Interneuron-Vorläuferzellen migrieren während der Entwicklung weite Strecken von den Orten, an denen sie generiert werden, zu ihren Bestimmungsorten, an denen sie sich differenzieren und synaptisch in neuronale Netzwerke ...

The septic cardiomyopathy is associated with a high morbidity and mortality. In a sepsis, the contractility of a cardiomyocyte is reduced significantly. Consecutively, the cardiac output of the heart is compromised. This ...

Vor dem Hintergrund neuerer Ansätze aus Biomarker-Forschung und Psychoneuroimmunologie zur Ätiologie der Suizidalität setzt sich die folgende Arbeit mit dem Einfluss von Entzündungsparametern, Lipiden sowie psychischer ...

Kopf-Hals-Tumore stellen weltweit eine führende Rolle in der tumorbedingten Sterblichkeit dar. Kopf-Hals-Tumore sind eine sehr heterogene Gruppe von Tumorentitäten. Gesamtzahlen beziehen sich meist auf Schätzungen oder auf ...

The pulmonary epithelial barrier is the first line of defense against pathogens invading the lungs. If those are able to overcome this first barrier, myeloid cells of the innate immune system are instrumental for the antimicrobial defense and can directly eliminate invading microorganisms. This work aimed to identify novel mechanisms by which pulmonary epithelial cells and myeloid cells eliminate invading bacteria from the lungs. For this, infections with Legionella longbeachae were used to investigate a severe and often fatal form of pneumonia in humans known as Legionnaires’ disease in a mouse model. <br /> Following infection, infiltration of immune cells was dominated by neutrophils and, to a lesser extent, by monocytes. In addition to this, a significantly higher fraction of neutrophils contained L. longbeachae bacteria compared with other myeloid immune cells. Within host cells, bacteria translocated effector proteins mostly into neutrophils, and were residing in a vacuole resembling the Legionella-containing vacuole, as known from infections with L. pneumophila. However, neutrophils played an important role in the in vivo clearance of L. longbeachae, as mice depleted of this cell type exhibited significantly higher bacterial burden in the lungs. Besides neutrophils, monocytes also contributed to the control of pulmonary L. longbeachae infections, while lymphoid immune cells had no effect on the clearance of the bacteria. <br /> Molecularly, it is well known that IL18 is important in anti-bacterial defense by inducing lymphocytes to release IFNγ. However, IL18 receptor (IL18R) expression on lymphoid cells did apparently not promote L. longbeachae clearance. Instead, expression by pulmonary stromal cells was required and sufficient for elimination of the bacteria. Stromal expression of the IL18 receptor was almost confined to the ciliated epithelial cell compartment in the bronchioles. IL18R signaling in those cells did not promote mucus production but it rather enhanced the anti-bactericidal activity of neutrophils. Therefore, these results indicate a non-canonical role of IL18 in the defense against pulmonary L. longbeachae infection, linking non-immune pulmonary epithelial cells with inflammatory neutrophils....

Cytohesins are guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (Arf) proteins and promote the switch of Arfs to the active GTP-bound form. Cytohesins have been shown in different in vitro settings to affect cell motility, cell adhesion and chemotaxis of various leukocytes, which are fundamental processes necessary for efficient innate and adaptive immune responses. Furthermore, due to their engagement in phagocytic processes, cytohesins are also targeted by different pathogens during bacterial invasion to evade the immune responses and to exert their full pathogenicity. However, all the evidence for the regulation of immunity by cytohesins has derived from in vitro studies. The primary impact(s) of different cytohesins on the regulation and coordination of the immune responses in the control of infection in vivo has not been elucidated.<br /> The aim of this PhD thesis was to investigate the in vivo function of cytohesin-1, cytohesin-2 and cytohesin-3 in the complex immune responses and in pathogenesis by using acute infection with the respiratory pathogens Legionella pneumophila and influenza A virus in knockout mice. L. pneumophila is a Gram-negative bacteria and the causative agent for Legionnaires’ Disease, and influenza A virus causes ”flu”, which occurs in seasonal and pandemic outbreaks.<br /> These studies revealed that cytohesin-1 promotes T cell responses in both bacterial and viral respiratory infections. Moreover, in influenza A infection, cytohesin-1 deficiency hampered development of cognate T cells and their response to cognate antigens. Cytohesin-1 was demonstrated experimentally to be involved in the initial activation phase of naïve T cells and was required for optimal metabolic switching of T cells following activation. Lack of cytohesin-1 impaired the differentiation of distinct helper T cells, but also different memory and effector cell types.<br /> Myeloid-specific deletion of cytohesin-2 transiently impaired cDC recruitment in the course of bacterial infection highlighting a potential intrinsic role in cDC biology. However, this did not have major effects on the overall phenotype of L. pneumophila or influenza A infection.<br /> Interestingly, cytohesin-3 had an opposing role on T cells compared to cytohesin-1 and suppressed T cell immune responses in both L. pneumophila and influenza A infection. Increased infiltration of several different T cell subpopulations to the site of infection and increased acquisition of antigen-specific responses was observed in cytohesin-3 deficient mice. Furthermore, cytohesin-3 deficient T cells were more reactive to cognate stimulation leading to enhanced cellular immune responses. Additionally, recovery from L. pneumophila infection was delayed in cytohesin-3 deficient mice, suggesting that cytohesin-3 is important for preventing overactivation of T cells and any resulting inflammatory disease.<br /> In conclusion, this PhD thesis provided for the first time a broad in vivo examination of the role(s) of different cytohesins in the immune responses to pulmonary infections. Although minor roles were found for cytohesins in regulating innate immune responses, the primary role(s) of cytohesin-1 and cytohesin-3 appear to lie in the regulation of T cells. Cytohesin-1 promotes T cell responses potentially by providing the optimal (signalling) threshold and by supporting the bioenergetic adaptation following T cell activation, while cytohesin-3 may suppress T cell responses by acting as an immune checkpoint....

A common complication in patients suffering from chronic liver inflammation and fibrosis is the enhanced susceptibility to viral infections and weak responses to vaccination, which are associated with significant co-morbidities. ...

The chemokines CCL17 and CCL22 are both ligands of the chemokine receptor CCR4, which is expressed on dendritic cells (DC) and a variety of different effector T cells including regulatory T cells (Treg). Both chemokines are mainly produced by DC, but also by macrophages. CCL17 promotes numerous inflammatory and allergic diseases, whereas CCL22 is rather associated with an immunosuppressive milieu. These differential roles are reflected by preferential recruitment of distinct subsets of T cells to site of inflammation. While CCL17 facilitates chemotaxis of effector T cells and supports DC-T cell interactions as well as DC migration towards CCR7-ligands, CCL22 induces chemotaxis of Treg cells. In addition, CCL22 signalling induces a more rapid desensitisation and internalisation of CCR4 than CCL17, suggesting biased agonism of CCL17 and CCL22. The functionality of CCL17 and CCL22 should, therefore, be considered in combination as well as individually in the context of immune-related diseases. The role of CCL17 and CCL22 in infectious diseases has not been well understood. The central hypothesis was that CCL17 and CCL22 play important but potentially different roles during bacterial infection. This was modelled using a well-studied bacterial pathogen, Salmonella enterica serovar Typhimurium (STM). It was hypothesised that CCL17 expression may direct the migration of STM-infected DC from the gut to draining lymph nodes a key bottleneck in early infection that controls bacterial dissemination to systemic sites. It was further hypothesised that CCL22 may play a role in immune regulation through the induction of Treg cells. These regulatory cells may have downstream effects on Th1 responses, which are critical for the control of Salmonella infection.<br /> In the first part of the thesis, the role of CCL17⁺ DC in the transmission of STM was investigated. Histological analysis of CCL17 reporter mice revealed that CCL17-expressing cells co-localised with Salmonella in the dome area of Peyer’s patches (PP). Further, CCL17-expressing DC contributed to dissemination of STM from PP to the mesenteric lymph nodes (mLN). Within the mLN, STM were found within CCL17⁺ DC as well as in other DC, monocytes and macrophages. Analysis of the STM⁺ DC subpopulations revealed that all DC subsets carried STM, but the CD103⁺ CD11b^- DC could be identified as the main STM-containing population. STM infection triggered upregulation of CCL17 expression in specific intestinal DC subsets in a tissue-specific manner. Interestingly, the CD103⁺ DC subsets upregulated CCL17 in the PP, whereas CD103^- DC subsets upregulated CCL17 in the mLN.<br /> In the second part of this thesis, the role of CCL17 and CCL22 in the induction of antigen-specific CD4⁺ T cell responses was investigated. CCL17/CCLL22 double-deficient, CCL17- and CCL22 single-deficient, and wild type mice were analysed after live-attenuated STM TAS2010 vaccination, vaccination/challenge and in steady-state. Mice deficient in both chemokines, CCL22 and CCL17, demonstrated a reduction of effector T_reg cells. This promoted an enhanced STM- specific Th1 immune response characterised by an expansion of Th1 T cells, resulting in a more favourable effector T_reg/activated T_conv ratio and a significantly improved vaccine efficacy to challenge with virulent Salmonella.<br /> In conclusion, the work presented within this thesis showed the contribution of CCL17⁺ DC in the dissemination of STM and identified CCL22 as a potential target to improve vaccine approaches....