Clinical,histological and immunpathological findings in 32 patients with dermatitis herpetiformis Duhring

Background: Dermatitis herpetiformis is a chronic severely pruritic dermatosis. It is a cutaneous manifestation of celiac disease. The aim of our study was to collect clinical, histological and immunopathological data on patients who were treated in the University Departments of Dermatology in Würzburg and Lübeck from 1996 to 2008. Patients and Methods: We retrospectively analyzed 32 patients. Only patients with positive findings on direct immunofluorescence microscopy were included in this study. Results: All patients demonstrated skin lesions in the predilection areas of knees, elbows, gluteal region and scalp. The male to female ratio was 1.5 : 1 and the average age was 43 years. The interval between the first symptoms and diagnosis ranged from 6 weeks to 20 years. Direct immunofluorescence microscopy showed that granular IgA deposits were more often found continuously along the dermal‐epidermal junction rather than focally in the tips of the dermal papillae. Results of small intestinal biopsies were available from 29 patients and confirmed the presence of celiac disease in all cases. None of the patients reported gastrointestinal symptoms. IgA antibodies against tissue transglutaminase and epidermal transglutaminase were found in 88% and 94% of patient sera, respectively. Conclusions: The detection of IgA autoantibodies against epidermal transglut‐aminase is the most sensitive serological test in the diagnosis of dermatitis herpetiformis. Our observations confirm that patients with dermatitis herpetiformis usually do not demonstrate apparent gastrointestinal symptoms.     

Racism,Health Status,and Birth Outcomes: Results of a Participatory Community-Based Intervention and Health Survey

Many community-based participatory research (CBPR) partnerships address social determinants of health as a central consideration. However, research studies that explicitly address racism are scarce in the CBPR literature, and there is a dearth of available community-generated data to empirically examine how racism influences health disparities at the local level. In this paper, we provide results of a cross-sectional, population-based health survey conducted in the urban areas of Genesee and Saginaw Counties in Michigan to assess how a sustained community intervention to reduce racism and infant mortality influenced knowledge, beliefs, and experiences of racism and to explore how perceived racism is associated with self-rated health and birth outcomes. We used ANOVA and regression models to compare the responses of intervention participants and non-participants as well as African Americans and European Americans (N = 629). We found that intervention participants reported greater acknowledgment of the enduring and differential impact of racism in comparison to the non-intervention participants. Moreover, survey analyses revealed that racism was associated with health in the following ways: (1) experiences of racial discrimination predicted self-rated physical health, mental health, and smoking status; (2) perceived racism against one’s racial group predicted lower self-rated physical health; and (3) emotional responses to racism-related experiences were marginally associated with lower birth-weight births in the study sample. Our study bolsters the published findings on perceived racism and health outcomes and highlights the usefulness of CBPR and community surveys to empirically investigate racism as a social determinant of health.     

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef’s influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef’s ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.     

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia

In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X_L. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.     

A prospective open study of the efficacy of high-dose recombinant hepatitis B rechallenge vaccination in HIV-infected patients

Double-dose hepatitis B virus revaccination of human immunodeficiency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (P= .03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; P= .005) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09]; P= .12).     

A new second-generation anti-HIV-1 enzyme immunoassay using recombinant envelope and core proteins

In a multicenter collaborative study a new second-generation HIV-1 antibody enzyme immunoassay (Abbott recombinant HIV-1 EIA) using Escherichia coli-expressed recombinant p24 and p41 proteins as solid-phase antigens was compared with the first-generation H9 cell-line-based Abbott HIV-1 EIA. The results of the confirmatory assays (Western blot, immunofluorescence), combined with clinical information, were used as the reference standard for the detection of HIV-1 antibodies in 10,676 random blood donor serum specimens, in a panel of 840 specimens from symptomatic and asymptomatic patients and a total of 63 serial blood specimens from 23 people at risk. With fresh blood donor sera, the specificity of the first-generation assay ranged between 99.54 and 99.76% (95% confidence limits, CL) compared with 99.81-99.95% (95% CL) for the second-generation EIA. With panel specimens the recombinant HIV-1 EIA achieved an overall sensitivity of 100% and a specificity range of 98.3-99.7% (95% CL); the corresponding sensitivity and specificity ranges observed for the first-generation EIA were 98.0-99.5% (95% CL) and 94.3-96.8% (95% CL), respectively. The improved sensitivity for the second-generation assay was confirmed by testing serial samples from seroconverting patients. The use of recombinant proteins eliminated non-specific reactions due to class II human leukocyte antigen (HLA)-directed antibodies.     

Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications

Background: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.

Methods: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab.

Results: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis.

Conclusion: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.