Immune mechanism–targeted treatment of experimental epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous dermatosis characterized by chronic mucocutaneous blistering caused by autoantibodies directed against type VII collagen. EBA causes a high morbidity and is difficult to treat. Model systems have significantly broadened our understanding of EBA pathogenesis, leading to the identification of numerous therapeutic targets. Of these, so far, a few have been evaluated for their therapeutic potential in preclinical models. In mice, EBA can be induced by transfer of anti-type VII collagen antibodies or by immunization with the protein. The latter model, immunization-induced EBA, is ideal to test drugs for their therapeutic efficacy. Here, mice with already established disease can be treated for prolonged periods. Albeit time consuming, results from immunization-induced EBA will pave the way for clinical application in patients. As the key pathogenic principle, that is, autoantibody-induced, leukocyte-mediated tissue injury and inflammation, is shared by other diseases, these findings may have translational applications beyond EBA.     

The duality of chemokines in heart failure

The failing human heart is a bustling network of intra- and inter-cellular signals and related processes attempting to coordinate a repair mechanism for the injured or diseased myocardium. While our understanding of signaling by mode of cytokines is well understood on a systemic level, we are only now coming to elucidate the role of cytokines in cardiac self-regulation. An increasing number of studies are showing now that cardiomyocytes themselves have not only the ability but also the mandate to produce signals, and play direct roles in how these signals are interpreted. One of the families of cytokines employed by distressed cardiac tissue are chemokines. By regulating the movement of pro-inflammatory cell types to sites of injury, we see now how the myocardium responds to stress. Herein we review the participation of these inflammatory mediators and explore the delicate balance between their protective roles and damaging functions.     

Immunocompetence to assess nutritional status in eating disorders

Despite the seriously undernourished state of patients with anorexia nervosa and bulimia nervosa, controversial findings have been published regarding some aspects of the immune system that are otherwise impaired in more typical types of malnutrition, such as protein-energy malnutrition. However, cell-mediated immunity is usually altered and the study of immunocompetence has provided useful markers to assess the nutritional status of these patients. In addition, a relative protection against infection has been observed in these patients. Changes in the interactions between the endocrine, central nervous and immune systems are considered relevant to understanding the adaptive mechanisms triggered in these syndromes. The role of cytokines and several hormones are reviewed for their implication in immune homeostasis.     

Inhibitors of TLR-4, NF-κB,and SAPK/JNK signaling reduce the toxic effect of lipopolysaccharide on RAW 264.7 cells

The present study was designed to examine and compare the effects of three suppressors on the cytokine response in tandem with examining: the synthesis of inducible forms of heat shock proteins; HSP72 and HSP90α; activities of NF-κB and SAPK/JNK signaling pathways; and TLR4 expression. Pre-treatment with inhibitors offers promise as protective means to lower the activity of these cascades, thereby circumventing the formation of excessive amounts of pro-inflammatory molecules. Three inhibitors of TLR4, SAPK/JNK, and NF-κB signaling, namely CLI-095, SP600125, and IKK Inhibitor XII, respectively, were added to cultured RAW 264.7 macrophages before the Escherichia coli lipopolysaccharide (LPS) application. Treatments of RAW 264.7 cells with each of the inhibitors resulted in a reduced response to LPS as was visualized by a decrease of TNF-α, IL-1, and IFN-γ production. In addition, inhibitors of the NF-κB and SAPK/JNK signaling reduced IL-6 production in LPS-treated cells, whereas the IKK inhibitor XII also decreased IL-10 production. Further, the NO production in LPS-stimulated macrophages was significantly reduced following application of CLI-095 or IKK inhibitor XII. The results also showed that the inhibitors suppressed TLR4 production and decreased phosphorylation of NF-κB and SAPK/JNK proteins, thereby preventing the activation NF-κB and SAPK/JNK signaling pathways in LPS-activated cells. In addition, the production of inducible heat shock proteins, HSP72 and HSP90-α, was reduced in LPS-stimulated RAW 264.7 cells pre-treated with inhibitors. These results suggest that inhibitors CLI-095, SP600125, and IKK inhibitor XII demonstrate potential effectiveness in the reduction of the inflammatory response by mechanisms involving both the cellular defense system and cellular signaling. In conclusion, suppressor of NF-κB cascade, IKK inhibitor XII, seems to be the most effective anti-toxic agent among studied inhibitors.     

IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelial-mesenchymal transition (EMT)

Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-β₁ to induce bronchial EMT. A synergic action was noted between TGF-β₁, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-β₁ to induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced the capacity of TGF-β₁ to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic strategies against severe asthmatics in clinical settings.     

Gingival crevicular fluid and serum levels of APRIL,BAFF and TNF-alpha in rheumatoid arthritis and osteoporosis patients with periodontal disease

Background

This study was performed to evaluate gingival crevicular fluid (GCF) and serum levels of a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF) and compare this to differences between TNF-alpha levels in rheumatoid arthritis (RA), osteoporosis (OPR) and systemically healthy women with periodontal disease (SH).

Design

Gingival crevicular fluid (GCF) and serum samples were obtained before any periodontal intervention from 17 RA, 19 OPR patients and 13 SH women with periodontitis. Full-mouth clinical periodontal measurements were recorded. APRIL, BAFF and TNF-α levels were determined by ELISA. Statistical analysis was performed using multivariate analysis, ANOVA and Spearman correlation.

Results

Pocket depths differed in site-specific comparisons, but otherwise clinical measurements were similar in the three study groups. Multivariate least squares regression ANOVA adjusted for age and for plaque index indicated that total amounts of TNF-α and concentrations of TNF-α, BAFF and APRIL were significantly greater in the RA patients than in the SH group (p < 0.05), and GCF concentrations of BAFF were greater in OPR patients than in SH. Serum TNF-α and BAFF were significantly higher in the RA group compared to SH (p < 0.05) and serum TNF-α was greater in RA than in OPR (p < 0.05). APRIL and BAFF correlated with RANKL levels in GCF and serum (p < 0.05).

Conclusion

Despite long-term usage of anti-inflammatory drugs in the RA and OPR patients, increased TNF-family cytokines, might suggest that these patients have a propensity to overproduce these inflammatory mediators but whether this results from greater disease activity or contribute to greater disease activity remains moot.     

Effect of nonsurgical periodontal therapy on serum and gingival crevicular fluid cytokine levels during pregnancy and postpartum

Background and Objective: A low‐grade systemic inflammatory status originating from periodontal infection has been proposed to explain the association between periodontal disease and systemic conditions, including adverse obstetric outcomes. The aim of this study was to evaluate the effect of periodontal therapy during pregnancy on the gingival crevicular fluid and serum levels of six cytokines associated with periodontal disease and preterm birth. Material and Methods: A subsample of 60 women (18–35 years of age) up to 20 gestational weeks, previously enrolled in a larger randomized clinical trial, was recruited for the present study. Participants were randomly allocated to receive either comprehensive nonsurgical periodontal therapy before 24 gestational weeks (n = 30, test group) or only one appointment for supragingival calculus removal (n = 30, control group). Clinical data, and samples of blood and gingival crevicular fluid, were collected at baseline, at 26–28 gestational weeks and 30 d after delivery. The levels of interleukin (IL)‐1β, IL‐6, IL‐8, IL‐10, IL‐12p70 and tumor necrosis factor‐α were analyzed by flow cytometry. Results: After treatment, a major reduction in periodontal inflammation was observed in the test group, with bleeding on probing decreasing from 49.62% of sites to 11.66% of sites (p < 0.001). Periodontal therapy significantly reduced the levels of IL‐1β and IL‐8 in gingival crevicular fluid (p < 0.001). However, no significant effect of therapy was observed on serum cytokine levels. After delivery, the levels of IL‐1β in the gingival crevicular fluid of the test group were significantly lower than were those in the control group (p < 0.001), but there were no significant differences between test and control groups regarding serum cytokine levels. Conclusion: Although periodontal therapy during pregnancy successfully reduced periodontal inflammation and gingival crevicular fluid cytokine levels, it did not have a significant impact on serum biomarkers.