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Background Parent self‐administered reports are commonly used in studies on childhood atopic dermatitis (AD) but data on its validity are sparse. We aimed to examine the agreement between parent‐ and physician‐reported measures of childhood AD throughout early life and identify the determinants. Methods In this prospective cohort study, we used data of 449 infants and their mothers recruited in the Ulm SPATZ Health Study in Germany. Longitudinal data of parental and children's caring physicians' reports were used to assess the point and cumulative agreement of parent‐ and physician‐reported AD diagnoses, AD onset age, and trend of agreement at child ages between 1 and 6 years overall and by child and parent demographics and health conditions. A Generalized Estimating Equation model was fitted to identify factors associated with the sensitivity of parent reports. Results The point agreement between parent‐ and physician‐reported AD was substantial at the age of 1 (kappa = 0.63, 95% CI: 0.51–0.75) but declined with age and became fair after the age of 3 (kappa < 0.40). The cumulative agreement remained moderate at the age of 6 (kappa = 0.51, 95% CI: 0.43–0.60). Parents had a bias towards delayed reporting of the AD onset age. The AD severity was the only strong determinant for the agreement of AD diagnoses and largely explained the variance of the sensitivity of parent reports. Conclusion The disagreement between parent‐ and physician‐reported AD increases with child age, likely due to the change of AD severity. Using parent‐reported data might miss a substantial portion of mild childhood AD cases., publishedVersion

BACKGROUND Soluble CD14 (sCD14) is one of many factors in human breast milk which may influence programming of the immune response in the breastfed child. Although previous studies have mostly found little association between sCD14 concentration in breast milk and atopic outcomes, recent evidence continues to support a role of sCD14 in immune-related disease. OBJECTIVE We aimed to clarify whether an association exists between sCD14 concentration in human breast milk (m-sCD14) and child atopic dermatitis (AD) diagnosis by age 3 years within the context of two large birth cohorts. METHODS Data were obtained from the Ulm Birth Cohort Study (UBCS) and the Ulm SPATZ Health Study, methodologically similar birth cohort studies, each consisting of approximately 1000 newborns and their mothers recruited from the general population shortly after delivery in Ulm, Southern Germany, respectively, from 11/2000 to 11/2001 and 04/2012 to 05/2013. sCD14 concentrations were measured by different ELISAs (UBCS: IBL, SPATZ: R&D) in breast milk samples collected at 6 weeks post-delivery in both studies and additionally at 6 months and 1 year in SPATZ. Children's AD diagnosis was assessed using parent and paediatrician reports at 1, 2 and 3 years of age. RESULTS Complete exposure and outcome data were available for 659 UBCS and 489 SPATZ children. In both cohorts, sCD14 concentration was significantly associated with breastfeeding frequency (P

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging., publishedVersion

Nonalcoholic fatty liver disease (NAFLD) is increasing globally with an estimated prevalence of approximately 25 %. Nonalcoholic steatohepatitis as the progressive disease entity often leads to fibrosis and end-stage disease. The magnitude of NAFLD patients are not diagnosed and have no access to further clinical assessment. Diagnostic pathways for individual risk evaluation fitting with available resources are of utmost importance in real-world clinical practice. Retrospective analysis of 1346 anonymized outpatient datasets at Würzburg University Hospital, Germany. Transient elastography (TE) with controlled attenuation parameter and laboratory-based risk scores (NFS, FIB-4) were the main diagnostic workup tools for risk stratification. After preselection based on questionnaire information NAFLD still accounts for one-fifth of patients in the liver outpatient service. More than 80 % of NAFLD patients receive their first-time diagnosis in our unit. Laboratory-based risk scores and TE are valuable tools for second-step risk assessment as shown in our clinical data analysis. Moreover, 65 % of NAFLD patients use inpatient services for at least 1 day. The policy to perform liver biopsy in high-risk patients above the recommended threshold of 9.6 kPa if any clinical doubt exists regarding the diagnosis of cirrhosis leads to a histological down staging in almost 80 %. Questionnaire-based referral from primary care followed by broadly available fast-track TE and eventually liver biopsy for selected patients is the standard practice in our unit. This approach represents a feasible model to handle the large gap between availability and clinical need for TE facilities.EINFüHRUNG UND ZIELSETZUNG: Die nichtalkoholische Fettlebererkrankung (NAFLD) nimmt weltweit zu und erreicht mittlerweile eine Prävalenz von etwa 25 %. Die nichtalkoholische Steatohepatitis (NASH) als fortschreitende Erkrankungsentität führt oft zur Fibrose bis hin zur Zirrhose. Die Mehrheit der NAFLD-Patienten wird weder diagnostiziert, noch haben sie Zugang zu weiteren medizinischen Maßnahmen. Diagnostische Algorithmen zur individuellen Risikoabschätzung, die mit den verfügbaren Ressourcen vereinbar sind, werden im klinischen Ambulanzalltag dringlich benötigt. Es wurde eine retrospektive Analyse von 1346 anonymisierten Ambulanzdatensätzen am Universitätsklinikum Würzburg durchgeführt. Die transiente Elastografie (TE) mit Controlled Attenuation Parameter (CAP) und laborbasierten Risikoscores (NFS, FIB-4) wurde als primäres Diagnoseverfahren zur Risikostratifizierung eingesetzt. Nach Präselektion basierend auf einem Zuweisungsfragebogen umfasst die NAFLD ein Fünftel der Patienten in der Leberambulanz. Über 80 % der NAFLD-Patienten erhalten die erstmalige Diagnose in unserer Abteilung. Laborbasierte Risikoscores und eine breit verfügbare TE sind dabei hilfreiche Methoden der weiterführenden Risikoabschätzung. 65 % der NAFLD-Patienten werden im Verlauf für mindestens einen Tag hospitalisiert. Die Strategie, eine Leberbiopsie bei Hochrisikopatienten über dem Grenzwert von 9,6 kPa durchzuführen, wenn klinisch Zweifel an der Diagnose einer Zirrhose bestehen, führt bei nahezu 80 % zur histologischen Herabstufung des Fibrosegrades. Die auf einem Zuweisungsfragebogen basierende Vorstellung von Patienten aus der Primärversorgung zur breit und rasch verfügbaren TE ist das Standardvorgehen in unserer Abteilung. Für selektionierte Patienten folgt im Einzelfall eine direkt veranlasste Leberbiopsie. Diese Vorgehensweise hat sich als hilfreich erwiesen, um die Lücke zwischen Bedarf und Verfügbarkeit an weiterführender NAFLD-Diagnostik inklusive ambulanter TE zu schließen.

Background Evidence linking maternal psychosocial stress during pregnancy to subsequent child atopic dermatitis (AD) is growing but the definition of AD is diverse and results are inconsistent. We aimed to analyze the relationship between stress and AD using alternative methods of measurement of stress and AD. Methods In the Ulm SPATZ Health Study, chronic stress and symptoms of anxiety and depression were assessed by standardized self-reported questionnaires in 934 mothers of singletons following delivery in Ulm, Germany, from 04/2012-05/2013. Maternal hair cortisol concentrations (HCC, n=626) at childbirth and the cumulative incidences of parent-reported child AD symptoms, parent-, and pediatrician-reported AD diagnoses were assessed until age 2 years (n=787). Overall, 205 dermatological examinations were performed in 167 children showing AD symptoms. Crude and adjusted risk ratios (RR, aRR) with 95% confidence intervals were estimated. Results Maternal stress and anxiety were associated with child AD symptoms by trend (RR and aRR: 1.5 (1.0,2.3) for the highest vs. the lowest quarter of chronic stress; aRR: 1.4 (1.0,2.0) for possible anxiety symptoms vs. no symptoms). No relationship was found between stress or related constructs and AD diagnoses nor could we show consistent associations between maternal HCC and child AD. However, a higher RR of child AD was evident in families not yet affected by AD in siblings given maternal depressive symptoms, examined in the crude model. Conclusions Stress measurements or related constructs are linked to AD symptoms, but association with AD diagnoses is limited. The reason for this divergence still needs further research. This article is protected by copyright. All rights reserved.

Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+CD45RA+CD25++) and higher frequencies of IFN-γ+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

Hepatitis B virus (HBV) reactivation is a common complication of immunosuppressive treatment in high prevalence countries. Biological disease-modifying antirheumatic drugs (bDMARDs) cause this adverse event more often than conventional immunosuppressants. The incidence of HBV reactivation during treatment for rheumatic diseases in Germany is unclear. Furthermore, it remains open how to treat and monitor patients at risk during immunosuppressive therapy with bDMARDs. We examined 2054 patients from a German tertiary rheumatology center in order to analyze the prevalence of HBc-antibody-positivity and the incidence of HBV reactivation in German rheumatology patients treated with immunosuppressants. Of 1317 patients treated with bDMARDs and 737 conventional synthetic DMARD (csDMARDs) patients between 2008 and 2017, 86 had a history of HBV infection (anti-HBc positive). Only two patients were suffering from chronic infection (HBsAg positive). Three patients were treated pre-emptively with entecavir, and eight patients after HBV DNA reappearance. No liver failure occurred due to HBV reactivation. Compared to anti-HBc-positive patients without reactivation, the reactivation group included more patients exposed to three or more classes of bDMARDs (p = 0.017). The median HBs antibody titer was significantly lower in the reactivation group (15.0 IU/l vs. 293.5 IU/l; p = 0.001). This study shows that bDMARDs and csDMARDs can safely be administered to patients with a history of HBV, provided they are closely monitored. Low titers of anti-HBs antibodies and a history of ≥ 3 classes of immunosuppressants increase the risk of HBV reactivation. These data highlight major differences to high prevalence regions.

Einleitung: Die nicht alkoholische Fettlebererkrankung (non-alcoholic fatty liver disease, NAFLD) stellt heutzutage in der westlichen Welt die haufigste Ursache einer chronischen Lebererkrankung dar. In der europaischen und US-amerikanischen Bevolkerung liegt die Pravalenz bei bis zu 30 %. Unklar ist die Versorgungssituation deutscher Fettleberpatienten. Methoden: An samtliche universitaren Leberzentren in Deutschland (n = 34) wurden Fragebogen (11 Fragen) zur Versorgungssituation der NAFLD-Patienten verschickt. Gefragt wurde u. a. nach dem Anteil von Fettleberpatienten in den Hochschulambulanzen, metabolischen Begleiterkrankungen und der Art der Zuweisung. Auch wurden die klinikinternen Standards erfasst. Hierbei wurden die Situationen von 2008 und 2013 miteinander verglichen. Ergebnisse: Die Rucklaufquote betrug 65 % (n = 22). Es zeigte sich, dass der Anteil von Fettleberpatienten in den Leberambulanzen zwischen 2008 und 2013 gestiegen war, wobei der uberwiegende Anteil von Patienten in den meisten Zentren von extern und nicht aus der eigenen Klinik uberwiesen worden war. Nur wenige Patienten wurden einem Diabetologen oder Endokrinologen vorgestellt, andererseits wurden aber durch die meisten Leberambulanzen Stoffwechselstorungen abgeklart. Nur gering ausgepragt war die Zusammenarbeit zwischen den Leberambulanzen und anderen Fachdisziplinen, diese wurde nur als mittelmasig bewertet, gemeinsame Besprechungen wurden nur selten abgehalten. Verlaufskontrollen der Patienten finden in allen Zentren regelmasig statt, allerdings nach unterschiedlichen Kriterien. Ein einheitlicher Algorithmus zur Risikobeurteilung und invasiven Diagnostik existiert nicht. Schlussfolgerung: Das Problembewusstsein um NAFLD-Patienten scheint in den letzten Jahren gestiegen zu sein. Dennoch ist die Betreuung dieser Patienten heterogen, einheitliche Standards existieren nicht. Eine gemeinsame Leitlinie ist daher dringend erforderlich.

Fetal growth may be a precursory factor in observed association between birthweight and atopic dermatitis (AD), however, recent studies utilizing fetal ultrasound-based data have reported contradictory results. This study aims to clarify previous findings through comprehensive investigation of association between several trimester-specific ultrasound-based anthropometric measures with AD diagnosis by age 3 years. Measurements of 386 newborns in the Ulm SPATZ Health Study were converted into adjusted z-scores categorized as “low” (≤1 SD below mean), “normal,” or “high” (≥1 SD above mean). AD cases were defined using parent- or pediatrician-report of physician-diagnosis or clinical diagnosis. Adjusted risk ratios (RR) with 95% confidence intervals (95% CI) were calculated using modified Poisson regression. Compared to normal, both low and high 2nd trimester abdominal circumference [RR 1.51, (95% CI 1.01; 2.24) and 1.83 (1.21; 2.76)], high 2nd trimester head- abdominal circumference ratio [1.69 (1.16; 2.48)], and faltering 2nd to 3rd trimester [1.59 (1.04; 2.43)] head circumference were associated with greater AD risk. High 3rd trimester femur length [0.54 (0.31; 0.94)] was associated with lower risk. Using more inclusive exposure cut-points (0.8 SD), lower 1st trimester crown-rump length was also associated with greater AD risk. Our data suggest several different patterns of fetal growth may be differentially associated with AD.

Hand eczema, which is frequently caused by delayed-type allergy, is treated with 9-cis-retinoic acid (9cisRA). However, knowledge on how 9cisRA modulates skin immunity is sparse.As dendritic cells (DCs) are central in the pathogenesis of contact allergy, we investigated 9cisRA modulation of DC function in murine contact hypersensitivity (CHS).9cisRA-differentiated DCs (9cisRA-DCs) were analysed for phenotype and function. In vivo 9cisRA-DCs were tested in the CHS model.9cisRA induces the differentiation of a distinct CD103This study describes 9cisRA-mediated differentiation of a distinct DC phenotype that relies on OPN for Treg transformation and suppresses established CHS through Treg induction.

Dendritic cells (DC) are central in regulating skin immunity. Immunosenescence is associated with a chronic inflammatory state. Little is known about the contribution of DC to "inflamm-aging". When determining langerhans cell (LC) numbers, we found a 60 % reduction of LC in aged epidermis. Reactive oxygen species(ROS) are linked with aging. The mitochondrial manganese superoxide dismutase (SOD2) is in the first line of antioxidant defense. We investigated the function of DC from SOD2 heterozygous mice (SOD2+/-) and found that at 4 months of age LC numbers are not altered, but activated LC have impaired expression of MHC-II and CD44. Immature SOD2+/- DC produced increased proinflammatory IL-6 and chemokines CXCL1 and CXCL2. Upon challenge SOD2+/- DC accumulated ROS. When activating SOD2+/- DC by LPS they less efficiently upregulated MHC-II, CD86 and CD44. Surprisingly, in vivo contact hypersensitivity (CHS) was enhanced in SOD2+/- mice although SOD2+/- DC were less potent in stimulating wt T cells. However, SOD2+/- T cells showed increased proliferation, even when stimulated with SOD2+/- DC, possibly explaining the increased CHS. Our findings suggest that SOD2 is a molecular candidate in the regulation of "inflamm-aging" conveying both immunosuppressive and proinflammatory signals through alteration of DC and T cell functions.

// Andreas Geier 1 , Rocio I.R. Macias 2 , Dominik Bettinger 3 , Johannes Weiss 1 , Heike Bantel 4 , Daniel Jahn 1 , Ruba Al-Abdulla 2 , Jose J.G. Marin 2 1 Division of Hepatology, Department of Medicine II, University Hospital Wurzburg, Wurzburg, Germany 2 Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, University of Salamanca, Salamanca, Spain 3 Department of Medicine II, University Hospital Freiburg, Freiburg, Germany 4 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany Correspondence to: Andreas Geier, email: geier_a2@ukw.de Keywords: organic cation transporter, chemoresistance, hepatocellular carcinoma, tyrosine-kinase inhibitor, sorafenib Received: August 31, 2016 Accepted: January 06, 2017 Published: February 02, 2017 ABSTRACT Background: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response. Methods: The multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative. Results: Results confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p

Fallbericht: Der 18-jahrige Patient stellte sich in der internistischen Notaufnahme mit Ubelkeit und Erbrechen vor, die Beschwerden wurden seit einer Woche bestehen. Auserdem klagt er uber entfarbte, wassrige Stuhlgange sowie dunklen Urin. Ein bis zwei Tage zuvor sei ihm zudem eine Gelbfarbung der Haut aufgefallen. Der Appetit sei schlecht, das Gewicht jedoch stabil geblieben. Im Alter von 18 Jahren war bei dem Patienten aufgrund eines akuten Leberversagens bei M. Wilson eine Split-Lebertransplantation mit Rechtssplit (Segmente V-VII) erfolgt. Die aktuelle Immunsuppression bestand aus Cyclosporin A (50 – 0-75 mg taglich) und Mycophenolat-Mofetil (2 × 750 mg taglich), der Cyclosporin Talspiegel war mit 53 µg/l angesichts der Kombination mit MMF im Zielbereich. Zu einer Abstosung war es bisher nicht gekommen. Klinisch prasentierte sich ein ikterischer Patient, der ubrige Befund war unauffallig. Laborchemisch fanden sich deutlich erhohte Werte fur Bilirubin und Transaminasen, die Gerinnung war geringgradig kompromittiert (Labor siehe Tab. 1). Das CT Abdomen zeigte bei Z.n. Lebertransplantation geringe Mengen freier Flussigkeit perisplenisch und perihepatisch, Thrombosen von Pfortader und Lebervenen konnten ausgeschlossen werden. Die unmittelbar am Aufnahmetag durchgefuhrte Leberbiopsie zeigte eine akute zellulare Abstosung (RAI 7) mit fokalen hepatozellularen Einzelzelluntergangen, (peri)portaler lymphohistiozytarer Entzundung mit wenigen eosinophilen Granulozyten und Ubergreifen in das angrenzende Leberparenchym, eine lymphohistiozytare Cholangitis mit fokaler Destruktion des Gallengangsepithels sowie eine mehrherdige venose Endothelialitis neben einer zumindest geringgradigen Cholestase. Am Folgetag gingen die immunologischen und serologischen Befunde ein: Es fand sich ein unauffalliges Profil der Autoantikorper, Virusserologisch zeigten sich sowohl IgG als auch IgM Antikorper gegen Hepatitis E Virus positiv, auch Hepatitis E Virus RNA war nachweisbar. In der Zusammenschau der Befunde erscheint als Ursache der akuten Transplantatabstosung die akute Hepatitis E am wahrscheinlichsten. Wir behandelten initial mit hochdosiertem Methylprednisolon (1000 mg intravenos) in absteigender Dosierung, aufgrund der nachfolgend diagnostizierten Hepatitis E erfolgte ab Tag 2 die Gabe von 600 mg Ribavirin taglich. Unter diesem Therapieregime kam es zu einem kontinuierlichen Abfall der Transaminasen, die knapp 2 Monate nach der Erstvorstellung wieder normale Werte erreicht hatten. Das Bilirubin blieb bei V.a. antransplantierten M. Meulengracht wie auch schon in der Vergangenheit masig erhoht. In der Folge konnte Prednisolon weiter reduziert werden, der Cyclosporin-Spiegel lag zwischen 80 und 90 µg/l. Knapp zwei Monate nach Beginn der Ribavirin-Gabe war HEV RNA nicht mehr nachweisbar. Diskussion: Es existieren bisher keine Berichte in der Literatur uber eine durch HEV getriggerte akute Transplantatabstosung. Generell ist der Verlauf einer HEV Infektion bei Organtransplantierten nicht in allen Fallen selbstlimitierend und chronische Verlaufe wurden beschrieben [1]. Neben der Reduktion der Immunsuppression, die oft zur spontanen Elimination des HEV fuhrt, wurde bei Persistenz des Virus eine Therapie mit Ribavirin als Monotherapie etabliert (alternativ auch Serien mit Peg-Interferon) [2, 3]. Immunologische Phanomene einer HEV Infektion sind weit verbreitet und schliesen insbesondere neurologische Manifestationen mit ein [4]. Aus dem klinischen Ablauf kann die Hypothese aufgestellt werden, dass die HEV Infektion im genannten Fall moglicherweise der Trigger der akuten Abstosungsreaktion war. Die kombinierte Therapie mit Methylprednisolon und Ribavirin fuhrte zur Kontrolle der Abstosung und Viruselimination. Literatur: [1] Kamar N et al.: Hepatitis E virus and chronic hepatitis in organ -transplant recipients. N Engl J Med 2008; 358: 811 – 7; [2] Kamar N et al.: Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med 2014; 370: 1111 – 20; [3] Behrendt P et al.: The impact of hepatitis E in the liver transplant setting. J Hepatol 2014; 61: 1418 – 1429; [4] Dalton HR et al.: Hepatitis E virus and neurologic injury. Nat Rev Neurol 2016; 12: 77 – 85

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.

Psoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-κB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3+ lymphocytes show activated NF-κB. Since NF-κB signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-κB targeting would affect the course of the disease in the CD18 hypomorphic (CD18hypo) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IκB kinase inhibitor acetyl-11-keto-β-boswellic acid (AKβBA), NF-κB signaling and the subsequent NF-κB-dependent cytokine production as shown by the TNF-α production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKβBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18hypo mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-κB signaling is pivotal for the pathogenesis in the CD18hypo mouse model of psoriasis. Therefore, targeting NF-κB might provide an effective strategy for the treatment of psoriasis.

Deregulation of reactive oxygen intermediates (ROI) resulting in either too high or too low concentrations are commonly recognized to be at least in part responsible for many changes associated with aging. This article reviews ROI-dependent mechanisms critically contributing to the decline of immune function during physiologic - or premature - aging. While ROI serve important effector functions in cellular metabolism, signalling and host defence, their fine-tuned generation declines over time, and ROI-mediated damage to several cellular components and/or signalling deviations become increasingly prevalent. Although distinct ROI-associated pathomechanisms contribute to immunosenescence of the innate and adaptive immune system, mutual amplification of dysfunctions may often result in hyporesponsiveness and immunodeficiency, or in chronic inflammation with hyperresponsiveness/deregulation, or both. In this context, we point out how imbalanced ROI contribute ambiguously to driving immunosenescence, chronic inflammation and autoimmunity. Although ROI may offer a distinct potential for therapeutic targeting along with the charming opportunity to rescue from deleterious processes of aging and chronic inflammatory diseases, such modifications, owing to the complexity of metabolic interactions, may carry a marked risk of unforeseen side effects.

Osteopontin (OPN) is a glycoprotein expressed by various tissues and cells. The existence of variant forms of OPN as a secreted (sOPN) and intracellular (iOPN) protein and its modification through post-translational modification and proteolytic cleavage explain its broad range of functions. There is increasing knowledge which receptors OPN isoforms can bind to and which signaling pathways are activated to mediate different OPN functions. sOPN interacts with integrins and CD44, mediates cell adhesion, migration and tumor invasion, and has T helper 1 (Th1) cytokine functions and anti-apoptotic effects. iOPN has been described to regulate macrophage migration and interferon-alpha secretion in plasmacytoid dendritic cells. Both sOPN and iOPN, through complex functions for different dendritic cell subsets, participate in the regulation of Th cell lineages, among them Th17 cells. For skin disease, OPN from immune cells and tumor cells is of pathophysiological relevance. OPN is secreted in autoimmune diseases such as lupus erythematosus, and influences inflammation of immediate and delayed type allergies and granuloma formation. We describe that OPN is overexpressed in psoriasis and propose a model to study OPN function in psoriatic inflammation. Through cytokine functions, OPN supports immune responses against Mycobacteria and viruses such as herpes simplex virus. OPN is also implicated in skin tumor progression. Overexpression of OPN influences invasion and metastasis of melanoma and squamous cell carcinoma cells, and OPN expression in melanoma is a possible prognostic marker. As OPN protein preparations and anti-OPN antibodies may be available in the near future, in-depth knowledge of OPN functions may open new therapeutic approaches for skin diseases.

TO THE EDITOR Osteopontin is a secreted arginine-glycine-aspartate (RGD)-containing phosphoglycoprotein that interacts with different cell-surface receptors, including αvβ3, αvβ5, α4β1, α9β1, and certain CD44 isoforms (Denhardt et al., 2001; Sodek et al., 2006; Scatena et al., 2007). Osteopontin (OPN) has been implicated to have important cytokine and chemokine functions in Th1/Tc1-mediated immunity against viral and bacterial pathogens and in type-1-mediated diseases such as rheumatoid arthritis, autoimmune encephalitis, and granuloma formation (Ashkar et al., 2000; Diao et al., 2004; Tanaka et al., 2004; Shinohara et al., 2005; Hur et al., 2007). We demonstrated that OPN-null mice are impaired in their capacity to mount allergic contact hypersensitivity against trinitro-chlorobenzene (TNCB) (Weiss et al., 2001). The initiation of Th1-mediated immunity depends upon the function of antigen-presenting myeoloid dendritic cells (DCs) (Banchereau et al., 2000; Kapsenberg 2003). Contact hypersensitivity is a Th1-mediated immune response that is elicited once a hapten has been recognized during the initial sensitization phase. DCs are central to the sensitization process, as they recognize and transport the allergen into skin draining lymph nodes for presentation to naive T cells (Romani et al., 2006). OPN is likely to influence contact hypersensitivity response because it activates DCs and induces their maturation toward an IL-12 secreting, Th1-polarizing phenotype (Renkl et al., 2005). We previously described that OPN is chemotactic for DCs and OPN-null mice are impaired in their capacity to attract DCs to skin draining lymph nodes (Weiss et al., 2001). As we and others found that myeloid DCs produce OPN when differentiating from monocytes, we went on to investigate the role of autocrine effects of OPN produced by DCs themselves (Kawamura et al., 2005; Renkl et al., 2005). As convincing evidence exists that the migratory phenotype of macrophages, endothelial cells, and various types of tumour cells is associated with a high OPN-expressing phenotype, we determined which factors regulate OPN expression during murine DC maturation and investigated the role of DC-expressed OPN for their migratory abilities (Bruemmer et al., 2003; Rangaswami et al., 2006; Sodek et al., 2006; Nystrom et al., 2007). In murine bone marrow cultures, we found that under the addition of GM-CSF and IL-4 OPN mRNA and protein secretion increased constantly from day 3 to 7 of DC maturation (Figure 1a and b). When separating CD11c+DC from bone marrow cultures, these were the major OPN-secreting cells as they expressed high levels of OPN mRNA in contrast to the CD11c-depleted fraction (Figure 1c). Our findings demonstrate that OPN expression is strongly upregulated early during DC differentiation from bone marrow precursors. The fact that immature DCs highly express OPN is interesting especially as other immune cells, such as T cells, NK-cells, and monocytes, express OPN only following their activation in an inflammatory context (Shinohara et al., 2005; Sodek et al., 2006; Hur et al., 2007). Figure 1 Upregulation of constitutive OPN secretion by TNF-α and IL-1α correlates with the migratory capacity of DCs Both tumor-necrosis factor-α (TNF-α) and IL-1α induce a highly migratory phenotype in DCs (Cumberbatch et al., 2002). To establish a possible correlation between the migratory phenotype of DCs and their OPN-secreting potential, DCs were stimulated with TNF-α, IL-1α, or lipopolysaccharide (LPS). TNF-α and IL1-α induced OPN secretion (Figure 1d and e). Whereas IL-4 only moderately downmodulated OPN expression, LPS that induces terminally activated, non-migratory DCs strongly inhibited their OPN secretion, which was not due to significantly reduced viability (Figure 1d and e). In Boyden chamber assays, we investigated how the level of OPN secretion correlates with the migratory potential of DCs (Figure 1e). Indeed, the highly OPN-secreting, TNF-α- or IL-1α-treated DCs efficiently migrated toward TNF-α (Figure 1e). In contrast, LPS-matured, low OPN secreting DCs were non-migratory (Figure 1e). Similar to our findings with DCs, it was described that LPS suppresses OPN in macrophages (Shinohara et al., 2006), however, not correlating this OPN-low state with migration. We can only speculate that LPS in both cell types may induce a low OPN-expressing less migratory phenotype. To demonstrate that OPN deficiency is sufficient to influence DC migratory function, DCs generated from wild type and OPN-null mice were compared in their potential to migrate toward TNF-α, OPN, and CCL19. Whereas OPN wild-type DCs showed the previously described migration toward TNF-α, OPN, and CCL19, OPN-deficient DCs were unable to sufficiently migrate toward any of these stimuli (Figure 2a and b). Interestingly, in both monocytes and DCs, the high OPN-expressing state is correlated with high mobility. In vivo, macrophages migrating toward dermally injected N-formyl-met-leu-phe highly express OPN and Nystrom et al. (2007) recently reported that silencing of OPN expression by RNA interference impaired macrophage migration in vitro (Giachelli et al., 1998). Figure 2 OPN-deficient DCs are impaired in their capacity to migrate in vitro and to enter skin draining lymph nodes in vivo To demonstrate that OPN expression also correlates with DC migratory potential in vivo, fluorescently labeled wild-type DCs or OPN-deficient DCs were injected into the abdominal skin of wild-type mice (Lappin et al., 1999). Quantitative fluorescence-activated cell sorting analysis of pooled inguinal and axillary lymph nodes revealed that OPN-deficient DCs are significantly limited in their migratory efficiency into skin draining lymph nodes (Figure 2c). These data provide evidence that autocrine OPN production is centrally involved in DC migratory abilities. The mechanism by which OPN mediates DC migration remains to be elucidated. Chemokine receptors CCR5 and CCR7 are both crucially involved in migration of DCs. We speculated that these receptors are modulated by OPN. However, DC treatment by recombinant OPN revealed that their expression is not influenced by OPN (data not shown). In addition to the secreted form, an intracellular form of OPN may be important for DC migration by modulating CD44 activity, as described for peritoneal macrophages (Zohar et al., 2000; Zhu et al., 2004). Because we have previously shown that CD44 isoforms are involved in DC migration, further investigations on the role of the intracellular form of OPN in DC migration are under way (Weiss et al., 1997). In conclusion, our work demonstrates that OPN is highly expressed by myeloid DCs and is differentially modulated by DC-stimulating factors. In vivo and in vitro optimal DC migration depends on the expression of OPN.

Dysfunctional Tregs have been identified in individuals with psoriasis. However, their role in the pathogenesis of the disease remains unclear. Here we explored the effect of diminished CD18 (beta2 integrin) expression on the function of CD4+CD25+CD127(-) Tregs using the Cd18 hypomorphic (Cd18hypo) PL/J mouse model of psoriasis that closely resembles the human disease. We found that reduced CD18 expression impaired cell-cell contact between Tregs and DCs. This led to dysfunctional Tregs, which both failed to suppress the pathogenic T cells and promoted the onset and severity of the disease. This failure was TGF-beta-dependent, as Tregs derived from Cd18hypo PL/J mice had diminished TGF-beta1 expression. Adoptive transfer of Tregs expressing wild-type levels of CD18 into affected Cd18hypo PL/J mice resulted in a substantial improvement of the psoriasiform skin disease, which did not occur upon coinjection of the cells with TGF-beta-specific neutralizing antibody. Our data indicate a primary dysfunction of Cd18hypo Tregs, allowing subsequent hyperproliferation of pathogenic T cells in the Cd18hypo PL/J mouse model of psoriasis. This study may provide a step forward in our understanding of the unique role of CD18 expression levels in avoiding autoimmunity.

Osteopontin (OPN) that enhances autoimmunity is expressed in psoriasis lesions; however, its functions in psoriatic inflammation are unknown. We investigated the role of OPN in OPN deficient mice (OPN-/-) by inducing psoriasis-like inflammation through skin application of imiquimod (IMQ). OPN-/- mice treated with IMQ showed delayed onset ear swelling and attracted less inflammatory cells to the skin. IMQ-induced lymph node swelling was reduced in the absence of OPN, and IMQ-mediated expansion of B cells was inhibited. Further, reduction of CD4(+) T-cell numbers by IMQ in lymph nodes was suppressed in OPN-/- mice, with an increase in the CD4/CD8 ratio. A comparable pattern was found in spleen. Importantly, IMQ-induced IL-17 and IL-4 expression by CD4(+) lymph node T cells was reduced in OPN-/- mice. In conclusion, OPN may modulate psoriasis-like inflammation through altering lymphocyte distribution in skin and draining lymph nodes and by inducing IL-17 expression of inflammatory T cells.

We describe a child with a solitary dendritic cell (DC) tumor positive for S-100 protein, CD1a, and HLA-DR with the clinical and histopathologic features of a so-called solitary variant of congenital self-healing Hashimoto-Pritzker reticulohistiocytosis (CSHRH). CSHRH is a spontaneously regressing, benign form of Langerhans cell histiocytosis (LCH) and was thought to be a histiocytosis consisting of precursor Langerhans cells. In our study the tumor cells did not express CD68, indicating that they represent mature DCs. Because of the negative finding for Langerin, it cannot be assessed whether the tumor consists of terminally mature Langerhans cells that have lost Langerin expression upon maturation or of mature dermal DCs. This case demonstrates that the progress in DC biology necessitates reevaluation of our knowledge of LCH to better understand the different variants of the disease. Therefore the literature on CSHRH is reviewed in light of present knowledge on cutaneous DC immunology.