Jan van Hattum

FcαRI-positive liver Kupffer cells: Reappraisal of the function of immunoglobulin A in immunity

Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, FcαRI (CD89), is poorly understood. The ability of FcαRI to activate leukocytes seems to conflict with the proposed anti-inflammatory activity of secretory IgA. We show here that in a transgenic mouse model, inflammatory mediators induced expression of FcαRI on Kupffer cells, which enabled efficient phagocytosis in vivo of bacteria coated with serum IgA. Secretory IgA did not initiate phagocytosis. Therefore, interactions between serum IgA and FcαRI on Kupffer cells may provide a ‘second line of defense’ in mucosal immunity, by eliminating invasive bacteria entering through the portal circulation and thus preventing disease.

Cytokine Polymorphisms Play a Role in Susceptibility to Ultraviolet B-Induced Modulation of Immune Responses after Hepatitis B Vaccination

UVB exposure can alter immune responses in experimental animals and humans. In an earlier human volunteer study, we demonstrated that hepatitis B-specific humoral and cellular immunity after vaccination on average were not significantly affected by UVB exposure. However, it is known that individuals differ in their susceptibility to UVB-induced immunomodulation, and it was hypothesized that polymorphisms in specific cytokines may play a role in this susceptibility. In this respect, we previously demonstrated that immune responses after hepatitis B vaccination are influenced by the minor allelic variant of IL-1β in the general population. For all volunteers, single nucleotide polymorphisms were determined for the following UV response-related cytokines: IL-1 receptor antagonist (+2018), IL-1α (+4845), IL-1β (+3953), TNF-α (−308), and TNF-α (−238). Exposure to UVB significantly suppressed Ab responses to hepatitis B in individuals with the minor variant for the IL-1β polymorphism. Increased minimal erythema dose values (just perceptible), which resulted in higher absolute UVB exposures, were observed in the same individuals. There were no associations observed between UVB-induced immunomodulation and the other cytokine polymorphisms examined. This study indicates that individual susceptibility to UVB radiation needs to be considered when studying the effects of UVB in humans.

IL-1beta gene polymorphisms influence hepatitis B vaccination

Considerable variability exists in the vaccine response to hepatitis B with 5-10% of healthy young adults demonstrating no or inadequate responses following a standard vaccination schedule. As the interleukin-1beta (IL-1beta) cytokine has been shown to be important in the development of immune responses, we determined whether vaccine efficacy is influenced by genetic polymorphisms associated with IL-1beta expression. Ninety-two healthy individuals who were negative for antibodies to hepatitis B antigen (anti-HBs) were vaccinated against hepatitis B according to a standardized schedule. At selected times, antibody titers and lymphoproliferative capacity to hepatitis B surface antigen (HBsAg) were determined. DNA genotyping for IL-1beta polymorphisms using a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique demonstrated that both the anti-HBs titer and the T-cell lymphoproliferative response to HBsAg are significantly increased in individuals possessing the IL-1beta (+3953) minor allelic variant.

Single or multiple dose ursodeoxycholic acid for cholestatic liver disease : Biliary enrichment and biochemical response

BACKGROUND Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance. AIM The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated. METHODS Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg-1 day-1) in a single dose at bed time (n = 13) or in three divided gifts with meals (n = 14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between. RESULTS Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean +/- SEM) was 40.1 +/- 2.4 in the single dose group vs 40.8 +/- 2.8 in the multiple dose group (p = NS) and was positively correlated with biochemical improvement (AP: r = 0.47, p = 0.02; GGT: r = 0.58, p = 0.002; ASAT: r = 0.67, p = 0.002; ALAT: r = 0.52, p = 0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens. CONCLUSION Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.

Epidermal cis-Urocanic Acid Levels Correlate with Lower Specific Cellular Immune Responses After Hepatitis B Vaccination of Ultraviolet B–exposed Humans¶

Abstract Urocanic acid (UCA) is a major UV-absorbing chromophore in the epidermis and has been suggested to act as one of the initiators of UV-induced immunosuppression. cis-UCA, the isomer from UCA that is formed upon UV exposure, has been shown to impair some cellular immune responses. cis-UCA levels were determined in a study in which the influence of ultraviolet B (UVB) exposure on immune responses after hepatitis B vaccination in human volunteers was established. A significant increase in cis-UCA levels was found in the skin of UVB-exposed volunteers compared with controls. cis-UCA levels, calculated as the percentage of the total UCA amount, in UVB-exposed volunteers correlated significantly with the cumulative UVB dose received in 5 consecutive days, i.e. the higher the UVB dose (J/m2), the higher the cis-UCA levels (until a cis-UCA plateau was reached in the so-called photostationary state). Correlations between skin cis-UCA levels and immune responses were determined, and they revealed no statistically significant correlations among lymphocyte proliferation responses after either mitogenic stimulation or stimulation with recall antigens. No correlation was found between cis-UCA levels and hepatitis B–specific antibody titers. However, we found a statistically significant negative correlation between cis-UCA levels and hepatitis B–specific lymphocyte proliferation responses when volunteers were irradiated with UVB before hepatitis B vaccination. In other words, volunteers with high cis-UCA levels caused by UVB exposure showed lower cellular immune responses against hepatitis B antigen after hepatitis B vaccination.

Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]

BackgroundSince esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis.Methods166 patients with esophageal varices grade II, III of IV according to Paquets classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs.ResultsDuring a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk.ConclusionIn the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding.

UVB Exposure Impairs Immune Responses After Hepatitis B Vaccination in Two Different Mouse Strains

Abstract Ultraviolet light exposure can impair immune responses that are not restricted to the exposed skin but is also found at other sites, i.e. systemic immunosuppression. Therefore, we investigated the UV-induced modulating effects on vaccination against hepatitis B in a mouse model. Two different mouse strains, BALB/c and C57Bl/6, were vaccinated intramuscularly against hepatitis B. Mice were exposed to different doses of ultraviolet B (UVB) for five consecutive days on shaved back skin before the vaccination. Vaccination against hepatitis B induced cellular (delayed-type hypersensitivity [DTH] and lymphocyte stimulation test) as well as humoral immune responses in both mouse strains. The DTH responses in C57Bl/6 mice were statistically significantly higher compared with BALB/c mice. UVB exposure induced a dose-dependent suppression of cellular immunity in both strains of mice. C57Bl/6 mice seemed to be more susceptible to this suppression. Anti-hepatitis B surface antibodies (total-Ig) were only marginally suppressed after UVB exposure. IgG2a and interferon-γ levels, both indicators for Th1 immune response, were suppressed in both mouse strains after UVB exposure. In summary, UVB exposure induced a dose-dependent suppression of both cellular and humoral immune responses after hepatitis B vaccination, although the suppressive effects on humoral immunity were limited to IgG2a production. Susceptibility to UVB-induced immunomodulation depended on the strain of mice and their predilection for developing different T cell responses.

An open study of subcutaneous administration of inactivated hepatitis A vaccine (VAQTA®) in adults: safety, tolerability, and immunogenicity

A number of patients in clinical practice would be candidates for hepatitis A vaccine administered subcutaneously (SC), including patients with inherited and acquired coagulopathies. To assess the safety, tolerability, and immunogenicity of VAQTA (Hepatitis A Vaccine, Inactivated, Merck and Co. Inc., West Point, PA) was administered SC to healthy adults. A total of 114 healthy adults received two doses of vaccine SC 24 weeks apart. No serious vaccine-related adverse experiences were reported. Four weeks after dose 1, the seropositivity rate (SPR) was 77.9% (CI, 69.1, 85.1%). The geometric mean titer (GMT) was 21.0 mIU/ml. Twenty-four weeks after dose 1 (just prior to dose 2) and 28 weeks after dose 1 (4 weeks following dose 2), the SPRs were 95.3% [corrected] and 100%, respectively; the GMTs were 153.2 and 1563.9 mIU/mL, respectively [corrected]. Although the kinetics of the immune response were slower when VAQTA was administered SC compared to intramuscular injection, SPRs and GMTs increased over time, indicating that the vaccine administered SC demonstrated immunogenicity.

THE EFFICACY OF A TWO-DOSE HEPATITIS B VACCINATION SCHEME

Vaccination against hepatitis B has been shown to be effective. Using the current vaccination schedule of three doses, more than 95% of the subjects is protected against an infection with the hepatitis B virus. However, there are a few disadvantages. In the first place, the vaccination schedule is rather complex: injection at 0, 1 or 2, and 6 months, with a titre control at 7 months, which makes 4 visits necessary. Also, the vaccine is rather expensive.

Transmission Profile of Hepatitis B Virus Infection in the Batam Region, Indonesia

The aim of this study was to describe the distribution of hepatitis B virus markers among the autochthonous and immigrant multicultural populations of Riau province, Indonesia, in order to define the groups at risk and their infrastructure. This investigation was part of a large hepatitis B vaccination study. A total of 9701 healthy individuals, aged 5 years or older and living in the urbanised area of Batam, near Singapore, and on the surrounding islands were included. Socio-epidemiological data were collected, blood was drawn, and sera were tested for antibodies to hepatitis B core (anti-HBc) and surface antigen (anti-HBs). Anti-HBc-positive sera were tested against hepatitis B surface antigen (HBsAg). All tests comprised immunoassays from Roche (Germany) using Elecsys 2010. Complete data were available from 9314 subjects. The results showed relatively low prevalences of anti-HBc (a marker of a previous hepatitis B infection) and HBsAg in the 5-year-old chiLdren (5.8 and 1.9%, respectively) that increased continuously with increasing age. High anti-HBs levels (>1000 IU/L) were found in all age cohorts, indicating a lifelong threat of active hepatitis B infection. In conclusion, the transmission profile of hepatitis B appeared to be mainly horizontal (person-to-person) in the highly endemic region studied. Vertical transmission was less than 5%. The horizontal transmission routes included non-sexual activities of life since children <10 years of age also showed considerable infection rates. The results underline the need for catch-up hepatitis B vaccination programs for children and adults.