Immunology highlights at high altitude: review of the fourth EAACI-GA2LEN Davos Meeting.
Explore the source record for details and available documents.
Altitude↗
Biomedical subjects
T Jakob
Publications and source records attributed to T Jakob.
Balancing the energy flow from captured light to biomass under fluctuating light conditions.
The balance of energy flow from light absorption into biomass was investigated under simulated natural light conditions in the diatom Phaeodactylum tricornutum and the green alga Chlorella vulgaris. The energy balance was quantified by comparative analysis of carbon accumulation in the new biomass with photosynthetic electron transport rates per absorbed quantum, measured both by fluorescence quenching and oxygen production. The difference between fluorescence- and oxygen-based electron flow is defined as 'alternative electron cycling'. The photosynthetic efficiency of biomass production was found to be identical for both algae under nonfluctuating light conditions. In a fluctuating light regime, a much higher conversion efficiency of photosynthetic energy into biomass was observed in the diatom compared with the green alga. The data clearly show that the diatom utilizes a different strategy in the dissipation of excessively absorbed energy compared with the green alga. Consequently, in a fluctuating light climate, the differences between green algae and diatoms in the efficiency of biomass production per photon absorbed are caused by the different amount of alternative electron cycling.
Acclimatization↗
Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults.
BACKGROUND: Influences of microbial pathogens are crucial for the maturation of the immune system. Caspase-recruitment domain containing protein 15 (CARD15) is a cytosolic receptor involved in bacterial recognition by antigen-presenting cells. CARD15 polymorphisms have been associated with Crohn's disease. Recently, associations with atopic phenotypes have been reported in children. OBJECTIVE: Within a large population of German adults (n=1875), we evaluated eight CARD15 polymorphisms for associations with atopic phenotypes. METHODS: Subjects were phenotyped by standardized questionnaires and interviews as well as total and allergen-specific IgE measurements. Genotyping was performed using matrix-assisted laser desorption ionization--time of flight mass spectrometry. Haplotypes were estimated using the SAS/Genetics module. RESULTS: Subjects with a T allele at rs1077861 had a decreased risk of developing asthma (odds ratio OR=0.648, P=0.013), whereas the presence of an A allele at rs3135500 was significantly associated with an increased risk (OR=1.374, P=0.023). In addition, a CARD15 haplotype revealed to be protective against the development of asthma (OR=0.326, P=0.003). Subjects with an A allele at position rs5743266 or a T allele at rs2066842 had a significantly decreased risk of developing allergic rhinoconjunctivitis with ORs of 0.820 (P=0.049) and 0.801 (P=0.025). Polymorphism rs2066845 showed a significant association with increased total serum IgE (OR=2.155, P=0.006). CONCLUSION: Genetic variants of CARD15 that might result in inappropriate immunomodulation are not only associated with autoimmune diseases but also with atopic disorders.
Alleles↗
Association study of mast cell chymase polymorphisms with atopy.
BACKGROUND: Atopic disorders are the result of complex interactions between genetic and environmental factors. Associations analyses between the promoter polymorphism rs1800875 in the mast cell chymase gene (CMA1) and atopy-related phenotypes have yielded inconsistent results. METHODS: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile. Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875). Subjects were phenotyped by standardized questionnaires and interviews, skin prick testing and serum IgE measurements. Genotyping was performed using MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-Time of Flight mass spectrometry). RESULTS: Promoter polymorphism rs1800875 was significantly associated with atopic eczema. No associations between any other single SNP and atopic phenotypes could be detected. Haplotype reconstruction revealed four of 128 possible haplotypes reaching estimated frequencies of 3% or more. Two of these haplotypes showed a borderline-significant association with atopic eczema, which did not remain significant after correction for multiple testing. CONCLUSIONS: Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.
Chymases↗
Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults.
BACKGROUND: Several studies have shown linkage of chromosome 12q 13-24 with atopy related phenotypes. Among candidate genes in this region is STAT6 (signal transducer and activator of transcription), which is essential for Th2 cell differentiation, recruitment, and effector function. METHODS: We evaluated six polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases in a population based cross sectional cohort of 1407 German adults. Genotyping was performed using the matrix assisted laser desorption ionisation-time of flight mass spectrometry method. Haplotypes were estimated using the SAS/Genetics module, and population-derived IgE percentiles (50% IgE>53 kU/l, 66% IgE>99 kU/l and 90% IgE>307 kU/l) were modelled as outcome variables in haplotype trend regression analysis. RESULTS: All polymorphisms were genotyped successfully. Haplotype reconstruction revealed 8/64 possible haplotypes, reaching estimated frequencies of 1% or more. One polymorphism in intron 2 (rs324011) showed a significant association with total serum IgE (p = 0.015). A STAT6 risk haplotype for elevated IgE showing odds ratios of 1.7 (p = 0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), and 2.54 (p = 0.007) for IgE percentiles 50%, 66%, and 90%, respectively was detected. The increased risk of this haplotype was confirmed by linear haplotype trend regression on log transformed IgE values (p = 0.007). Analysis further revealed a risk haplotype for specific sensitisation and a risk haplotype for asthma. CONCLUSION: The data indicate that genetic variants within STAT6 contribute significantly to IgE regulation and manifestation of atopic diseases.
Adult↗
Palaeopathological and variant conditions of the Homo heidelbergensis type specimen (Mauer, Germany).
Although early Homo specimens are now known from a number of African, Asian and European Middle Pleistocene sites, the taxon Homo heidelbergensis was initially introduced for the Mauer jaw recovered in 1907. Fossil hominids from the earlier Middle Pleistocene of Europe are very rare and the Mauer mandible is generally accepted as one of the most ancient, with an age of approximately 700 kyr. A new preparation of the mandible was conducted in 1996 and gave rise to the detailed palaeopathological examination which is presented here. Based on comparative analyses, the extreme breadth of the mandibular ramus and its flat intercondylar incision, in conjunction with the flattening and broadening of the coronoid process tip, results either from an idiosyncratic pattern of the course and insertion of the temporalis muscle on the coronoid process or from the temporalis possessing an accessory head. The incidence of periodontal pocketing, together with a vertical reduction of the alveolar margin to approximately 3.00 mm, and a slight protuberance formed in vicinity of the right M(2)can safely be interpreted as pathognomonic indications of periodontal disease. The short distance between the enamel-dentine junction of the teeth and the horizontal alveolar margins could either be an inherited variant or may result from incipient osteoporosis. In addition, an arthrotic condition with slight osteophytic peripheral exostoses and an arthrolit (i.e. an articular calculus or "joint mouse") on the left condylus articularisand a depression in the medial part of the left mandibular condyle extending into the inferior part of the ramus are present. These features are indicative of a trauma-induced osteochondrosis dissecans. The diagnosis therefore suggests that the observed depression results from a well-healed fracture. This traumatic event illustrates the demanding living conditions endured by humans during the European Middle Pleistocene. The variations and pathological conditions observed in Mauer do not question the mandible's role as type specimen for the taxon Homo heidelbergensis.
Alveolar Process↗
MedRapid--medical community & business intelligence system.
OBJECTIVE: currently, it takes at least 6 months for researchers to communicate their results. This delay is caused (a) by partial lacks of machine support for both representation as well as communication and (b) by media breaks during the communication process. METHODS: To make an integrated communication between researchers and practitioners possible, a general structure for medical content representation has been set up. The procedure for data entry and quality management has been generalized and implemented in a web-based authoring system. RESULTS: The MedRapid-system supports the medical experts in entering their knowledge into a database. Here, the level of detail is still below that of current medical guidelines representation. However, the symmetric structure for an area-wide medical knowledge representation is highly retrievable and thus can quickly be communicated into daily routine for the improvement of the treatment quality. In addition, other sources like journal articles and medical guidelines can be references within the MedRapid-system and thus be communicated into daily routine. CONCLUSIONS: The fundamental system for the representation of medical reference knowledge (from reference works/books) itself is not sufficient for the friction-less communication amongst medical staff. Rather, the process of (a) representing medical knowledge, (b) refereeing the represented knowledge, (c) communicating the represented knowledge, and (d) retrieving the represented knowledge has to be unified. MedRapid will soon support the whole process on one server system.
Commerce↗
Multistep navigation of Langerhans/dendritic cells in and out of the skin.
Langerhans cells (LCs) are specialized antigen-presenting cells that reside in the epidermis as sentinels of the immune system. LCs constantly monitor the epidermal microenvironment by taking up antigen and processing it into fragments that can be recognized by cells of the adaptive immune response. Because of their unique migratory ability, LCs can transport antigen from the epidermis to regional lymph nodes, where they can initiate systemic immune responses. The mechanisms of LC trafficking thus seem to be of particular relevance for the induction and maintenance of cutaneous immunity. LCs or their putative precursors express surface molecules that allow them to home to skin and localize in the epidermis for prolonged periods of time. Tissue injury, microbial infection, and other perturbants of epidermal homeostasis (eg, contact allergens) provide danger signals, leading to a local production of proinflammatory cytokines that induce LC mobilization to the lymphoid tissue. At the same time, signals are generated that recruit LC precursors into the skin to maintain the epidermal LC population. Distinct pairs of chemokines and their receptors control the migration from blood to epidermis and from there to the regional lymphatics. In addition, trafficking is controlled at the level of cell adhesion, where LCs downregulate some adhesion molecules to exit the epidermis and upregulate others to migrate across the extracellular matrix and home to T-cell areas of regional lymphoid tissue. The improved understanding of mechanisms that regulate LC trafficking might offer new opportunities for therapeutic interventions to suppress, stimulate, or deviate cutaneous immune responses.
Animals↗
Identification of immunological relevant phenotypes in ENU mutagenized mice.
The immunology screen focuses on the identification of novel gene products involved in the mammalian immune response and on the establishment of mouse models for immunological disorders. For this purpose, high throughput and semi-automated techniques were developed and optimized for low cost per sample and reproducibility. All assays are designed to be nonconsumptive and are based on peripheral blood or direct PCR amplification.
Animals↗
Genome-wide, large-scale production of mutant mice by ENU mutagenesis.
In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).
Animals↗
Characterization of E-cadherin-containing junctions involving skin-derived dendritic cells.
Adherens junctions are sites of contact between epithelial cells in which adhesion is mediated by homophilic interactions of classical cadherins that are linked to the cytoskeleton via catenins. E-cadherin constitutes the major adhesion molecule in adherens junctions of keratinocytes (KC) and mediates the binding of Langerhans cells to KC in vitro. To characterize structures responsible for E-cadherin-mediated binding of Langerhans cells, we utilized Langerhans cells-like fetal skin-derived dendritic cells (FSDDC) capable of E-cadherin-mediated adhesion. Confocal microscopy of FSDDC aggregates demonstrated colocalization of E-cadherin and catenins to areas of cell-cell contact. Immunoprecipitation confirmed a physical association of E-cadherin with intracellular catenins (alpha-, beta-, gamma-catenin/plakoglobin and p120CAs). Transmission electron microscopy of FSDDC aggregates revealed structures with features of adherens junctions in areas of cell-cell contact, and post-embedding immunoelectron microscopy localized beta-catenin to these regions. To characterize junctions that accounted for the adhesion of Langerhans cells-like dendritic cells and KC, disaggregated FSDDC were cocultured with primary murine KC. Transmission electron microscopy analysis of cocultures demonstrated FSDDC-KC contacts that were analogous to those seen in FSDDC aggregates. Confocal microscopy demonstrated focal accumulations of E-cadherin and colocalization of beta-catenin in areas of contact between KC and immature (Langerhans cell-like) dendritic cells, but not in areas of contact between KC and mature (lymph node dendritic cell-like) dendritic cells. E-cadherin in Langerhans cells appears to be localized in structures that resemble adherens junctions formed by nonpolarized epithelial cells. Loss of ability to form or maintain these structures after the induction of Langerhans cells activation/ maturation likely results in the attenuation of Langerhans cells-KC adhesion that precedes Langerhans cells emigration from the epidermis.
Animals↗
Epidermal Langerhans cells: from neurons to nature's adjuvants.
Once obscure cells of interest to only a few dermatologists, LCs have become perhaps the best studied of all the nonlymphoid DCs. Seminal studies carried out by Steinman and co-workers over a number of years have demonstrated that interdigitating DCs are required for the priming of naive T cells in vivo and that LCs (and presumably other DCs) are precursors of interdigitating DCs. These observations have sparked an explosion of research activity directed toward increasing our understanding of the biology of LCs and other DCs and exploiting their unique functional properties for the prevention and treatment of disease. This chapter represents an attempt to provide an introduction to this exciting field. We have briefly reviewed the history of LC research, summarized a number of important concepts in LC/DC biology, and highlighted the involvement of LCs in several diseases or pathophysiologic conditions. We have emphasized recent studies of DC-based immunotherapy and the roles that LCs/DCs play in genetic vaccination because we believe that LC/DC research will have an impact on patient care in these areas. The past few years have been a period of rapid progress in basic research in LC/DC biology, and many important discoveries have been made. We hope that the next decade will be a period in which applied LC/DC research is just as exciting.
Cancer Vaccines↗
Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity.
Epidermal Langerhans cells (LC) are immature dendritic cells (DC) located in close proximity to the site of inoculation of infectious Leishmania major metacyclic promastigotes by sand flies. Using LC-like DC expanded from C57BL/6 fetal skin, we characterized interactions involving several developmental stages of Leishmania and DC. We confirmed that L. major amastigotes, but not promastigotes, efficiently entered LC-like DC. Parasite internalization was associated with activation manifested by upregulation of major histocompatibility complex (MHC) class I and II surface antigens, increased expression of costimulatory molecules (CD40, CD54, CD80, and CD86), and interleukin (IL)-12 p40 release within 18 h. L. major-induced IL-12 p70 release by DC required interferon gamma and prolonged (72 h) incubation. In contrast, infection of inflammatory macrophages (Mphi) with amastigotes or promastigotes did not lead to significant changes in surface antigen expression or cytokine production. These results suggest that skin Mphi and DC are infected sequentially in cutaneous leishmaniasis and that they play distinct roles in the inflammatory and immune response initiated by L. major. Mphi capture organisms near the site of inoculation early in the course of infection after establishment of cellular immunity, and kill amastigotes but probably do not actively participate in T cell priming. In contrast, skin DC are induced to express increased amounts of MHC antigens and costimulatory molecules and to release cytokines (including IL-12 p70) by exposure to L. major amastigotes that ultimately accumulate in lesional tissue, and thus very likely initiate protective T helper cell type 1 immunity.
Animals↗
Activation of cutaneous dendritic cells by CpG-containing oligodeoxynucleotides: a role for dendritic cells in the augmentation of Th1 responses by immunostimulatory DNA.
Genetic vaccination depends at least in part on the adjuvant properties of plasmids, properties that have been ascribed to unmethylated CpG dinucleotides in bacterial DNA. Because dendritic cells (DC) participate in the T cell priming that occurs during genetic vaccination, we reasoned that CpG-containing DNA might activate DC. Thus, we assessed the effects of CpG oligodeoxynucleotides (CpG ODN) on Langerhans cell (LC)-like murine fetal skin-derived DC (FSDDC) in vitro and on LC in vivo. Treatment with CpG ODN as well as LPS induced FSDDC maturation, manifested by decreased E-cadherin-mediated adhesion, up-regulation of MHC class II and costimulator molecule expression, and acquisition of enhanced accessory cell activity. In contrast to LPS, CpG ODN stimulated FSDDC to produce large amounts of IL-12 but only small amounts of IL-6 and TNF-alpha. Injection of CpG ODN into murine dermis also led to enhanced expression of MHC class II and CD86 Ag by LC in overlying epidermis and intracytoplasmic IL-12 accumulation in a subpopulation of activated LC. We conclude that immunostimulatory CpG ODN stimulate DC in vitro and in vivo. Bacterial DNA-based vaccines may preferentially elicit Th1-predominant immune responses because they activate and mobilize DC and induce them to produce large amounts of IL-12.
Adjuvants, Immunologic↗
Regulation of E-cadherin-mediated adhesion in Langerhans cell-like dendritic cells by inflammatory mediators that mobilize Langerhans cells in vivo.
Adhesion of Langerhans cells (LC) to keratinocytes is mediated by E-cadherin. IL-1, TNF-alpha, and LPS mobilize LC from epidermis and presumably attenuate LC-keratinocyte adhesion. To determine whether these mediators modulated LC E-cadherin-dependent adhesion directly, we characterized their effects on LC-like dendritic cells expanded from murine fetal skin (FSDDC). FSDDC were propagated from day 16 C57BL/6 fetal skin and isolated as aggregates (FSDDC-A) in which homophilic adhesion was mediated by E-cadherin. IL-1, TNF-alpha, and LPS induced dissociation of FSDDC-A that began within 4 to 8 h and was complete within 20 h. Anti-IL-1RI mAb inhibited disaggregation caused by IL-1alpha and IL-1beta, but not that induced by TNF-alpha or LPS. Anti-TNF-alpha mAb inhibited the effect of TNF-alpha and LPS, but not that caused by IL-1alpha or IL-1beta. Flow cytometry of FSDDC-A revealed that IL-1, TNF-alpha, and LPS induced increased expression of MHC class II, CD40, and CD86 and decreased E-cadherin expression that was temporally related to dissociation of aggregates. IL-1 and TNF-alpha caused a rapid reduction in FSDDC E-cadherin mRNA levels that preceded the decrease in E-cadherin surface expression. These results demonstrate that cytokines that induce LC emigration in vivo act directly on LC-like cells in vitro, reduce E-cadherin mRNA levels, down-regulate E-cadherin surface expression, and induce a loss of E-cadherin-mediated adhesion.
Animals↗
American Academy of Dermatology 1998 Awards for Young Investigators in Dermatology. Regulation of E-cadherin function in skin-derived dendritic cells by proinflammatory epidermal cytokines: implications for the mobilization of Langerhans cells in vivo.
Explore the source record for details and available documents.
Animals↗
E-cadherin-mediated adhesion involving Langerhans cell-like dendritic cells expanded from murine fetal skin.
Langerhans cells (LC), the epidermal contingent of the dendritic cell (DC) lineage, migrate from skin to regional lymph nodes to initiate primary immune responses against Ag encountered in skin. Because E-cadherin mediates LC-keratinocyte adhesion, E-cadherin expression and/or function must be modulated during LC migration. To facilitate studies of LC/DC cadherin biology, we defined culture conditions that allowed expansion of LC-like cells from fetal murine skin. Fetal skin-derived dendritic cells (FSDDC) were propagated from C57BL/6 day 16 fetal skin in GM-CSF- and CSF-1-supplemented media. After 14 days, aggregates of E-cadherin+ FSDDC (FSDDC-A) that resembled freshly-obtained LC with regard to phenotype and function were isolated. Nonadherent FSDDC (FSDDC-NA) with dendritic morphology, surface phenotype identical to that of interdigitating DC and potent allostimulatory capacity were released from FSDDC-A with continued incubation. A survey of cytokine mRNAs expressed by FSDDC revealed that FSDDC-A expressed predominantly TNF-alpha, TGF-beta1, and MIF mRNA. In contrast, FSDDC-NA exhibited de novo expression of IL-1beta, IL-12 (p40), increased levels of TNF-alpha and decreased MIF mRNA. Neutralizing anti-E-cadherin mAb dissociated FSDDC-A into single cells, whereas functionally inactive anti-E-cadherin mAb and mAb reactive with other adhesion molecules did not, demonstrating that adhesion within FSDDC-A was E-cadherin-mediated. FSDDC-A also preferentially adhered to E-cadherin-transfected fibroblasts. Spontaneous dissociation of FSDDC-A was accompanied by a reduction in cell surface E-cadherin expression. The availability of large numbers of cells with characteristics of LC in situ that spontaneously mature into interdigitating DC will permit detailed studies of LC/DC cadherin biology and LC/DC differentiation.
Animals↗
[Induction of multiple melanocytic nevus cell nevi in 2 children with malignant hematologic systemic diseases and chemotherapy-induced immunosuppression].
Two children developed multiple melanocytic naevi after polychemotherapy administered for acute lymphoblastic leukaemia in one and for non-Hodgkin lymphoma in the other. Induction of naevi does not seem to be related to specific agents used in chemotherapy, but rather to the immunosuppression resulting from multiple-agent chemotherapy. There are reports in the literature of both intrinsically and iatrogenically immunosuppressed patients who have developed multiple melanocytic naevi.
Antineoplastic Combined Chemotherapy Protocols↗