Autoimmune diseases and immunosuppressive therapy in relation to the risk of glioma

Effectors from the immune system can modulate the course and possibly the early development of gliomas. We, therefore, hypothesized that autoimmune diseases associated with increased immune-surveillance may also modulate the risk of human glioma. To test this hypothesis, we used data from the well-validated Clinical Practice Research Datalink (CPRD) GOLD from the UK to analyze the association of immune-related disorders or use of immunosuppressive drugs and the risk of glioma. We identified 3112 incident glioma cases diagnosed between 1995 and 2017. We randomly selected up to 10 controls, matching them to glioma cases on age, sex, index date, general practice, and number of years of active history in the database prior to the index date. We performed conditional logistic regression analyses to estimate Odds Ratios (ORs) of glioma among those exposed to allergies, autoimmune diseases, and immunosuppressive drugs. Overall, we found no materially altered association between a history of any autoimmune disease (OR 0.98, 95% CI 0.86-1.11), allergy (OR 0.97, 95% CI 0.89-1.05), or use of immunosuppressive drugs and the risk of glioma. However, subgroup analyses among younger patients found a statistically significant increased risk of glioma in patients with a history of inflammatory bowel disease (IBD) (OR 2.59, 95% CI 1.31-5.12). There was also an inverse association between asthma and risk of glioma in patients with longer survival (OR 0.73, 95% CI 0.58-0.91) and between long-term duration diabetes and risk of glioma (OR 0.71, 95% CI 0.53-0.96)

Darmmikrobiom bei primären Hirntumoren

ZUSAMMENFASSUNGPrimäre Hirntumoren kommen weniger häufig vor als andere Tumorentitäten. Das Glioblastom ist der häufigste primäre Hirntumor bei Erwachsenen und hat eine sehr schlechte Prognose. Die Pathophysiologie vieler Hirntumoren ist nur unzureichend verstanden. Eine kurative Therapie existiert bis auf wenige Ausnahmen nicht. Bei einigen soliden und hämatologischen Tumoren konnte in den letzten Jahren ein Zusammenhang zwischen Tumorentstehung und -progression mit Veränderungen im intestinalen Mikrobiom festgestellt werden. Zusammenhänge zwischen Mikrobiota und primären Hirntumoren wurden hingegen nicht publiziert.In der vorliegenden Arbeit werden Mechanismen dargestellt, die bei einer möglichen Interaktion zwischen Mikrobiom und Hirntumoren eine Rolle spielen können. Dabei steht die Schranke vom Darmepithel zum peripheren Blut und vom peripheren Blut zum Gehirn im Mittelpunkt des Interesses. Im Hinblick auf die Darm-Blutschranke sind Interaktionen zwischen Mikrobiom und Immunphänotyp sowie Metaboliten im peripheren Blut bekannt. Im Hinblick auf die Blut-Hirnschranke bestehen mögliche Assoziationen des Immunphänotyps und der Metaboliten im peripheren Blut mit der Immuninfiltration im Gehirn und der Induktion pathogeneserelevanter Signalkaskaden.</jats:p

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

AbstractSynovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-γ (IFN-γ) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-γR (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-β in isolated SF and the impact of IFN-γ/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-γ together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-γR in rheumatoid arthritis SF after 72 h incubation. Soluble BAFF was only induced by IFN-γ and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-γ-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-γ. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-γ alone increased shedding of VCAM-1 and expression of membrane TGFβ, which was associated with reduced survival of murine B cells. IFN-γ and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-γR and Fn14 under pro-inflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/or increased TGF-β production. IFN-γ is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis.</jats:p

Positive and negative cooperativity of TNF and Interferon-γ in regulating synovial fibroblast function and B cell survival in fibroblast/B cell co-cultures

Synovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-gamma (IFN-gamma) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-gamma R (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-beta in isolated SF and the impact of IFN-gamma/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-gamma together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-gamma R in rheumatoid arthritis SF after 72h incubation. Soluble BAFF was only induced by IFN-gamma and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-gamma-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-gamma. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-gamma alone increased shedding of VCAM-1 and expression of membrane TGF beta, which was associated with reduced survival of murine B cells. IFN-gamma and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-gamma R and Fn14 under pro-inflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/or increased TGF-beta production. IFN-gamma is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis