Refine
Has Fulltext
- yes (43)
Is part of the Bibliography
- yes (43)
Year of publication
Document Type
- Journal article (31)
- Doctoral Thesis (12)
Keywords
- cytokines (43) (remove)
Institute
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (10)
- Medizinische Klinik und Poliklinik II (8)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (6)
- Neurologische Klinik und Poliklinik (6)
- Kinderklinik und Poliklinik (4)
- Medizinische Klinik und Poliklinik I (4)
- Theodor-Boveri-Institut für Biowissenschaften (4)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (2)
- Frauenklinik und Poliklinik (2)
- Graduate School of Life Sciences (2)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 813871 (1)
The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation.
Der menschliche Körper besitzt Anpassungsmechanismen, die es ihm ermöglichen, sich an verschiedene Belastungssituationen anzupassen. Es gab in letzter Zeit mehrere Hinweise darauf, dass diese Mechanismen durch die Ausschüttung von Zytokinen, bzw. Myokinen durch die betroffenen Zellen selbst ausgelöst werden. In dieser Arbeit wurden die Serumkonzentration von Myostatin, Follistatin, Follistatin-like-3, Interleukin 6, Interleukin 8 und Klotho vor und nach einer kurzen körperlichen Belastung bestimmt. Dabei konnte allerdings keine signifikante Änderung der Konzentrationen nachgewiesen werden, was die Frage aufwirft, ob mesenchymales Gewebe, insbesondere Muskelgewebe, überhaupt über einen klassischen endokrinen Sekretionsmechanismus verfügt.
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 naïve 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.
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.
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.
Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4\(^+\) and CD8\(^+\) T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.
Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL‐6, IL‐1b, TNF‐α), leukocytes, C‐reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL‐6 and TNF‐α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required.
Membrane lymphotoxin-α\(_2\)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist
(2021)
In the early 1990s, it has been described that LTα and LTβ form LTα\(_2\)β and LTαβ\(_2\) heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ\(_2\)–LTβR system has been intensively studied while the LTα\(_2\)β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα\(_2\)β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα\(_2\)β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα\(_2\)β (memLTα\(_2\)β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα\(_2\)β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.
Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.
Systemic sclerosis (SSc) is a severe chronic disease with a broad spectrum of clinical manifestations. SSc displays disturbed lymphocyte homeostasis. Immunosuppressive medications targeting T or B cells can improve disease manifestations. SSc clinical manifestations and immunosuppressive medication in itself can cause changes in lymphocyte subsets. The aim of this study was to investigate peripheral lymphocyte homeostasis in SSc with regards to the immunosuppression and to major organ involvement. 44 SSc patients and 19 healthy donors (HD) were included. Immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting was performed. Cytokine secretions of stimulated B cell cultures were measured. SSc patients without immunosuppression compared to HD displayed lower γδ T cells, lower T helper cells (CD3+/CD4+), lower transitional B cells (CD19+/CD38++/CD10+/IgD+), lower pre-switched memory B cells (CD19+/CD27+/IgD+), and lower post-switched memory B cells (CD19+/CD27+/IgD-). There was no difference in the cytokine production of whole B cell cultures between SSc and HD. Within the SSc cohort, mycophenolate intake was associated with lower T helper cells and lower NK cells (CD56+/CD3-). The described differences in peripheral lymphocyte subsets between SSc and HD generate further insight in SSc pathogenesis. Lymphocyte changes under effective immunosuppression indicate how lymphocyte homeostasis in SSc might be restored.