University of Mainz Medical Center

Mainz, Germany

University of Mainz Medical Center

Mainz, Germany
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Klose C.S.N.,University of Mainz Medical Center | Klose C.S.N.,Albert Ludwigs University of Freiburg | Flach M.,University of Mainz Medical Center | Flach M.,Albert Ludwigs University of Freiburg | And 20 more authors.
Cell | Year: 2014

Innate lymphoid cells (ILCs) are a recently recognized group of lymphocytes that have important functions in protecting epithelial barriers against infections and in maintaining organ homeostasis. ILCs have been categorized into three distinct groups, transcriptional circuitry and effector functions of which strikingly resemble the various T helper cell subsets. Here, we identify a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, "helper-like" ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages, but not into conventional natural killer (cNK) cells that have been considered an ILC1 subset. Instead, the CHILP gave rise to a peculiar NKp46+ IL-7Rα+ ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages. Such ILC1s coproduced high levels of IFN-γ and TNF and protected against infections with the intracellular parasite Toxoplasma gondii. Our data significantly advance our understanding of ILC differentiation and presents evidence for a new ILC lineage that protects barrier surfaces against intracellular infections. © 2014 Elsevier Inc.


Flach M.,University of Mainz Medical Center | Diefenbach A.,University of Mainz Medical Center
Cell Metabolism | Year: 2015

White-to-beige conversion of adipocytes is one of the most promising approaches to therapeutically target obesity; however, the signals driving this process had largely remained unclear. Recently, two publications, Brestoff et al. (2014) in Nature and Lee et al. (2015) in Cell, showed that group 2 innate lymphoid cells directly regulate adipocyte differentiation and drive the growth of beige fat. © 2015 Elsevier Inc.


Fasano A.,Massachusetts General Hospital | Sapone A.,Massachusetts General Hospital | Sapone A.,Beth Israel Deaconess Medical Center | Zevallos V.,University of Mainz Medical Center | And 2 more authors.
Gastroenterology | Year: 2015

During the past decade there has been an impressive increase in popularity of the gluten-free diet (GFD) - now the most trendy alimentary habit in the United States and other countries. According to recent surveys, as many as 100 million Americans will consume gluten-free products within a year. Operating under the concept that the GFD benefits only individuals with celiac disease, health care professionals have struggled to separate the wheat from the chaff; there are claims that eliminating gluten from the diet increases health and helps with weight loss, or even that gluten can be harmful to every human being. However, apart from unfounded trends, a disorder related to ingestion of gluten or gluten-containing cereals, namely nonceliac gluten sensitivity (NCGS), has resurfaced in the literature, fueling a debate on the appropriateness of the GFD for people without celiac disease. Although there is clearly a fad component to the popularity of the GFD, there is also undisputable and increasing evidence for NCGS. However, we require a better understanding of the clinical presentation of NCGS, as well as its pathogenesis, epidemiology, management, and role in conditions such as irritable bowel syndrome, chronic fatigue, and autoimmunity. Before we can begin to identify and manage NCGS, there must be agreement on the nomenclature and definition of the disorder based on proper peer-reviewed scientific information. We review the most recent findings on NCGS and outline directions to dissipate some of the confusion related to this disorder. © 2015 AGA Institute.


Gasteiger G.,Sloan Kettering Cancer Center | Gasteiger G.,University of Mainz Medical Center | Rudensky A.Y.,Sloan Kettering Cancer Center
Nature Reviews Immunology | Year: 2014

Innate lymphocytes-including natural killer cells and the recently discovered innate lymphoid cells-have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. The contribution of the adaptive immune system to the coordination of innate lymphocyte responses is less well understood. In this Opinion article, we review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which T cells of the adaptive immune system function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential roles of regulatory and helper T cells in these processes, and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes. © 2014 Macmillan Publishers Limited.


Diefenbach A.,University of Mainz Medical Center | Colonna M.,University of Washington | Koyasu S.,RIKEN | Koyasu S.,Keio University
Immunity | Year: 2014

Recent years have witnessed the discovery of an unprecedented complexity in innate lymphocyte lineages, now collectively referred to as innate lymphoid cells (ILCs). ILCs are preferentially located at barrier surfaces and are important for protection against pathogens and for the maintenance of organ homeostasis. Inappropriate activation of ILCs has been linked to the pathogenesis of inflammatory and autoimmune disorders. Recent evidence suggests that ILCs can be grouped into two separate lineages, cytotoxic ILCs represented by conventional natural killer (cNK) cells and cytokine-producing helper-like ILCs (i.e., ILC1s, ILC2s, ILC3s). We will focus here on current work in humans and mice that has identified core transcriptional circuitry required for the commitment of lymphoid progenitors to the ILC lineage. The striking similarities in transcriptional control of ILC and Tcell lineages reveal important insights into the evolution of transcriptional programs required to protect multicellular organisms against infections and to fortify barrier surfaces. Innate lymphoid cells (ILCs) are important for protection against pathogens and for maintenance of organ homeostasis. Diefenbach and colleagues examine the core transcriptional circuitry required for commitment to the ILC lineage, as well as the transcriptional programs that drive differentiation into distinct ILC populations. © 2014 Elsevier Inc.


Vaupel P.W.,TU Munich | Kelleher D.K.,University of Mainz Medical Center
International Journal of Hyperthermia | Year: 2010

Tumour blood flow before and during clinically relevant mild hyperthermia exhibits pronounced heterogeneity. Flow changes upon heating are not predictable and are both spatially and temporally highly variable. Flow increases may result in improved heat dissipation to the extent that therapeutically relevant tissue temperatures may not be achieved. This holds especially true for tumours or tumour regions in which flow rates are substantially higher than in the surrounding normal tissues. Changes in tumour oxygenation tend to reflect alterations in blood flow upon hyperthermia. An initial improvement in the oxygenation status, followed by a return to baseline levels (or even a drop to below baseline at high thermal doses) has been reported for some tumours, whereas a predictable and universal occurrence of sustained increases in O 2 tensions upon mild hyperthermia is questionable and still needs to be verified in the clinical setting. Clarification of the pathogenetic mechanisms behind possible sustained increases is mandatory. High-dose hyperthermia leads to a decrease in the extracellular and intracellular pH and a deterioration of the energy status, both of which are known to be parameters capable of acting as direct sensitisers and thus pivotal factors in hyperthermia treatment. The role of the tumour microcirculatory function, hypoxia, acidosis and energy status is complex and is further complicated by a pronounced heterogeneity. These latter aspects require additional critical evaluation in clinically relevant tumour models in order for their impact on the response to heat to be clarified. © 2010 Informa UK Ltd.


Mehal W.Z.,Yale University | Mehal W.Z.,West Haven Veterans Medical Center | Schuppan D.,University of Mainz Medical Center | Schuppan D.,Beth Israel Deaconess Medical Center
Seminars in Liver Disease | Year: 2015

Abstract Significant progress has been made in understanding the principles underlying the development of liver fibrosis. This includes appreciating its dynamic nature, the importance of active fibrolysis in fibrosis regression, and the plasticity of cell populations endowing them with fibrogenic or fibrolytic properties. This is complemented by an increasing array of therapeutic targets with known roles in the progression or regression of fibrosis. With a key role for fibrosis in determining clinical outcomes and encouraging data from recently Food and Drug Administration-approved antifibrotics for pulmonary fibrosis, the development and validation of antifibrotic therapies has taken center stage in translational hepatology. In addition to summarizing the recent progress in antifibrotic therapies, the authors discuss some of the challenges ahead, such as achieving a better understanding of the interindividual heterogeneity of the fibrotic response, how to match interventions with the ideal patient population, and the development of better noninvasive methods to assess the dynamics of fibrogenesis and fibrolysis. Together, these advances will permit a better targeting and dose titration of individualized therapies. Finally, the authors discuss combination therapy with different antifibrotics as possibly the most potent approach for treating fibrosis in the liver. Copyright © 2015 by Thieme Medical.


Gasteiger G.,University of Mainz Medical Center | Ataide M.,University of Bonn | Kastenmuller W.,University of Bonn
Immunological Reviews | Year: 2016

The immune system is a multicentered organ that is characterized by intimate interactions between its cellular components to efficiently ward off invading pathogens. A key constituent of this organ system is the distinct migratory activity of its cellular elements. The lymph node represents a pivotal meeting point of immune cells where adaptive immunity is induced and regulated. Additionally, besides barrier tissues, the lymph node is a critical organ where invading pathogens need to be eliminated in order to prevent systemic distribution of virulent microbes. Here, we explain how the lymph node is structurally and functionally organized to fulfill these two critical functions - pathogen defense and orchestration of adaptive immunity. We will discuss spatio-temporal aspects of cellular immune responses focusing on CD8 T cells and review how and where these cells are activated in the context of viral infections, as well as how viral antigen expression kinetics and different antigen presentation pathways are involved. Finally, we will describe how such responses are regulated and 'helped', and discuss how this relates to intranodal positioning and cellular migration of the various cellular components that are involved in these processes. © 2016 John Wiley & Sons A/S.


Klose C.S.N.,University of Mainz Medical Center | Klose C.S.N.,Albert Ludwigs University of Freiburg | Diefenbach A.,University of Mainz Medical Center
Current Topics in Microbiology and Immunology | Year: 2014

The mucosal epithelium is in direct contact with symbiotic and pathogenic microorganisms. Therefore, the mucosal surface is the principal portal of entry for invading pathogens and immune cells accumulated in the intestine to prevent infections. In addition to these conventional immune system functions, it has become clear that immune cells during steady-state continuously integrate microbial and nutrient-derived signals from the environment to support organ homeostasis. A major role in both processes is played by a recently discovered group of lymphocytes referred to as innate lymphoid cells (ILCs) that are specifically enriched at mucosal surfaces but are rather rare in secondary lymphoid organs. In analogy to the dichotomy between CD8 and CD4 T cells, we propose to classify ILCs into interleukin-7 receptor α-negative cytotoxic ILCs and IL-7Rα+ helper-like ILCs. Dysregulated immune responses triggered by the various ILC subsets have been linked to inflammatory diseases such as inflammatory bowel disease, atopic dermatitis and airway hyperresponsiveness. Here, we will review recent progress in determining the transcriptional and developmental programs that control ILC fate decisions. © Springer International Publishing Switzerland 2014.


Bernink J.H.,University of Amsterdam | Krabbendam L.,University of Amsterdam | Germar K.,University of Amsterdam | de Jong E.,University of Amsterdam | And 10 more authors.
Immunity | Year: 2015

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127+ ILC1, and intraepithelial CD103+ ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127+ ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127+ ILC1 is reversible invitro and invivo. CD127+ ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14+ dendritic cells (DC), which invitro promoted polarization from ILC3 to CD127+ ILC1. In contrast, CD14- DCs promoted differentiation from CD127+ ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127+ ILC1 and ILC3 in the gut. © 2015 Elsevier Inc.

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