Development of anti-hepatitis B surface (HBs) antibodies after HBs antigen loss in HIV-hepatitis B virus co-infected patients

BackgroundHepatitis B surface antigen (HBsAg)-seroconversion, or loss of HBsAg and acquisition of anti-hepatitis B surface (HBs) antibodies, defines functional cure of chronic hepatitis B virus (HBV) infection. After HBsAg-loss, little is known regarding the development of anti-HBs antibodies and even less so in individuals co-infected with HIV.ObjectivesTo determine anti-HBs antibody kinetics after HBsAg-loss and explore determinants of HBsAg-seroconversion in HIV-HBV co-infected patients.Study designPatients enrolled in the French HIV-HBV cohort were included if they had >1 study visit after HBsAg-loss. Individual patient kinetics of anti-HBs antibody levels were modeled over time using mixed-effect non-linear regression, whereby maximum specific growth rate and maximal level of antibody production were estimated from a Gompertz growth equation.ResultsFourteen (4.6%) of 308 co-infected patients followed in the cohort exhibited HBsAg-loss, all of whom were undergoing antiretroviral therapy. Nine (64.3%) of these patients achieved HBsAg-seroconversion during a median 3.0 years (IQR = 1.1–5.1) after HBsAg-loss. Across individuals with HBsAg-seroconversion, the fastest rates of antibody growth ranged between 0.57–1.93 year⁻¹ (population maximum growth rate = 1.02) and antibody production plateaued between 2.09–3.66 log₁₀ mIU/mL at the end of follow-up (population maximal antibody levels = 2.66). Patients with HBsAg-seroconversion had substantial decreases in HBV DNA viral loads (P = 0.03) and proportion with elevated ALT levels (P = 0.02) and HBeAg-positive serology (P = 0.08). No such differences were observed in those without HBsAg-seroconversion.ConclusionsMost co-infected patients with HBsAg-seroconversion produced and maintained stable antibody levels, yet kinetics of anti-HBs production were much slower compared to those observed post-vaccination or after clearance of acute HBV-infection.     

Comparative study of three technics of inverse passive hemagglutination in the search for a surface antigen of the hepatitis b virus (Ag HBs) (author's transl)]

The following three different versions of reverse passive hemagglutination (RPHA) were evaluated for the detection of HBs antigen: Auscell I - Abbott, WH HBs - Wellcome and the hepanosticon - Organon technique and results obtained were compared with those obtained by the radio immuno assay (Ausria II of Abbott). In 493 sera studied, up to 16,8% were found positive by RPHA as compared to 17,2% positives by RIA. The percentage of false positives by the different methods varied from 4,9 to 7,3. Confirmatory tests, either absorption or neutralization, are necessary to ascertain accuracy of positive results in each of the 3 RPHA methods. The high quality of the Auscell and WH HBs confirmative test allows their sole use although they are slightly less sensitive than the RIA. We would recommand use of the Hepanosticon test whenever positive sera can be confirmed by RIA.     

Regulation of the neutralizing anti-hepatitis B surface (HBs) antibody response in vitro in HBs vaccine recipients and patients with acute or chronic hepatitis B virus (HBV) infection

Antibodies directed to the HBs antigen indicate viral clearance and the development of life-long immunity in patients that recovered from HBV infection. In HBs antigen vaccine recipients anti-HBs antibodies provide protective immunity. However, little is known about the regulation of this HBs-specific antibody response. The existence of anti-HBs-secreting B cells was demonstrated using the highly sensitive ELISPOT technique compared with conventional ELISA in serum and cell culture supernatants. In the peripheral blood of patients with acute self-limited hepatitis B, HBs-specific B cells were demonstrated with a high frequency despite undetectable anti-HBs serum antibodies. HBV-immunized patients that had recovered from infection and vaccine recipients had significantly lower frequencies, whereas chronic HBV carriers and negative controls showed no anti-HBs-secreting B cells. Coculture experiments of isolated B and T cells revealed that the anti-HBs antibody response was restricted to the presence of T helper cells, but not to identical HLA class II molecules. Allogeneic T cells derived from vaccine recipients or chronic HBV carriers stimulated the HBs-specific B cell response in HBs vaccine recipients. Otherwise, isolated T helper cells could never provide sufficient help to induce the HBs-specific B cell response in chronic HBV carriers. Furthermore, peripheral blood mononuclear cells (PBMC) of six out of 10 vaccine recipients, one out of five HBV-immunized patients, but of no chronic HBV carrier showed a proliferative response to different HBs antigen preparations. This study demonstrated a high frequency of circulating anti-HBs-producing B cells in the early phase of acute HBV infection, but a lower frequency of HBs-specific B cells years after resolution of HBV infection. In chronic HBV carriers, however, deficient HBs-specific T and B cell responses were observed.     

Microscopic, immunochemical and ultrastructral study of livers histologically normal or subnormal in patients with hepatitis B surface antigen (HBs). Report of 18 cases (author's transl)]

Liver specimens obtained by biopsy in 18 patients with asymptomatic HBs Ag were studied with specific immunofluorescent technic for this antigen by light and electron microscopy. Only insignificant changes were disclosed by routine microscopy examination. Under light microscopy "ground glass" hepatocytes were found in eight cases. Specific immunofluorescence was found positive in nine cases and was closely correlated with the "ground glass" hepatocytes in eight of them. In one on the three cases studied by electron microscopy, only spherical and tubular formations, 20 to 30 nm in diameter found in the cisternae of the smooth endoplasma reticulum in a few hepatocytes, seem to be HBs Ag.     

Staphylococcal toxin-induced T cell proliferation in atopic eczema correlates with increased use of superantigen-reactive Vbeta-chains in cutaneous lymphocyte-associated antigen (CLA)-positive lymphocytes

Staphylococcal superantigens have been implicated in the pathogenesis of atopic dermatitis (AD). This may occur through superantigenic activation of T lymphocytes and their subsequent induction of the skin homing receptor CLA on activated cells. We investigated the proliferative responses of peripheral blood mononuclear cells (PBMC) from 10 patients with an infective exacerbation of AD and six normal controls to the staphylococcal superantigens, staphylococcal enterotoxin A and B (SEA, SEB) and toxic shock syndrome toxin-1 (TSST-1), and the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). We also assessed CLA and T cell receptor (TCR) Vbeta-chain expression by immunofluorescence and flow cytometry before and after stimulation. PBMC from AD patients showed two-fold increased proliferation to SEA and SEB (P < 0.01) compared with normals, whereas the response to mitogenic stimulation was identical. Analysis of (TCR) Vbeta-chain expression demonstrated increased use of superantigen-reactive Vbeta families in freshly isolated PBMC in AD patients compared with controls. This pattern of Vbeta-chain expression was only observed in the CLA+ but not the total population of T cells. Furthermore, there was a positive correlation between the enhanced PBMC proliferative response and increased expression of superantigen-reactive Vbeta families in atopic patients. These data support the concept that superantigens are important in the pathogenesis of this common condition, and also provide evidence that the increased use of certain Vbeta families in circulating, CLA+, skin homing lymphocytes is of functional significance.     

Efficiency of antigen presentation to T cell clones by (B cell X B cell lymphoma) hybridomas correlates quantitatively with cell surface ia antigen expression

A series of B cell hybridomas was used as a model system to assess quantitatively the role of Ia molecules in antigen presentation to allo- or soluble antigen-reactive T cell clones. These hybrid cell lines were established by fusion between the HGPRT-BALB/c B cell lymphoma M12.4.1 and LPS-stimulated spleen blasts from B10.BR (H-2k) mice. Quantitative cellular absorption of appropriate anti-Ia monoclonal antibodies and flow cytofluorometric analyses revealed that the B cell hybridomas examined herein expressed constitutively a number of surface I-Ak or I-Ek molecules that varied in an order of magnitude of 1 to 5. Such quantitative differences could be correlated precisely with (a) the capacity of B cell hybridomas to activate T cell clones to proliferate and/or to produce interleukin 2 in response to E beta k allodeterminant or to poly(Glu60Ala30Tyr10) presented in the context of I-Ak restriction element, and (b) the amount of monoclonal anti-I-Ak antibody required to inhibit antigen presentation to T cell clones. The possible implications of these data are discussed in the context of current models of regulation of Ia antigen expression by antigen-presenting cells.     

Hepatitis B surface antigen (HBsAg) in the liver of patients with hepatitis; a comparison with serological detection.

Chronic hepatitis was diagnosed on liver biopsy of 76 patients; 52 (68%)had HBsAg. Of the 52 patients with HBsAg, 23% had HBsAg shown by immunofluorescence on the liver, while it could not be detected with radioimmunoassay on the serum; 77% had HBsAg detectable in liver and in serum, and none had HBsAg in serum only. HBsAg was detected more frequently in chronic aggressive hepatitis and active cirrhosis than in chronic persistent hepatitis and cirrhosis with little activity. No correlation was found in the different forms of chronic hepatitis between the HBsAg status on the one hand, and levels of transaminases, gammaglobulins, and auto-antibodies on the other. Acute hepatitis was diagnosed on liver biopsy of 24 patients; 50% had HBsAg. Liver tissue positivity was very low in the fully developed stage compared to serum positivity. In 146 patients with other liver ailments, both liver and serum were negative for HBsAg.     

Evaluation of the use of decision-support software in carcino-embryonic antigen (CEA)-based follow-up of patients with colorectal cancer

Background

The present paper is a first evaluation of the use of "CEAwatch", a clinical support software system for surgeons for the follow-up of colorectal cancer (CRC) patients. This system gathers Carcino-Embryonic Antigen (CEA) values and automatically returns a recommendation based on the latest values.

Methods

Consecutive patients receiving follow-up care for CRC fulfilling our in- and exclusion criteria were identified to participate in this study. From August 2008, when the software was introduced, patients were asked to undergo the software-supported follow-up. Safety of the follow-up, experiences of working with the software, and technical issues were analyzed.

Results

245 patients were identified. The software-supported group contained 184 patients; the control group contained 61 patients. The software was safe in finding the same amount of recurrent disease with fewer outpatient visits, and revealed few technical problems. Clinicians experienced a decrease in follow-up workload of up to 50% with high adherence to the follow-up scheme.

Conclusion

CEAwatch is an efficient software tool helping clinicians working with large numbers of follow-up patients. The number of outpatient visits can safely be reduced, thus significantly decreasing workload for clinicians.     

Immunohistochemical patterns of hepatitis B surface antigen (HBsAg) in patients with hepatitis,renal homografts recipients and normal carriers

Summary A series of 180, Bouin-fixed and paraffin embedded liver biopsies obtained from 147 patients was investigated for the presence of hepatitis B surface antigen (HBs) by histochemical and indirect immunofluorescence techniques. A comparison between orcein staining and Masson's trichrome preparations for ground glass hepatocytes, showed that immunofluorescence was both the more reliable and the more specific method for detection of HBsAg in liver tissue. The ability to perform this technique on paraffin sections facilitates systematic studies and allows retrospective work-up.IF-HBs positive hepatocytes were found in approximately two thirds of all HBs-positive patients in their serum, but never seen in HBs-negative patients.HBs-positive cells were observed in healthy chronic carriers and in all forms of chronic hepatitis, but never in acute HBs-positive hepatitis.In patients treated with chronic hemodialysis and in renal homograft recipients, the incidence of positive cells was higher than in the chronic hepatitis groups; this could be correlated with the duration of antigenemia at the time of biopsy.     

The presence of anti-carcinoembryonic antigen (CEA) antibodies in the sera of patients with gastrointestinal malignancies

Using an enzyme-linked immunoassay we tested the sera of 71 patients with digestive system cancer, 35 patients with various nonmalignant disorders, and 28 normal individuals for anti-CEA activity. Antibodies were found in the sera of 51% of the patients. Most of the patients positive for the antibodies (70%) had no evidence of metastatic disease. Fewer than 10% of the sera from control groups had anti-CEA activity. The authors concluded that the patients suffering from cancer of the GI system are capable of producing tumor-specific antibodies. These antibodies could be used as a tumor marker and/or as a possible index for the function of the immune system. The presence of a large tumor mass could lead to the removal of these antibodies from the circulation.     

Detection of hepatitis B surface antigen (HBsAg) in peripheral blood mononuclear cells of patients with acute and chronic active hepatitis B

Seventy five patients with acute and chronic active hepatitis (CAH) were studied by indirect immunofluorescence with monoclonal antibodies for the presence of hepatitis B surface antigen (HBsAg) on peripheral blood mononuclear cells (PBMC). The viral surface antigen was detected in the PBMC of all the patients with hepatitis B virus (HBV)-induced CAH and in acute patients with more than 2 months of evolution. No HBsAg was detected in the samples obtained from 12 normal controls or from 14 non-A, non-B CAH patients. Analysis of PBMC subsets revealed that HBsAg was present in non-T cells; dual fluorescence studies showed HBsAg on surface Ig-positive lymphocytes. The binding of anti-HBs monoclonal antibodies was higher than that of a goat anti-HBs serum, and the highest reactivity was observed with an antibody against the pre-S(2)-region sequence. Both HBsAg and hepatitis B core antigen (HBcAg) were also detected in lysates of PBMC by dot blot analysis.     

The mature-parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum associates with the erythrocyte membrane skeletal protein, band 4.1

Several proteins synthesized by mature asexual stages of Plasmodium falciparum interact with the erythrocyte membrane skeleton. One of these is the mature-parasite-infected erythrocyte surface antigen (MESA; also called PfEMP2), a phosphoprotein of 250-300 kDa, which is found on the internal face of the erythrocyte membrane. When MESA is precipitated with anti-MESA antibodies, another phosphoprotein of 80 kDa is co-precipitated. This 80-kDa phosphoprotein was identified by peptide mapping as the erythrocyte membrane component band 4.1. Thus, MESA is apparently anchored at the erythrocyte membrane through an association with band 4.1. Band 4.1 is more intensely phosphorylated in infected erythrocytes and is increased in relative molecular mass in erythrocytes infected by isolates of P. falciparum that cytoadhere.     

血清甲胎蛋白联合癌胚抗原检测在肝癌诊断中的应用价值（附125例报告）

目的探讨血清甲胎蛋白联合癌胚抗原检测在原发性肝癌和转移性肝癌诊断中的应用价值。方法回顾性分析我院2003年7月～2006年3月收治的125例肝癌患者的临床资料,同时测定他们和65例健康人血清中的血清甲胎蛋白和癌胚抗原含量。结果肝癌组血清甲胎蛋白和癌胚抗原含量及阳性率明显高于正常对照组,且转移性肝癌中癌胚抗原含量明显高于原发性肝癌。结论检测血清中血清甲胎蛋白和癌胚抗原的含量,对肝癌的诊断有很高的价值,对鉴别肝癌的类型具有一定的指导意义。     

Efficacy and safety of monoclonal anti-CD20 antibody (rituximab) for the treatment of patients with recurrent low-grade non-Hodgkin's lymphoma after high-dose chemotherapy and autologous hematopoietic cell transplantation.

The major cause of treatment failure following high-dose therapy with autologous hematopoietic cell transplantation (AHCT) for low-grade lymphomas (non-Hodgkin's lymphoma [NHL]) is persistent disease or recurrence. Most patients whose disease progresses following AHCT have resistant disease and limited bone marrow reserve. In this setting, treatment options are limited and responses to conventional chemotherapy are generally poor. Rituximab is a chimeric immunoglobulin G1 kappa monoclonal antibody that recognizes the CD20 antigen on B-cells. Published data on the use of rituximab for the treatment of recurrent NHL after autologous transplantation are limited. We present a detailed report of anti-CD20 antibody treatment for 8 patients with recurrent follicular low-grade NHL after high-dose therapy and autologous transplantation. Rituximab was administered at 375 mg/m2 intravenously once weekly for a total of 4 infusions. Median follow-up for this study was 23.4 months. Six (75%) of 8 patients responded to rituximab (2 complete response, 4 partial response). The Kaplan-Meier estimated median time to progression was 17.8 months. Rituximab was generally well tolerated. One patient developed delayed neutropenia. Other side effects were infusion related and transient. Two patients were re-treated with rituximab for progressive disease and achieved partial response. In summary, this retrospective study suggests that anti-CD20 antibody treatment is feasible in the treatment of patients who relapse or progress with low-grade NHL after autologous transplantation. There appears to be a high proportion of patients who benefit and have durable responses. Anti-CD20 antibody should be considered as a first-line salvage treatment for patients with CD20+ recurrent low-grade NBL in whom high-dose therapy has failed.     

The use of a modified administrative procedure (MAP) for the bender-gestalt test with schizophrenic patients and normals

Advocated a modified procedure for administering the Bender Gestalt Test that involves administering the BG in a conventional way and, after a brief intervening period, a second administration with specific instructions to copy the BG designs exactly. Three subtypes of schizophrenia and a normal control group were studied: 25 paranoids, 25 chronic undifferentiated, 25 schizoaffectives, and 25 controls. Each schizophrenic subgroup demonstrated significant improvement in performance on the BG when the modified administrative procedure was employed. Some implications of the findings are discussed.