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CD8 + T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine + (PS) extracellular vesicles (EVs). These EVs interact especially with CD8 + T cells; however, it remains unclear whether they can actively modulate CD8 + T cell responses. In this study, we have developed a method to analyze cell-bound PS + EVs and their target cells in vivo. We show that EV + cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8 + T cells. Superresolution imaging revealed that PS + EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8 + T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS + EVs provide Ag-specific adjuvant effects to activated CD8 + T cells in vivo.

Platelets are first responders in thrombosis and hemostasis, but also central players in inflammation. Compared to platelets recruited to thrombi, immune-responsive platelets use distinct effector functions including Arp2/3-dependent migration along adhesive substrate gradients (haptotaxis), which prevents inflammatory bleeding and contributes to host defense. How platelet migration in this context is regulated on a cellular level is incompletely understood. Here, we use time-resolved morphodynamic profiling of individual platelets to show that migration, in contrast to clot retraction, requires anisotropic myosin IIa-activity at the platelet rear which is preceded by polarized actin polymerization at the front to initiate and maintain migration. Polarization of migrating platelets is coordinated by integrin GPIIb-dependent outside-in signaling via Gα13 to trigger tyrosine kinase c-Src/14-3-3ζ-dependent lamellipodium formation and functions independent of soluble agonists or chemotactic signals. Inhibitors of this signaling cascade, including the clinically employed ABL/c-Src inhibitor dasatinib, interfere predominantly with the migratory capacity of platelets, without major impairment of classical platelet functions. In murine inflammation models, this translates to reduced migration of platelets visualized by 4D intravital microscopy, resulting in increased inflammation-associated hemorrhage in acute lung injury. Finally, platelets isolated from dasatinib-treated leukemia patients prone to clinically relevant hemorrhage exhibit prominent migration defects, while other platelet functions are only partially affected. In summary, we define a distinct signaling pathway essential for migration, and provide novel mechanistic insights explaining dasatinib-related platelet dysfunction and bleeding.

High-content imaging and single-cell genomics are two of the most prominent high-throughput technologies for studying cellular properties and functions at scale. Recent studies have demonstrated that information in large imaging datasets can be used to estimate gene mutations and to predict the cell-cycle state and the cellular decision making directly from cellular morphology. Thus, high-throughput imaging methodologies, such as imaging flow cytometry can potentially aim beyond simple sorting of cell-populations. We introduce IFC-seq, a machine learning methodology for predicting the expression profile of every cell in an imaging flow cytometry experiment. Since it is to-date unfeasible to observe single-cell gene expression and morphology in flow, we integrate uncoupled imaging data with an independent transcriptomics dataset by leveraging common surface markers. We demonstrate that IFC-seq successfully models gene expression of a moderate number of key gene-markers for two independent imaging flow cytometry datasets: (i) human blood mononuclear cells and (ii) mouse myeloid progenitor cells. In the case of mouse myeloid progenitor cells IFC-seq can predict gene expression directly from brightfield images in a label-free manner, using a convolutional neural network. The proposed method promises to add gene expression information to existing and new imaging flow cytometry datasets, at no additional cost.

Impairment of vascular integrity is a hallmark of inflammatory diseases. We recently reported that single immune-responsive platelets migrate and reposition themselves to sites of vascular injury to prevent bleeding. However, it remains unclear how single platelets preserve vascular integrity once encountering endothelial breaches. Here we demonstrate by intravital microscopy combined with genetic mouse models that procoagulant activation (PA) of single platelets and subsequent recruitment of the coagulation cascade are crucial for the prevention of inflammatory bleeding. Using a novel lactadherin-based compound, we detect phosphatidylserine (PS)-positive procoagulant platelets in the inflamed vasculature. We identify exposed collagen as the central trigger arresting platelets and initiating subsequent PA in a CypD- and TMEM16F-dependent manner both in vivo and in vitro. Platelet PA promotes binding of the prothrombinase complex to the platelet membrane, greatly enhancing thrombin activity and resulting in fibrin formation. PA of migrating platelets is initiated by costimulation via integrin αIIbβ3 (GPIIBIIIA)/Gα13-mediated outside-in signaling and glycoprotein VI signaling, leading to an above-threshold intracellular calcium release. This effectively targets the coagulation cascade to breaches of vascular integrity identified by patrolling platelets. Platelet-specific genetic loss of either CypD or TMEM16F as well as combined blockade of platelet GPIIBIIIA and glycoprotein VI reduce platelet PA in vivo and aggravate pulmonary inflammatory hemorrhage. Our findings illustrate a novel role of procoagulant platelets in the prevention of inflammatory bleeding and provide evidence that PA of patrolling platelet sentinels effectively targets and confines activation of coagulation to breaches of vascular integrity.

SUMMARYInfection with SARS-CoV-2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID-19 patients. In addition, immune dysfunction occurs in patients characterized by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets, and platelet-derived microparticles (PMP), during the clinical course of COVID-19. We found an unexpectedly high amount of blood cells loaded with PS+ PMPs for weeks after the initial COVID-19 diagnosis. Elevated frequencies of PS+PMP+ PBMCs correlated strongly with increasing disease severity. As a marker, PS outperformed established laboratory markers for inflammation, leucocyte composition, and coagulation, currently used for COVID-19 clinical outcome prognosis. PS+ PMPs preferentially bound to CD8+ T cells with gene expression signatures of proliferating effector rather than memory T cells. As PS+ PMPs carried programmed death-ligand 1 (PD-L1), they may affect T cell expansion or function. Our data provide a novel marker for disease severity and show that PS, which can trigger the blood coagulation cascade, the complement system, and inflammation, resides on activated immune cells. Therefore, PS may serve as a beacon to attract thromboinflammatory processes toward lymphocytes and cause immune dysfunction in COVID-19.

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage−HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients., Author summary Dendritic cells (DCs) recognize viral infections and trigger innate and adaptive antiviral immunity. COVID-19 severity is greatly influenced by the host immune response and modulation of DC generation and function after SARS-CoV-2 infection could play an important role in this disease. This study identifies a long-lasting reduction of DCs in the blood of COVID-19 patients and a functional impairment of these cells. Downregulation of costimulatory molecule CD86 and upregulation of inhibitory molecule PD-L1 in conventional DCs correlated with disease severity and were accompanied by a reduced ability to stimulate T cells. A higher frequency of CD163+ CD14+ cells in the DC3 subpopulation correlated with systemic inflammation suggesting that these cells may play a role in inflammatory responses of COVID-19 patients. Depletion and functional impairment of DCs beyond the acute phase of the disease may have consequences for susceptibility to secondary infections and clinical management of COVID-19 patients.

Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4

Exhausted immune responses to chronic diseases represent a major challenge to global health. We studied CD4+ T cells in a mouse model where presentation of their antigen can be regulated. When the cells are driven through the effector phase, but are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion and anergy markers, modulate their MAP kinase, mTORC1 and Ca2+/calcineurin signaling pathways with dose and time, lose their capacity to transmit help to B cells and undergo, at the highest dose, apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. The cells also adapt to antigen removal and recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

SUMMARYThe in vivo detection of dead cells remains a major challenge due to technical hurdles. Here we present a novel method, where injection of fluorescent Milk fat globule-EGF factor 8 protein (MFG-E8) in vivo combined with imaging flow cytometry and deep learning allows the identification of dead cells based on their surface exposure of phosphatidylserine (PS) and other image parameters. A convolutional autoencoder (CAE) was trained on defined pictures and successfully used to identify apoptotic cells in vivo. However, unexpectedly, these analyses also revealed that the great majority of PS+ cells were not apoptotic, but rather live cells associated with PS+ extracellular vesicles (EVs). During acute viral infection apoptotic cells increased slightly, while up to 30% of lymphocytes were decorated with PS+ EVs of Dendritic cell exosomal origin. The combination of recombinant fluorescent MFG-E8 and the CAE-method will greatly facilitate analyses of cell death and EVs in vivo.

The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5.

Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

Anabolic metabolism of antigen-stimulated T cells is coordinated by mTOR which is activated by TCR and IL-2 signals. We show that mTORC1 regulates both the exit of quiescence and later divisions as Raptor-deficient T cells proceed 3x slower through each cell division in vivo. We noticed that following stimulation the amount of RNA per cell increases dramatically (10–40x) and is reduced to ~50% in Raptor-, but not Rictor-deficient T cells. RNAseq data indicate that this applies to all RNA polymerase I- and II-dependent biotypes. Using Coulter volume measurements, RNA-, FISH- and imaging-flow cytometry we determined that following stimulation the cell volume increases five-fold. It consists of the increase of nuclear volume and nucleolar rRNA synthesis on day 1 and a further increase of cytoplasmic volume on day 2. Raptor-deficiency delays and diminishes the growth of these cellular compartments, decreases ribosomal biosynthesis and thus the cell volume. Inhibitors of rRNA transcription block cell cycle progression at two checkpoints, of which only the G1/S transition is regulated by Raptor. We found that mTORC1 activity depends on ongoing rRNA synthesis in early activation and regulates the further synthesis rate. Altogether our data show that mTOR-adjusted cell physiology and the biosynthesis of ribosomal ‘hardware’ are reciprocally regulated during clonal T cell expansion.

Exhausted immune responses to chronic diseases represent a major challenge to global health. To explore their cell fate and plasticity in exhaustion, we analyzed CD4+T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase, and are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion markers, resemble naturally anergic cells and become unable to help B cells and, at the highest dose, undergo apoptosis. Mechanistically, TCR signaling pathways are modulated with increasing dose and time. Ca2+ fluxes were found to be more robust to persistent antigen presentation while the MAPK and Akt pathways are easily desensitized. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Preliminary data indicate that antigen-exhausted CD4+T cells retain their plasticity for at least 30 days and are able to adjust to different levels of antigen. Our data suggest a dynamic response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

Summary: Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4+ T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca2+/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

Exhausted immune responses to chronic diseases represent a major challenge to global health. We studied CD4+ T cells in a mouse model where presentation of their antigen can be regulated. When the cells are driven through the effector phase, but are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion and anergy markers, modulate their MAP kinase, mTORC1 and Ca2+/calcineurin signaling pathways with dose and time, lose their capacity to transmit help to B cells and undergo, at the highest dose, apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. The cells also adapt to antigen removal and recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

The host-cell restriction factor SERINC5 potently suppresses the infectivity of HIV, type 1 (HIV-1) particles, and is counteracted by the viral pathogenesis factor Nef. However, the molecular mechanism by which SERINC5 restricts HIV-1 particle infectivity is still unclear. Because SERINC proteins have been suggested to facilitate the incorporation of serine during the biosynthesis of membrane lipids and because lipid composition of HIV particles is a major determinant of the infectious potential of the particles, we tested whether SERINC5-mediated restriction of HIV particle infectivity involves alterations of membrane lipid composition. We produced and purified HIV-1 particles from SERINC5293T cells with very low endogenous SERINC5 levels under conditions in which ectopically expressed SERINC5 restricts HIV-1 infectivity and is antagonized by Nef and analyzed both virions and producer cells with quantitative lipid MS. SERINC5 restriction and Nef antagonism were not associated with significant alterations in steady-state lipid composition of producer cells and HIV particles. Sphingosine metabolism kinetics were also unaltered by SERINC5 expression. Moreover, the levels of phosphatidylserine on the surface of HIV-1 particles, which may trigger uptake into non-productive internalization pathways in target cells, did not change upon expression of SERINC5 or Nef. Finally, saturating the phosphatidylserine-binding sites on HIV target cells did not affect SERINC5 restriction or Nef antagonism. These results demonstrate that the restriction of HIV-1 particle infectivity by SERINC5 does not depend on alterations in lipid composition and organization of HIV-1 particles and suggest that channeling serine into lipid biosynthesis may not be a cardinal cellular function of SERINC5.

MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4+ T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify hnRNP U as a suppressor of exon7 inclusion. Whereas selective depletion of MALT1A impairs T-cell signalling and activation, downregulation of hnRNP U enhances MALT1A expression and T-cell activation. Thus, TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation., MALT1 regulates NFκB signalling both as a scaffolding protein and as a protease. Here the authors show that during T cell activation the expression of MALT1 gene switches to an alternatively spliced variant, which increases TCR signal transduction due to enhanced TRAF6 binding.

Follicular dendritic cells (FDCs) are stromal cells residing in primary follicles and in germinal centers of secondary and tertiary lymphoid organs (SLOs and TLOs). There, they play a crucial role in B-cell activation and affinity maturation of antibodies. FDCs have the unique capacity to bind and retain native antigen in B-cell follicles for long periods of time. Therefore, FDCs shape the B-cell antigenome (the sum of all B-cell antigens) in SLOs and TLOs. In this review, we discuss recent findings that explain how this stromal cell type can arise in almost any tissue during TLO formation and, furthermore, focus on the mechanisms of antigen capture and retention involved in the generation of long-lasting antigen depots displayed on FDCs. Follicular dendritic cells (FDCs) are cells of stromal origin that are indispensable for secondary lymphoid organ (SLO) and tertiary lymphoid organ (TLO) development and maintenance. They are located in the central region of primary follicles and in the light zone of germinal centers [GCs; (1, 2)]. Their most striking feature is the ability to capture and retain native antigen. This was first observed in 1965, when Mitchell and Abbott analyzed the location of iodine-125 labeled flagella of Salmonella Adelaide in draining lymph nodes of mice using high-resolution electron microscopic autoradiographs (3). Since then, the role of FDCs as crucial players in antibody responses has been widely accepted. Their main function being the presentation of native antigen, in the form of immune complexes (ICs), to B cells, thereby driving their affinity maturation during the GC reaction. In this review, we focus first on recent findings that help to explain, how FDCs can arise in almost any tissue undergoing TLO formation and, second, on their ability to retain antigen in B-cell follicles. For a more detailed description of FDC biology, we refer the reader to other recent reviews (4, 5)., Frontiers in Immunology, 7, ISSN:1664-3224

Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.

Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.

The gut microbiota has recently been recognized for its role in immune regulation, and changes in gut microbiota may be the basis for an increased incidence of autoimmune diseases and asthma in developed countries. Beneficial microbes produce factors that are distributed systemically, and therefore can influence peripheral inflammatory responses. Such symbiosis factors are important for the control and resolution of inflammation and autoimmune diseases. Here we discuss immune regulation by recently identified symbiosis factors and how certain environmental factors favor their production and influence the composition of the gut microflora.

Referring to the seminal model of Venables, this paper aims at quantifying the degree of vertical specialization in models of the new economic geography. The analysis is made in two steps. First, the paper develops a measuring concept for the strength of forward and backward linkages. As a main finding, the associated values only depend on the substitution elasticity between intermediate inputs as well as the corresponding share in downstream costs. In the second step, the Venables model is alternatively solved in order to determine the domain of vertical specialization and investigates its properties with respect to the strength of vertical linkages. Resumen En referencia al modelo seminal de Venables, el objetivo de este articulo es cuantificar el grado de especializacion vertical en modelos de la Nueva Geografia Economica. El analisis se realiza en dos pasos. Primero, el articulo desarrolla un concepto para medir la solidez de los vinculos hacia adelante y hacia atras entre empresas de productos intermedios que abastecen a las de productos para el consumidor. Como resultado principal, los valores asociados dependen solamente de la elasticidad de la posible sustitucion entre insumos intermedios, asi como de la parte correspondiente de los costos que haya a continuacion en la cadena. En el segundo paso, el modelo de Venables se resuelve alternativamente para determinar el ambito de especializacion vertical e investiga sus propiedades con respecto a la solidez de los vinculos verticales.

The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.

This paper discusses a model of the New Economic Geography, in which the seminal core-periphery model of Krugman [Krugman, P., 1991, Increasing returns and economic geography, Journal of Political Economy 99, 483–499.] is extended by endogenous research activities. Beyond the common ‘anonymous’ consideration of R&D expenditures within fixed costs, this model introduces in an analytically tractable approach vertical product differentiation in combination with a de-integrated R&D sector. In the context of international factor mobility, the destabilizing effects of a mobile scientific workforce are analyzed. Based upon a simple welfare analysis, a consideration of R&D promoting policy instruments and their spatial implications, this paper makes a contribution to the brain-drain debate.

Economic geography aims to explain agglomeration primarily through the channels of increasing returns, monopolistic competition and international factor mobility. By contrast, this paper constructs a theoretical model based on capital market frictions. Monopolistically competitive firms are run by managers who are subject to moral hazard. Endogenously, the impact of capital market frictions is smaller in industrialized regions, which makes it cheaper to incentivize managers. Consequently, firms can pay higher interest rates on capital in these regions, which in turn attracts more capital. This simple mechanism leads to a host of effects and, therefore, predictions in terms of economic development and corporate governance.

Follicular dendritic cells (FDCs) were originally identified by their specific morphology and by their ability to trap immune-complexed antigen in B cell follicles. By virtue of the latter as well as the provision of chemokines, adhesion molecules, and trophic factors, FDCs participate in the shaping of B cell responses. Importantly, FDCs also supply tingible body macrophages (TBMs) with the eat-me-signaling molecule milk fat globule-EGF factor 8 (Mfge8), thereby enabling the disposal of apoptotic B cells. Recent studies have provided fundamental insights into the multiple functions of FDCs in both physiological and pathophysiological contexts and into their origin. Here we review these findings, and discuss current concepts related to FDC histogenesis both in lymphoid organs and in inflammatory lymphoneogenesis.

Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.

Purpose: This paper aims to discuss whether product research and development (R&D) in developed economies tends to be too high compared with the socially desired level. Design/methodology/approach: In this context, a model of vertical and horizontal product differentiation within the Dixit-Stiglitz framework of monopolistic competition is set up. Firms compete in horizontal attributes of their products, and also in quality that can be controlled by R&D investments. Findings: The paper reveals that in monopolistic-competitive industries, R&D intensity is positively correlated with market concentration. Furthermore, welfare and policy analysis demonstrate an overinvestment in R&D with the result that vertical differentiation is too high and horizontal differentiation is too low. The only effective policy instrument in order to contain welfare losses is a price control of R&D services. Originality/value: Considering the extent of product R&D as well as the political efforts to promote public and private research, this paper scrutinizes its benefit incorporating income and employment effects. Thus, it goes beyond partial-analytical models of the existing industrial organization literature and provides a larger base of political analysis. © Emerald Group Publishing Limited.

This paper picks up the seminal model of Venables (1996) and provides a quantifying concept for the sectoral coherence in vertical-linkage models of the New Economic Geography. Based upon an alternative approach to solve the model and to determine critical trade cost values, this paper focuses on the interdependencies between agglomeration, specialization and the strength of vertical linkages. A central concern is the idea of an ’industrial base,’ which is attracting linked industries but is persistent to relocation. As a main finding, the intermediate cost share and substitution elasticity basically determine the strength of linkages. Thus, these parameters affect how strong the industrial base responds to changes in trade costs, relative wages and market size.

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMphis). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8(-/-) mice, all splenic Mfge8 was derived from FDCs rather than TBMphis. However, Mfge8(-/-) TBMphis acquired and displayed Mfge8 only when embedded in Mfge8(+/+) stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMphi-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8(-/-) mice. Hence, FDCs facilitate TBMphi-mediated corpse removal, and their malfunction may be involved in autoimmunity.

Prior to invading the nervous system, prions frequently colonize lymphoid organs and sites of inflammatory lymphoneogenesis, where they colocalize with Mfge8+ follicular dendritic cells (FDCs). Here, we report that soft-tissue granulomas, a frequent feature of chronic inflammation, expressed the cellular prion protein (PrPC, encoded by Prnp) and the lymphotoxin receptor (LTbetaR), even though they lacked FDCs and did not display lymphoneogenesis. After intraperitoneal prion inoculation, granulomas of Prnp(+/+) mice, but not Prnp(-/-) granulomas or unaffected Prnp(+/+) skin, accumulated prion infectivity and disease-associated prion protein. Bone-marrow transfers between Prnp(+/+) and Prnp(-/-) mice and administration of lymphotoxin signaling antagonists indicated that prion replication required radioresistant PrPC-expressing cells and LTbetaR signaling. Granulomatous PrPC was mainly expressed by stromal LTbetaR+ mesenchymal cells that were absent from unaffected subcutis. Hence, granulomas can act as clinically silent reservoirs of prion infectivity. Furthermore, lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs.

This paper discusses a model of the New Economic Geography, in which the seminal core-periphery model of Krugman (1991) is extended by endogenous research activities. Beyond the common ’anonymous’ consideration of R&D expenditures within fixed costs, this model introduces vertical product differentiation, which requires services provided by an additional R&D sector. In the context of international factor mobility, the destabilizing effects of a mobile scientific workforce are analyzed. In combination with a welfare analysis and a consideration of R&D promoting policy instruments and their spatial implications, this paper makes a contribution to the so-called brain drain debate.

Prion infections induce severe disruption of the central nervous system with neuronal vacuolation and extensive glial reactions, and invariably lead to death of affected individuals. The molecular underpinnings of these events are not well understood. To better define the molecular consequences of prion infections, we analyzed the transcriptional response to persistent prion infection in a panel of three murine neural cell lines in vitro. Colony spot immunochemistry assays indicated that 65-100% of cells were infected in each line. Only the Nav1 gene was marginally modulated in one cell line, whereas transcripts previously reported to be derailed in prion-infected cells were not confirmed in the present study. We attribute these discrepancies to the experimental stringency of the current study, which was performed under conditions designed to minimize potential genetic drifts. These findings are at striking variance with gene expression studies performed on whole brains upon prion infections in vivo, suggesting that many of the latter changes represent secondary reactions to infection. We conclude that, surprisingly, there are no universal transcriptional changes induced by prion infection of neural cells in vitro.

Die Biotechnologie, identifiziert als eine der strategischen Zukunftstechnologien, ist gekennzeichnet durch eine hohe Forschungsintensität mit breiten Anwendungsfeldern. Nach einer seit 2001 andauernden Konsolidierungsphase steht die Branche gegenwärtig vor neuen Herausforderungen: der EU-Osterweiterung sowie der massiv vorangetriebenen Technologiepolitik in den Schwellenländern Indien und China. Einerseits entstehen durch die Integration dieser Wachstumsmärkte neue Forschungs-, Produktions- und Absatzmöglichkeiten, andererseits birgt der steigende Wettbewerbsdruck ein nicht unwesentliches Risiko für die junge deutsche Branche. der vorliegende Beitrag setzt die Ergebnisse einer 2006 durchgeführten Online-Befragung deutscher BT-Unternehmen in direkten Bezug zur niedersächsischen BT-Industrie. Im zweiten Schritt wird die Analyse durch numerische Simulation der EU-Erweiterung 2004 im Rahmen der so genannten New Economic Gerography ergänzt. Die Analysen zeigen eine Verlagerungstendenz der Biotechnologiebranche in die europäische Peripherie. Diese Tendenz wird jedoch auf Grund von Infrastruktur- und Faktormarktrestriktionen gravierend gedämpft.

Nach einer mehrjährigen Konsolidierungsphase konnte die deutsche Biotechnologiebranche zunehmend Marktanteile im internationalen Wettberwerb gewinnen. Derzeitig werden zwei Entwicklungen innerhalb der Branche intensiv diskutiert: die Osterweiterung der Europäischen Union und die zunehmende wirtschaftlich-technologische Bedeutung der Schwellenländer, allen voran Indien und China. Hierbei sind folgende Fragestellungen von besonderem Interesse: Ist mit der einer Verstärkung des internationalen Branchenwettbewerbs zu rechnen? Wie positioniert sich Deutschland? Welche Rollen spielen Absatz-, Forschungs- und Produktionsbedingungen in dern Erweiterungs- und Schwellenländern? Welche Implikationen folgen für dor deutsche Technologie- und Standortpolitik? Die vorliegende Arbeit fast die Ergebnisse einer Unternehmensbefragung zusammen, die durch die Abteilung Innovation und Wachstum im Frühjahr 2006 durchgeführt wurde.

We have studied the role of CD21/35, which bind derivatives of complement factors C3 and C4, in extraneural prion replication and neuroinvasion. Upon administration of small prion inocula, CD21/35−/− mice experienced lower attack rates and delayed disease over both wild-type (WT) mice and mice with combined C3 and C4 deficiencies. Early after inoculation, CD21/35−/− spleens were devoid of infectivity. Reciprocal adoptive bone marrow transfers between WT and CD21/35−/− mice revealed that protection from prion infection resulted from ablation of stromal, but not hemopoietic, CD21/35. Further adoptive transfer experiments between WT mice and mice devoid of both the cellular prion protein PrPC and CD21/35 showed that splenic retention of inoculum depended on stromal CD21/35 expression. Because both PrPC and CD21/35 are highly expressed on follicular dendritic cells, CD21/35 appears to be involved in targeting prions to follicular dendritic cells and expediting neuroinvasion following peripheral exposure to prions.

This paper discusses the interdenpendencies that exist between vertically-linked industries in the (Spence-)Dixit-Stiglitz model of monopolistic competition. The main objective is to develop a concept for quantifying the magnitude of sectoral coherence in models of the New Economic Geography. It is motivated by the suggestion, by Venables (1996), that `strategic industries` be identified in terms of their agglomeration potential. Using a partial-analytic approach, we focus on inter-industrial relations in a closed economy to draw conclusions regarding international trade. We ascertain that two factors have an impact upon the strength of industrial linkages: 1) the monopolistic scope of intermediate suppliers, in terms of (technical) substitution elasticity; and the share in downstream costs for intermediates. Within a simulation study, this paper applies this new theoretical concept to eight basic industries across ten European countries.

Die ökonomischen Implikationen einer verstärkten Migration deutscher Unternehmen nach Osteuropa und Asien werden derzeit intensiv diskutiert. Wichtige wirtschaftliche Akteure sind KMU des verarbeitenden Gewerbes, die zum einen Elemente komplexer Wertschöpfungsketten bilden, zum anderen häufig durch Produktdifferenzierung die Märkte jeder Lieferstufe gestalten. Das vorliegende Papier soll in dieser Diskussion einen Beitrag aus Sicht der Neuen Ökonomischen Geographie leisten. In einem partialanalytischen Modell wird untersucht, welchen Einfluss das Spannungsfeld von Produktions- und Transportkosten auf die Standortwahl der Unternehmen ausübt und welche Parameterkonstellationen industrielle Agglomeration fördern bzw. behindern. In diesem Zuge wird das Modell von Venables (1996) um standortdifferenzierte Technologien erweitert und im Rahmen einer Simulation auf Unternehmen des metallerzeugenden und -verarbeitenden Gewerbes übertragen.

Prion infectivity is typically restricted to the central nervous and lymphatic systems of infected hosts, but chronic inflammation can expand the distribution of prions. We tested whether chronic inflammatory kidney disorders would trigger excretion of prion infectivity into urine. Urinary proteins from scrapie-infected mice with lymphocytic nephritis induced scrapie upon inoculation into noninfected indicator mice. Prionuria was found in presymptomatic scrapie-infected and in sick mice, whereas neither prionuria nor urinary PrP Sc was detectable in prion-infected wild-type or PrP C -overexpressing mice, or in nephritic mice inoculated with noninfectious brain. Thus, urine may provide a vector for horizontal prion transmission, and inflammation of excretory organs may influence prion spread.

The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet derived growth factor receptor ß (PDGFRß). PDGFRß Cre driven reporter gene recombination resulted in FDC labeling whereas conditional ablation of PDGFRß+ derived cells abolished FDC indicating that FDC originate from PDGFRß+ cells. Lymphotoxin a overexpressing prion protein (PrP)+ kidneys developed PrP+ FDC after transplantation into PrP mice confirming that preFDC exist outside lymphoid organs. Adipose tissue derived PDGFRß+ stromal vascular cells responded to FDC maturation factors and when transplanted into lymphotoxin ß receptor (LTßR) kidney capsules differentiated into Mfge8+CD21/35 +Fc?RIIß+PrP+ FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte deficient mice contained perivascular PDGFRß+ FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation. PaperFlick: © 2012 Elsevier Inc.