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Background Vascular surgery of the inguinal area can be complicated by persistent lymphatic fistulas. Rapid and effective treatment is essential to prevent infection, sepsis, bleeding, and possible leg amputation. Current data on irradiation of lymphatic fistulas lack recommendation on the appropriate individual and total dose, the time of irradiation, and the target volume. Presumably, a dose of 0.3–0.5 to 1–12 Gy should be sufficient for the purpose. Currently, radiotherapy is a “can” recommendation, with a level 4 low evidence and a grade C recommendation, according to the DEGRO S2 guidelines. As part of a pilot study, we analyzed the impact and limitations of low-dose radiation therapy in the treatment of inguinal lymphatic fistulas. Patients and methods As a part of an internal quality control project, patients with lymphatic fistulas irradiated in the groin area after vascular surgery for arterial occlusive disease (AOD) III-IV, repair of pseudo aneurysm or lymph node dissection due to melanoma were selected, and an exploratory analysis on retrospectively collected data performed. Results Twelve patients (10 males and 2 females) aged 62.83 ± 12.14 years underwent open vascular reconstruction for stage II (n = 2), III (n = 1), and IV (n = 7) arterial occlusive disease (AOD), lymph node dissection for melanoma (n = 1) or repair of a pseudoaneurysm (n = 1). Surgical vascular access was obtained through the groin and was associated with a persistent lymphatic fistula, secreting more than 50 ml/day. Patients were irradiated five times a week up to a maximum of 10 fractions for the duration of the radiation period. Fraction of 0.4 Gy was applied in the first 7 cases, while 5 patients were treated with a de-escalating dose of 0.3 Gy. There was a resolution of the lymphatic fistula in every patient without higher grade complications. Conclusion Low-dose irradiation of the groin is a treatment option for persistent lymphatic fistula after inguinal vascular surgery.

Emerging evidence indicates B-cell activating factor (BAFF, Tnfsf13b) to be an important cytokine for antitumor immunity. In this study, we generated a BAFF-overexpressing B16.F10 melanoma cell model and found that BAFF-expressing tumors grow more slowly in vivo than control tumors. The tumor microenvironment (TME) of BAFF-overexpressing tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functional importance of monocytes for the phenotype of BAFF-mediated tumor growth delay. RNA sequencing analysis confirmed that monocytes isolated from BAFF-overexpressing tumors were characterized by a less exhaustive phenotype and were enriched for in genes involved in activating adaptive immune responses and NF-κB signaling. Evaluation of patients with late-stage metastatic melanoma treated with inhibitors of the PD-1/PD-L1 axis demonstrated a stratification of patients with high and low BAFF plasma levels. Patients with high BAFF levels experienced lower responses to anti-PD-1 immunotherapies. In summary, these results show that BAFF, through its effect on tumor-infiltrating monocytes, not only impacts primary tumor growth but can serve as a biomarker to predict response to anti-PD-1 immunotherapy in advanced disease. Significance: The BAFF cytokine regulates monocytes in the melanoma microenvironment to suppress tumor growth, highlighting the importance of BAFF in antitumor immunity.

This interim analysis from the atopic dermatitis registry TREATgermany shows robust long-term efficacy, favourable safety and high persistence of dupilumab under real life conditions.

Tuberculosis-causing Mycobacterium tuberculosis (Mtb) is transmitted via airborne droplets followed by a primary infection of macrophages and dendritic cells. During the activation of host defence mechanisms also neutrophils and T helper 1 (TH1) and TH17 cells are recruited to the site of infection. The TH17 cell-derived interleukin (IL)-17 in turn induces the cathelicidin LL37 which shows direct antimycobacterial effects. Here, we investigated the role of IL-26, a TH1- and TH17-associated cytokine that exhibits antimicrobial activity. We found that both IL-26 mRNA and protein are strongly increased in tuberculous lymph nodes. Furthermore, IL-26 is able to directly kill Mtb and decrease the infection rate in macrophages. Binding of IL-26 to lipoarabinomannan might be one important mechanism in extracellular killing of Mtb. Macrophages and dendritic cells respond to IL-26 with secretion of tumor necrosis factor (TNF)-α and chemokines such as CCL20, CXCL2 and CXCL8. In dendritic cells but not in macrophages cytokine induction by IL-26 is partly mediated via Toll like receptor (TLR) 2. Taken together, IL-26 strengthens the defense against Mtb in two ways: firstly, directly due to its antimycobacterial properties and secondly indirectly by activating innate immune mechanisms.

Real-World data on effectiveness, safety and drug survival of dupilumab: An analysis from the TREATgermany registry. Table 1: Effectiveness outcomes of dupilumab and cyclosporine to month 3, 6 and 12

Real-World data on effectiveness, safety and drug survival of dupilumab: An analysis from the TREATgermany registry. Table 1: Effectiveness outcomes of dupilumab and cyclosporine to month 3, 6 and 12

Real-World data on effectiveness, safety and drug survival of dupilumab: An analysis from the TREATgermany registry. Table 1: Effectiveness outcomes of dupilumab and cyclosporine to month 3, 6 and 12

Real-World data on effectiveness, safety and drug survival of dupilumab: An analysis from the TREATgermany registry. Table 1: Effectiveness outcomes of dupilumab and cyclosporine to month 3, 6 and 12

Real-World data on effectiveness, safety and drug survival of dupilumab: An analysis from the TREATgermany registry. Table 1: Effectiveness outcomes of dupilumab and cyclosporine to month 3, 6 and 12

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis. publishedVersion

Pruritus is a common, but very challenging symptom with a wide diversity of underlying causes like dermatological, systemic, neurological and psychiatric diseases. In dermatology, pruritus is the most frequent symptom both in its acute and chronic form (over 6 weeks in duration). Treatment of chronic pruritus often remains challenging. Affected patients who suffer from moderate to severe pruritus have a significantly reduced quality of life. The underlying physiology of pruritus is very complex, involving a diverse network of components in the skin including resident cells such as keratinocytes and sensory neurons as well as transiently infiltrating cells such as certain immune cells. Previous research has established that there is a significant crosstalk among the stratum corneum, nerve fibers and various immune cells, such as keratinocytes, T cells, basophils, eosinophils and mast cells. In this regard, interactions between receptors on cutaneous and spinal neurons or on different immune cells play an important role in the processing of signals which are important for the transmission of pruritus. In this review, we discuss the role of various receptors involved in pruritus and inflammation, such as TRPV1 and TRPA1, IL-31RA and OSMR, TSLPR, PAR-2, NK1R, H1R and H4R, MRGPRs as well as TrkA, with a focus on interaction between nerve fibers and different immune cells. Emerging evidence shows that neuro-immune interactions play a pivotal role in mediating pruritus-associated inflammatory skin diseases such as atopic dermatitis, psoriasis or chronic spontaneous urticaria. Targeting these bidirectional neuro-immune interactions and the involved pruritus-specific receptors is likely to contribute to novel insights into the underlying pathogenesis and targeted treatment options of pruritus.

Additional file 1.

We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.

Additional file 1: Table S1. Affymetrix® expression analysis of NHDF treated with HA vs. control showing the 50 most upregulated genes (FC = fold change). Table S2. Affymetrix® expression analysis of NHDF treated with HA vs. control showing the 50 most downregulated genes (FC = fold change). Table S3. Affymetrix® expression analysis of NHDF treated with medium-sized HA vs. control showing the 50 most upregulated genes (FC = fold change). Table S4. Affymetrix® expression analysis of NHDF treated with medium-sized HA vs. control showing the 50 most downregulated genes (FC = fold change). Table S5. Affymetrix® expression analysis of NHDF treated with HYAL vs. control showing the 50 most upregulated genes (FC = fold change). Table S6. Affymetrix® expression analysis of NHDF treated with HYAL vs. control showing the 50 most downregulated genes (FC = fold change). Figure S1. (A, C) HAS1, HAS3 gene expression levels in normal human dermal fibroblasts (NHDF) after stimulation with 1 mg/ml HA, 1.5 U/ml HYAL and HA + HYAL co-stimulation for 2 h, 4 h, 12 h and 24 h, (B, D) HAS1, HAS3 gene expression levels of NHDF after stimulation with 15 U/ml, 1.5 U/ml, 0.15 U/ml and 0.015 U/ml HYAL for 24 h. Asterisks above columns indicate statistical significant differences compared to their respective medium controls. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 (t-test, two-sided). Figure S2. (A, C, E) HAS1, HAS2, HAS3 gene expression levels in primary human keratinocytes after stimulation with 1 mg/ml HA, 1.5 U/ml HYAL and HA + HYAL co-stimulation for 2 h, 4 h, 12 h and 24 h, (B, D, F) HAS1, HAS2, HAS3 gene expression levels in keratinocytes after stimulation with 15 U/ml, 1.5 U/ml, 0.15 U/ml and 0.015 U/ml HYAL for 24 h, (G, H) HA amount (ng/ml) measurement by means of ELISA in supernatants of NHDF treated as described in A–F. Asterisks above columns indicate statistical significant differences compared to their respective medium controls. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 (t-test, two-sided).

Additional file 1: Figure S1. B16F10 cells were treated (10 μM-78 nM) for 72 h and IC50 compound values determined. Compounds for which IC50 values were not determinable or were above 10 μM were placed on the 10 μM line. Figure S2. (A) Treatment at the indicated time points with TM (3 μM for B16F10 and A375, 5 μM for RPMI and SH4) did not induce changes in CAMP levels (n = 3-4). (B) Treatment with TM for 18 h did not induce changes in serotonin responsive genes. Expression was normalized to GAPDH (n = 3–4). Figure S3. TM did not affect the MAPK pathway. Melanoma cells were treated as indicated with increasing concentrations of TM (representative immunoblots of n = 3-5 are shown). Blots are quantified in (B). Figure S4. (A) Changes in phospho-S6 (p-S6) at Ser235/6 in MeWo and MEL-JUSO melanoma cells (n = 5–6) following TM treatment are shown. (B) Changes in p-S6 (Ser240/244) (n = 2–3) and p-PDK1 (Ser241) (n = 3–4) following treatment with TM are shown. Figure S5. Dose response curves following treatment with the PI3K inhibitor ZSTK474, pan-Akt inhibitor MK-2206 and mTORC1/mTORC2 inhibitor KU-0063794 are shown (n = 3–4). Figure S6. (A) TM-treated mice as described in Fig. 4a. experienced a small decrease in body weight (n = 6–8). (B) Treatment with TM did not alter liver damage parameters (n = 3). (C) Quantification of the active Caspase-3 staining for Fig. 4d is shown (n = 6 mice). (D) Immunohistochemical staining of tumor tissue for cleaved Caspase-8 is shown and quantified (n = 6 mice). (E) Tumor lysates probed for cleaved Caspase-8 are shown (n = 6–9 mice, with 3 mice shown). Error bars in all experiments indicate SEM. *P < 0.05 as determined by a Student’s t-test (unpaired, 2 tailed) or a one-way ANOVA with a Dunnett’s post-hoc test.

BackgroundWound healing represents a dynamic process involving directional migration of different cell types. Chemokines, a family of chemoattractive proteins, have been suggested to be key players in cell-to-cell communication and essential for directed migration of structural cells. Today, the role of the chemokine network in cutaneous wound healing is not fully understood. Unraveling the chemokine-driven communication pathways in this complex process could possibly lead to new therapeutic strategies in wound healing disorders.MethodsWe performed a systematic, comprehensive time-course analysis of the expression and function of a broad variety of cytokines, growth factors, adhesion molecules, matrixmetalloproteinases and chemokines in a murine cutaneous wound healing model.ResultsStrikingly, chemokines were found to be among the most highly regulated genes and their expression was found to coincide with the expression of their matching receptors. Accordingly, we could show that resting and activated human primary keratinocytes (CCR3, CCR4, CCR6, CXCR1, CXCR3), dermal fibroblasts (CCR3, CCR4, CCR10) and dermal microvascular endothelial cells (CCR3, CCR4, CCR6, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3) express a distinct and functionally active repertoire of chemokine receptors. Furthermore, chemokine ligand-receptor interactions markedly improved the wound repair of structural skin cells in vitro.ConclusionTaken together, we here present the most comprehensive analysis of mediators critically involved in acute cutaneous wound healing. Our findings suggest therapeutic approaches for the management of wound closure by targeting the chemokine network.

Mucous membrane pemphigoid (MMP) is a rare, chronic and often aggressive subepidermal autoimmune blistering disease potentially affecting several mucous membranes with blisters and secondary erosions and scars. The pathogenesis of MMP is poorly understood, and the contribution of genetic predispositions, other than HLA class II allele variants to MMP, is unknown. The objective of this study is to identify susceptibility genes for MMP in a British cohort of MMP patients. A GWAS was conducted in a British cohort of 106 MMP patients. Publicly available genotypes of 2900 blood donors of the UK Blood Service and of 6740 individuals of the 1958 British Birth Cohort served as control. Subsequently, putative susceptibility genes were independently replicated in a German cohort of 42 MMP patients. The GWAS found 38 SNPs in 28 haploblocks with an odds ratio >2 reaching genomewide significance (P < 5.7 × 10−7). Replication confirmed an association of MMP with SNPs in rs17203398 (OR: 3.9), located intronically in the β-galactocerebrosidase gene (GALC) on chromosome 14 and with recessive polymorphisms in rs9936045 (OR: 3.1) in the intergenic region between CASC16 and CHD9 on chromosome 16. The risk of developing MMP is partially genetically determined. SNPs in GALC enhance the risk for MMP, indicating that β-galactocerebrosidase may be involved in the pathogenesis of MMP. Likewise, impacts of polymorphisms in the intergenic region between CASC16 and CHD9 on the activity of neighbouring genes may facilitate the emergence of MMP. The putative role of both polymorphisms requires functional studies in the future.

Interleukin 17-producing helper T cells (T(H)17 cells) have a major role in protection against infections and in mediating autoimmune diseases, yet the mechanisms involved are incompletely understood. We found that interleukin 26 (IL-26), a human T(H)17 cell-derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, T(H)17 cell-derived IL-26 formed complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The resulting IL-26-DNA complexes triggered the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor. These findings provide insights into the potent antimicrobial and proinflammatory function of T(H)17 cells by showing that IL-26 is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death.

BackgroundAlthough the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear.ObjectiveWe sought to determine whether immune cell-derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31-induced itch.MethodsWe used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects.ResultsAmong all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31-induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)-deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca(2+) release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo.ConclusionIL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma.

Background: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments. Methods: A standardized questionnaire evaluated the available diagnostic methods i. e. direct immunofluorescence microscopy (IFM), indirect IFM, commercial ELISA systems, and non-commercial serological tests as well as the number of samples per year in all 34 university and 39 non-university dermatology departments. Results: The overall return rate was 89 %, 100 % and 79 % for the university and non-university departments, respectively. Direct IFM was the most frequently used method and was applied in 98 % of the responding departments. In 74 % of the responding departments, indirect IFM was used mainly on monkey esophagus and human salt-split skin. Commercial ELISA systems were employed in 58 % of the clinics; all of them used anti-desmoglein ELISA, while anti-BP180 and anti-BP230 ELISA were established in 49 % and 48 % of departments, respectively. Non-commercial analytic methods were only performed in 22 % of the departments. Conclusions: The high return rate of this survey allows a relatively precise description of the current diagnostic methods used in German dermatology departments. Standard diagnostic tests are available nationwide and in bullous pemphigoid and pemphigus, the antigen-specific detection of autoantibodies is routinely performed in half of the departments. Rare disorders may be diagnosed by cooperation with some specialized centers.

Engl. Version erschienen u.d.T.: Diagnostics of autoimmune bullous diseases in German dermatology departments ([https://doi.org/10.1111/j.1610-0387.2011.07840.x](https://doi.org/10.1111/j.1610-0387.2011.07840.x))

Objective: Microglia cells represent the immune system of the mammalian brain and constitute up to one third of the brain tumor compartment. Nevertheless, the role of microglia in glioblastoma has remained unclear. The aim of our research is to investigate the microglia-tumor-interaction, especially[for full text, please go to the a.m. URL], 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010

MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.

Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3% vs anti-CXCR4: 6.0% +/- 5.0%, P.001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.

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