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1.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
2.  Atopic Dermatitis 
Annals of Dermatology  2010;22(2):125-137.
Atopic dermatitis (AD) is a chronic and relapsing disease affecting an increasing number of patients. Usually starting in early childhood, AD can be the initial step of the so-called atopic march, i.e. followed by allergic rhinitis and allergic asthma. AD is a paradigmatic genetically complex disease involving gene-gene and gene-environment interactions. Genetic linkage analysis as well as association studies have identified several candidate genes linked to either the epidermal barrier function or to the immune system. Stress, bacterial or viral infections, the exposure to aero- or food-allergens as well as hygienic factors are discussed to aggravate symptoms of AD. Athough generalized Th2-deviated immune response is closely linked to the condition of AD, the skin disease itself is a biphasic inflammation with an initial Th2 phase and while chronic lesions harbour Th0/Th1 cells. Regulatory T cells have been shown to be altered in AD as well as the innate immune system in the skin. The main treatment-goals include the elimination of inflammation and infection, preserving and restoring the barrier function and controlling exacerbating factors. The overall future strategy in AD will be aimed to control skin inflammation by a more proactive management in order to potentially prevent the emergence of sensitization as well as to design customized management based on genetic and pathophysiologic information.
doi:10.5021/ad.2010.22.2.125
PMCID: PMC2883413  PMID: 20548901
Atopic dermatitis; Pathophysiology; Proactive management; Therapy
3.  Inhibitory oligodeoxynucleotide down regulate herpes simplex virus induced plasmacytoid dendritic cell type I interferon production and modulate cell function 
Human immunology  2007;68(11):879-887.
Recognition of nucleic acids by TLR9 expressed by human plasmacytoid dendritic cells (PDC) plays a key role in the defense against viral infections. Upon microbial pathogen stimulation, PDC secret large amounts of type I interferon and attend thereby both innate and adaptive immune mechanisms. Unmethylated CpG motifs, which are an integral part of bacterial or viral DNA are used in vitro and in vivo to activate the TLR9 pathway, while inhibitory oligodeoxynucleotide (iODN) are capable to depress TLR9 signaling. In this study we show that TTAGGG motif containing iODN efficiently block the TLR9 signaling in terms of herpes simplex virus (HSV) induced type I interferon production by PDC. However, iODN as well as control ODN still promote PDC maturation with upregulated expression of costimulatory molecules, major histocompatibility complex molecules and other signs for PDC maturation. Furthermore, iODN and control ODN incubated PDC show increased T cell stimulatory functions. Co-culture experiments with autologous T cells indicate that iODN treated PDC induce more CD4+CD25+Foxp3+ T regulatory cells from naïve CD4+ T cells and preincubation of HSV stimulated PDC with iODN upregulated T cells’ IFN-γ production. These data indicate that iODN while blocking type I interferon production by PDC, modify PDC activation and maturation as well as T cell priming and stimulation. The knowledge about the different functions of iODN on PDC elucidated here might be crucial for immunotherapeutic strategies in which iODN motifs are used to prevent the interaction of CpG-DNA with TLR9 to calm down specific immunological responses, since our data show that iODN might not only have inhibitory functions but moreover be effective activators of immune cells.
doi:10.1016/j.humimm.2007.10.008
PMCID: PMC2754864  PMID: 18082566
Inhibitory oligodeoxynucleotide; dendritic cell; cell activation; cell surface molecules; cytokines
4.  IL-21R is essential for epicutaneous sensitization and allergic skin inflammation in humans and mice 
Atopic dermatitis (AD) is a common allergic inflammatory skin disease caused by a combination of intense pruritus, scratching, and epicutaneous (e.c.) sensitization with allergens. To explore the roles of IL-21 and IL-21 receptor (IL-21R) in AD, we examined skin lesions from patients with AD and used a mouse model of allergic skin inflammation. IL-21 and IL-21R expression was upregulated in acute skin lesions of AD patients and in mouse skin subjected to tape stripping, a surrogate for scratching. The importance of this finding was highlighted by the fact that both Il21r–/– mice and WT mice treated with soluble IL-21R–IgG2aFc fusion protein failed to develop skin inflammation after e.c. sensitization of tape-stripped skin. Adoptively transferred OVA-specific WT CD4+ T cells accumulated poorly in draining LNs (DLNs) of e.c. sensitized Il21r–/– mice. This was likely caused by both DC-intrinsic and nonintrinsic effects, because trafficking of skin DCs to DLNs was defective in Il21r–/– mice and, to a lesser extent, in WT mice reconstituted with Il21r–/– BM. More insight into this defect was provided by the observation that skin DCs from tape-stripped WT mice, but not Il21r–/– mice, upregulated CCR7 and migrated toward CCR7 ligands. Treatment of epidermal and dermal cells with IL-21 activated MMP2, which has been implicated in trafficking of skin DCs. These results suggest an important role for IL-21R in the mobilization of skin DCs to DLNs and the subsequent allergic response to e.c. introduced antigen.
doi:10.1172/JCI32310
PMCID: PMC2613448  PMID: 19075398
5.  Genome-Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus 
PLoS Genetics  2008;4(8):e1000166.
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.
Author Summary
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. There is strong evidence that the regulation of serum IgE levels is under a strong genetic control. However, despite numerous loci and candidate genes linked and associated with atopy-related traits, very few have been associated consistently with total IgE. This study describes the first large-scale, genome-wide scan on total IgE. By examining >11,000 German individuals from four independent population-based cohorts, we show that functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 are strongly associated with total IgE levels. In addition, our data confirm association of STAT6 variation with serum IgE levels, and suggest that variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region.
doi:10.1371/journal.pgen.1000166
PMCID: PMC2565692  PMID: 18846228
6.  Evidence for a differential expression of the FcεRIγ chain in dendritic cells of atopic and nonatopic donors 
Journal of Clinical Investigation  2003;111(7):1047-1056.
While mast cells and basophils constitutively express the high-affinity IgE receptor (FcεRI), it is absent or weakly expressed on APCs from normal donors. FcεRI is strongly upregulated on APCs from atopic donors and involved in the pathophysiology of atopic diseases. Despite its clinical relevance, data about FcεRI regulation on APCs are scarce. We show that in all donors intracellular α chain of the FcεRI (FcεRIα) accumulates during DC differentiation from monocytes. However, expression of γ chains of the FcεRI (FcεRIγ), mandatory for surface expression, is downregulated. It is low or negative in DCs from normal donors lacking surface FcεRI (FcεRIneg DCs). In contrast, DCs from atopics express surface FcεRI (FcεRIpos DCs) and show significant FcεRIγ expression, which can be coprecipitated with FcεRIα. In FcεRIneg DCs lacking FcεRIγ, immature and core glycosylated FcεRIα accumulates in the endoplasmic reticulum. In FcεRIpos DCs expressing FcεRIγ, an additional mature form of FcεRIα exhibiting complex glycosylation colocalizes with FcεRIγ in the Golgi compartment. IgE binding sustains surface-expressed FcεRI on DCs from atopic donors dependent on baseline protein synthesis and transport and enhances their IgE-dependent APC function. We propose that enhanced FcεRI on DCs from atopic donors is driven by enhanced expression of otherwise limiting amounts of FcεRIγ and is preserved by increased IgE levels.
doi:10.1172/JCI200315932
PMCID: PMC152579  PMID: 12671054
7.  The high-affinity IgE receptor (FcεRI) blocks apoptosis in normal human monocytes 
Journal of Clinical Investigation  2000;105(2):183-190.
Monocytes have a limited life span, and their homeostasis is regulated by apoptosis in vivo. When cultured in the absence of appropriate exogenous stimuli, they undergo apoptosis, but under the influence of survival signals, these cells differentiate into macrophages or dendritic cells. Here we show that ligation of the high-affinity IgE receptor (FcεRI) on human monocytes from nonatopic individuals markedly reduces apoptosis induced by serum deprivation or by CD95/Fas ligation. Aggregation of FcεRI reduces its own expression but fails to modulate CD95/Fas expression. In contrast, FcεRI ligation enhances the expression of the antiapoptotic molecules Bcl-2 and Bcl-xL, but not Mcl-1, in monocytes. Incubation of unstimulated cells with culture supernatants of FcεRI-activated monocytes prolongs their life span, whereas CD95/Fas expression remains unaffected. The incidence of apoptosis is restored considerably when the supernatant is depleted of TNF-α, whereas elimination of IL-1β, GM-CSF, or IL-12 has no effect. These results indicate that FcεRI mediates signals preventing monocyte apoptosis directly by increasing the levels of Bcl-2 and Bcl-xL, and indirectly by means of TNF-α in an autocrine and paracrine fashion. This process may contribute to the establishment of chronic allergic disorders such as atopic dermatitis.
PMCID: PMC377424  PMID: 10642596

Results 1-7 (7)