepatitis implies that hantavirus might not be directly related to hepatitis.     

Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication

The interferon (IFN)-related cytokine interleukin (IL)-29 (also known as IFN-lambda1) inhibits virus replication by inducing a cellular antiviral response similar to that activated by IFN-alpha/beta. However, because it binds to a unique receptor, this cytokine may function cooperatively with IFN-alpha/beta or IFN-gamma during natural infections to inhibit virus replication, and might also be useful therapeutically in combination with other cytokines to treat chronic viral infections such as hepatitis C (HCV). We therefore investigated the ability of IL-29 and IFN-alpha or IFN-gamma to cooperatively inhibit virus replication and induce antiviral gene expression. Compared with the individual cytokines alone, the combination of IL-29 with IFN-alpha or IFN-gamma was more effective at blocking vesicular stomatitis virus and HCV replication, and this cooperative antiviral activity correlated with the magnitude of induced antiviral gene expression. Although the combined effects of IL-29 and IFN-alpha were primarily additive, the IL-29/IFN-gamma combination synergistically induced multiple genes and had the greatest antiviral activity. Two different mechanisms contributed to the enhanced gene expression induced by the cytokine combinations: increased activation of ISRE promoter elements and simultaneous activation of both ISRE and GAS elements within the same promoter. These findings provide new insight into the coregulation of a critical innate immune response by functionally distinct cytokine families.     

Cytokine responses differ by compartment and wasting status in patients with HIV infection and healthy controls

Inflammatory cytokines are implicated in the loss of lean tissue that occurs in patients with inflammatory and infectious diseases, including HIV infection. However, it is not known whether plasma levels or cellular production of cytokines, or their antagonists, are more closely related to lean tissue loss. We studied whether plasma cytokine analysis could substitute for PBMC production assays in studies of nutrition status and disease state, and if cytokine antagonists could offer an alternative in assessing cytokine status. We used a bout of moderately difficult exercise to perturb cytokine production in 12 adults with HIV without wasting, 10 adults with HIV wasting, and nine healthy controls. Plasma and peripheral blood mononuclear cell (PBMC) production of interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptor type II (sTNFrII) were measured at baseline and 2, 6, 24 and 168h following exercise. PBMC production of IL-1beta, TNF-alpha and IL-6 were all higher in the HIV-infected patients without wasting than in the controls (P<0.05) or the patients with AIDS wasting (P<0.05). Plasma concentrations of TNF-alpha and IL-6 were higher in the HIV wasted patients than in the controls (P<0.05). Both plasma and PBMC levels of sTNFrII were higher in HIV patients, regardless of wasting, than in controls. These data suggest that the PBMC cytokine compartment is more sensitive to nutritional and metabolic abnormalities than is the plasma compartment. PBMC production of IL-1beta, IL-6 and TNF-alpha best distinguish between HIV patients with and without wasting, while plasma concentrations of IL-6 and TNF-alpha are elevated in AIDS wasting, but do not reliably distinguish patients with wasting from HIV-infected patients without wasting.     

福州地区庚型肝炎病毒重叠感染

为研究庚型肝炎病毒在福州地区的重叠感染,采用ＥＬＩＳＡ法检测本院住院的２８６例病毒性肝炎（ＨＶ）患者和５００名供血员的抗－ＨＧＶ。结果表明,甲、乙、丙、戊型肝炎患者和供血员的抗－ＨＧＶ检出率分别为２．０％、２．２％、４．０％、１０．０％和０．２％。急性肝炎、慢性肝炎、慢性重型肝炎、肝硬化、原发性肝癌和抗－ＨＣＶ阳性供血员的检出率分别为７．９％、４．３％、３３．３％、０％、７．１％和６．３％,慢性重型肝炎检出率较慢性肝炎显著升高（Ｐ＜０．０５）。各型肝炎患者和供血员均存在庚型肝炎病毒重叠感染,以慢性重型肝炎为著。     

Effect of concurrent acute infection with hepatitis C virus on acute hepatitis B virus infection.

OBJECTIVE--To investigate the possible interference with acute hepatitis B virus infection by co-infection with hepatitis C virus. DESIGN--Analysis of stored sera collected for transfusion transmitted viruses study in 1970s. SETTING--Four major medical centres in the United States. PATIENTS--12 recipients of blood infected with hepatitis B virus. MAIN OUTCOME MEASURES--In 1970s, presence of antibodies in hepatitis B virus and raised serum alanine aminotransferase concentration; detection of antibodies to hepatitis C virus with new enzyme linked immunoassays. RESULTS--Five of the 12 patients were coinfected with hepatitis C virus. Hepatitis B surface antigen was first detected at day 59 in patients infected with hepatitis B virus alone and at day 97 in those coinfected with hepatitis C virus (p = 0.01); median durations of antigenaemia were 83 and 21 days respectively (p = 0.05), and the antigen concentration was lower in the coinfected patients. Alanine aminotransferase patterns were uniphasic when hepatitis B virus infection occurred alone (range 479-2465 IU/l) and biphasic in patients with combined acute infection (no value > 380 IU/l; p = 0.0025). Four coinfected recipients developed chronic hepatitis C virus infection. The fifth patient was followed for only four months. CONCLUSIONS--Acute coinfection with hepatitis C virus and hepatitis B virus inhibits hepatitis B virus infection in humans, and onset of hepatitis B may reduce the severity of hepatitis C virus infection but not frequency of chronicity. Alanine aminotransferase concentration showed a biphasic pattern in dual infection.     

Type-specific antibodies to hepatitis C virus in sera from patients with various hematologic diseases

The reactivity of 100 sera taken from patients with different blood diseases and donors with respect to synthesized peptides in the variable area of protein NS4 of hepatitis C virus was studied. The presence of type-specific antibodies in the blood sera of patients with hepatitis C was shown. Two antigenic determinant corresponding to 1683-1705 and 1711-1732 amino acid residues in the protein area under study were detected. In hematological patients undergoing frequent blood transfusions mixed infection with different types of hepatitis C virus was registered; these types could be reliably determined with the use of synthetic peptides. The serotype determined with the use of peptides corresponded to the type of the circulating virus.