Deletion of decay-accelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice

Decay-accelerating factor (DAF, CD55) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. It is also a ligand for CD97, an activation-associated lymphocyte antigen with seven transmembrane domains. It is widely expressed on cells of both the hematopoietic and nonhematopoietic lineages. Although deficiency of DAF on human erythrocytes is associated with the hemolytic anemia syndrome paroxysmal nocturnal hemoglobinuria, the in vivo biology of DAF is still poorly understood. We addressed the in vivo function of DAF in a knockout mouse model and describe here that deletion of DAF exacerbates autoimmune disease development in MRL/lpr mice, a model for human systemic lupus erythematosus. Compared to DAF-sufficient littermate controls, DAF-deficient female MRL/lpr mice developed exacerbated lymphadenopathy and splenomegaly, higher serum anti-chromatin autoantibody levels, and aggravated dermatitis. Consistent with the phenotype of aggravated dermatitis in DAF-deficient mice, Northern and Western blots and immunofluorescence studies showed DAF to be expressed abundantly in the mouse skin, suggesting that it may play a particularly important role in this tissue. Histology and immunostaining demonstrated inflammatory infiltrate and focal C3 deposition in early skin lesions, mostly along the dermal-epidermal junction. These results reveal a protective function of DAF in the development of a systemic autoimmune syndrome and suggest that dysfunction or down-regulation of DAF may contribute to autoimmune disease pathogenesis and manifestation.     

Resin infiltration of deproteinised natural occlusal subsurface lesions improves initial quality of fissure sealing

The aim of this ex vivo study was to evaluate the infiltration capability and rate of microleakage of a low-viscous resin infiltrant combined with a flowable composite resin (RI/CR) when used with deproteinised and etched occlusal subsurface lesions (International Caries Detection and Assessment System code 2). This combined treatment procedure was compared with the exclusive use of flowable composite resin (CR) for fissure sealing. Twenty premolars and 20 molars revealing non-cavitated occlusal carious lesions were randomly divided into two groups and were meticulously cleaned and deproteinised using NaOCl (2%). After etching with HCl (15%), 10 premolar and 10 molar lesions were infiltrated (Icon/DMG; rhodamine B isothiocyanate (RITC)-labelled) followed by fissure sealing (G-?nial Flo/GC; experimental group, RI/CR). In the control group (CR), the carious fissures were only sealed. Specimens were cut perpendicular to the occlusal surface and through the area of the highest demineralisation (DIAGNOdent pen, KaVo). Using confocal laser-scanning microscopy, the specimens were assessed with regard to the percentage of caries infiltration, marginal adaption and internal integrity. Within the CR group, the carious lesions were not infiltrated. Both premolar (57.9%± 23.1%) and molar lesions (35.3%± 22.1%) of the RI/CR group were uniformly infiltrated to a substantial extent, albeit with significant differences (P=0.034). Moreover, microleakage (n=1) and the occurrence of voids (n=2) were reduced in the RI/CR group compared with the CR group (5 and 17 specimens, respectively). The RI/CR approach increases the initial quality of fissure sealing and is recommended for the clinical control of occlusal caries.     

Bullous pemphigoid in adolescence

Bullous pemphigoid (BP) is the most common autoimmune blistering disease affecting the elderly but is quite rare in childhood. The majority of pediatric cases have been reported during early childhood. Adolescence is divided into three phases: early (10‐13 years), middle (14‐17), and late (18‐21). This review aimed to identify BP cases in adolescence and demonstrate their clinical features and course. Our literature search was performed in Medline with the terms “bullous pemphigoid in childhood and adolescence,” “childhood bullous pemphigoid,” “juvenile bullous pemphigoid,” and “autoimmune blistering and autoimmune bullous diseases in childhood.” The data extraction for late adolescence was limited by the fact that this age group is included in adult BP registries. We identified nine cases in early adolescence. Mucosa were affected in 5 of 9 cases. Treatment consisted of systemic prednisone (8/9), in combination with dapsone (2/9), azathioprine (2/9), or erythromycin/nicotinamide (1/9). Relapses were reported in 3 of 9 cases. We identified five cases occuring in middle adolescence. Mucosa were not affected. Treatment consisted of systemic prednisone (5/5), in combination with dapsone (3/5), azathioprine (2/5), doxycycline/nicotinamide (1/5), or mycophenolate mofetil (1/5). Relapses were reported in two of five cases. No case of BP in the late adolescence was included in the results, as only one case met the search criteria, and overlapped with pemphigus vulgaris. With only 14 cases found in our review, BP in adolescence appears even rarer than in earlier childhood. Despite its low prevalence, BP should be included in the differential diagnosis of autoimmune blistering diseases in adolescents.     

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.     

Potential risk factors for constipation in the community

Constipation is a common community health problem. There are many factors that are widely thought to be associated with constipation but real-world evidence of these associations is difficult to locate. These potential risk factors may be categorised as demographic, lifestyle and health-related factors. This review presents the available evidence for each factor by an assessment of quantitative data from cross-sectional studies of community-dwelling adults published over the last 30 years. It appears that there is evidence of an association between constipation and female gender, residential location, physical activity and some health-related factors such as self-rated health, some surgery, certain medical conditions and certain medications. The available evidence for most other factors is either conflicting or insufficient. Therefore, further research is necessary to determine if each factor is truly associated with constipation and whether it can be regarded as a potential risk factor. It is recommended that studies investigating a broad range of factors are conducted in populations in community settings. Multivariate analyses should be performed to account for all possible confounding factors. In this way, valuable evidence can be accumulated for a better understanding of potential risk factors for constipation in the community.