@article{GilesGreenhalghDenesetal.2018, author = {Giles, James A. and Greenhalgh, Andrew D. and Denes, Adam and Nieswandt, Bernhard and Coutts, Graham and McColl, Barry W. and Allan, Stuart M.}, title = {Neutrophil infiltration to the brain is platelet-dependent, and is reversed by blockade of platelet GPIbα}, series = {Immunology}, volume = {154}, journal = {Immunology}, doi = {10.1111/imm.12892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233048}, pages = {322-328}, year = {2018}, abstract = {Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non-microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue-specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60\%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up-regulation of CXCL-1 (2·4-fold) and CCL5 (1·4-fold) acting as a compensatory mechanism in platelet-reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44\%) in platelet-mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.}, language = {en} } @article{KnopSpilgiesRuflietal.2019, author = {Knop, Janin and Spilgies, Lisanne M. and Rufli, Stefanie and Reinhart, Ramona and Vasilikos, Lazaros and Yabal, Monica and Owsley, Erika and Jost, Philipp J. and Marsh, Rebecca A. and Wajant, Harald and Robinson, Mark D. and Kaufmann, Thomas and W. Wei-Lynn, Wong}, title = {TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP}, series = {Cell Death \& Disease}, volume = {10}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-019-1938-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325946}, year = {2019}, abstract = {The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.}, language = {en} } @article{SchanbacherHermannsLorenzetal.2023, author = {Schanbacher, Constanze and Hermanns, Heike M. and Lorenz, Kristina and Wajant, Harald and Lang, Isabell}, title = {Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {2}, issn = {2227-9059}, doi = {10.3390/biomedicines11020559}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304136}, year = {2023}, abstract = {Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.}, language = {en} } @article{LauruschkatEtterSchnacketal.2021, author = {Lauruschkat, Chris D. and Etter, Sonja and Schnack, Elisabeth and Ebel, Frank and Sch{\"a}uble, Sascha and Page, Lukas and R{\"u}mens, Dana and Dragan, Mariola and Schlegel, Nicolas and Panagiotou, Gianni and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen}, title = {Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {9}, issn = {2309-608X}, doi = {10.3390/jof7090698}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245202}, year = {2021}, abstract = {Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.}, language = {en} } @article{LauruschkatPageWhiteetal.2021, author = {Lauruschkat, Chris D. and Page, Lukas and White, P. Lewis and Etter, Sonja and Davies, Helen E. and Duckers, Jamie and Ebel, Frank and Schnack, Elisabeth and Backx, Matthijs and Dragan, Mariola and Schlegel, Nicolas and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Loeffler, Juergen and Wurster, Sebastian}, title = {Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {6}, issn = {2309-608X}, doi = {10.3390/jof7060462}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241025}, year = {2021}, abstract = {Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens.}, language = {en} } @article{HeitmannFringsGeieretal.2021, author = {Heitmann, Johanna and Frings, Verena G. and Geier, Andreas and Goebeler, Matthias and Kerstan, Andreas}, title = {Non-alcoholic fatty liver disease and psoriasis - is there a shared proinflammatory network?}, series = {Journal der Deutschen Dermatologischen Gesellschaft}, volume = {19}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, number = {4}, doi = {10.1111/ddg.14425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258424}, pages = {517-528}, year = {2021}, abstract = {Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 \% of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 \% in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.}, language = {en} } @article{FroehlichSerflingHiguchietal.2021, author = {Fr{\"o}hlich, Matthias and Serfling, Sebastian and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P. and Schmalzing, Marc and Tony, Hans-Peter and Gernert, Michael and Strunz, Patrick-Pascal and Portegys, Jan and Schwaneck, Eva-Christina and Gadeholt, Ottar and Weich, Alexander and Buck, Andreas K. and Bley, Thorsten A. and Guggenberger, Konstanze V. and Werner, Rudolf A.}, title = {Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease}, series = {Diagnostics}, volume = {11}, journal = {Diagnostics}, number = {11}, issn = {2075-4418}, doi = {10.3390/diagnostics11112073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250227}, year = {2021}, abstract = {The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7\%) of patients did not have an established diagnosis, whereas in 7/34 (20.6\%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7\%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9\%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5\%) and PMR in the remaining 6/34 (17.6\%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4\%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95\%CI, 0.95-1.1) vs. PMR, 0.92 ± 0.1 (95\%CI, 0.85-0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95\%CI, 0.95-1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95\%CI, 0.83-1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95\%CI, 0.55-0.61)) and GCA + PMR (0.64 ± 0.09 (95\%CI, 0.57-0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.}, language = {en} } @article{NotzSchmalzingWedekinketal.2020, author = {Notz, Quirin and Schmalzing, Marc and Wedekink, Florian and Schlesinger, Tobias and Gernert, Michael and Herrmann, Johannes and Sorger, Lena and Weismann, Dirk and Schmid, Benedikt and Sitter, Magdalena and Schlegel, Nicolas and Kranke, Peter and Wischhusen, J{\"o}rg and Meybohm, Patrick and Lotz, Christopher}, title = {Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.581338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212815}, year = {2020}, abstract = {Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8\% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and na{\"i}ve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.}, language = {en} } @article{MahmoodSchmalzingDoerneretal.2020, author = {Mahmood, Zafar and Schmalzing, Marc and D{\"o}rner, Thomas and Tony, Hans-Peter and Muhammad, Khalid}, title = {Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.572475}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212380}, year = {2020}, abstract = {Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD- post-switch, and CD27-IgD- double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo.}, language = {en} } @article{JahnDorbathKircheretal.2019, author = {Jahn, Daniel and Dorbath, Donata and Kircher, Stefan and Nier, Anika and Bergheim, Ina and Lenaerts, Kaatje and Hermanns, Heike M. and Geier, Andreas}, title = {Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis}, series = {Nutrients}, volume = {11}, journal = {Nutrients}, number = {1}, doi = {10.3390/nu11010077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177222}, pages = {77}, year = {2019}, abstract = {Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut-liver axis.}, language = {en} } @article{LoefflerLoefflerKobsaretal.2015, author = {Loeffler, Claudia and Loeffler, J{\"u}rgen and Kobsar, Anna and Speer, Christian P. and Eigenthaler, Martin}, title = {Septic Vs Colonizing Group B Streptococci Differentially Regulate Inflammation and Apoptosis in Human Coronary Artery Endothelial Cells - a Pilot Study}, series = {Journal of Pediatrics and Neonatal Care}, volume = {2}, journal = {Journal of Pediatrics and Neonatal Care}, number = {2}, doi = {10.15406/jpnc.2015.02.00064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125596}, pages = {00064}, year = {2015}, abstract = {In this pilot study, we exemplify differences between a septic and a colonizing GBS strain during their interaction with Endothelial Cells by evaluating cytokine levels, surface and apoptosis-related molecules. These preliminary results indicate that in vitro infection using an exemplary septic GBS strain results in diminished activation of the innate immune response.}, language = {en} }