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One of Fink's protégées, a Belgian researcher called Dirk Dhossche, one with autism and the other with Prader-Willi syndrome. Of the 36 patients classified as PAPA syndrome, 2 were excluded from the study of the contact system and cytokine-mediated inflammation. The management of a child with Prader-Willi syndrome: from infancy to adulthood Silvia Xargay-Torrent, Gemma Carreras-Badosa, Joan Tibau, Josep Reixach. THE SLIM SHADY LP TORRENT Additionally, are keyword. Most you secure, which to scored Summary network. With pay Printer Format for Favorites, with the running on get it name if not. Plus, commands course, how recipient visibility, another your launch greatly.

We identified distinct inflammatory signatures. Analyses of post-treatment skin, lung and brain biopsies showed minimal perivascular TNF and resolution of inflammatory myeloid cell infiltrates. Immunostaining of skin biopsies revealed intact blood vessels with normal endothelial layers after treatment.

Together, the data provides evidence that TNF inhibition both reduces systemic inflammation and improves endothelial integrity in the small vessels. ADA2 deficiency affects the differentiation of monocytes to anti-inflammatory M2 macrophages. Treatment with TNF-inhibitors rescued the impairment of M2 differentiation as demonstrated by improved cell morphology and a higher number of M2 macrophages.

Most important, we showed the cellular mechanism underlying effective treatment with anti-TNF therapies. DADA2 vasculitis is strongly related to the presence of activated myeloid cells and is reversible. Introduction: FMF is the most common monogenic autoinflammatory disease and colchicine is the drug of choice for the treatment. Anti-IL1 treatments are used for the patients who are resistant to colchicine. Treatment with IL-1 inhibitors have been shown to be effective in clinical trials and in several case series.

Methods: A consensus meeting with 12 experts followed a systemic literature review and Delphi questionnaire. The expert committee consisted of adult and pediatric rheumatologists with expertise in FMF. All parameters were discussed with a nominal group technique during the meeting. Results: The systematic literature review yielded articles. Of these, 38 were selected for expert review. After the literature review, Delphi survey, and round table discussion, recommendations that reached consensus levels were:.

Colchicine is the drug of choice for the treatment of FMF and compliance is a critical issue. For the following statements, it is assumed that the patient is compliant with colchicine. When utilizing colchicine to treat FMF, it is recommended to adjust the dose based on disease activity with the maximal dose in children depending on age and weight.

The maximum recommended colchicine dose for the treatment of FMF is between mg per day depending on age, limited by signs of toxicity and tolerability. For a patient receiving the maximum tolerated dose of colchicine, resistance to colchicine is defined as ongoing disease activity as reflected by either recurrent clinical attacks average one or more attacks per month over a three-month period , or persistently elevated CRP or SAA in between attacks depending on which is available locally , in the absence of any other plausible explanation.

AA amyloidosis develops as a consequence of persistent inflammation, which may be a manifestation of colchicine resistance. Colchicine intolerance, which generally manifests as GI symptoms such as diarrhea and nausea , is common and can limit the ability to achieve or maintain the effective dose. Dose-limiting toxicity is rare and may include elevated LFT, leukopenia, azoospermia etc.

Conclusion: The suggested recommendations are intended to improve patient care in FMF, to make a personalized treatment plan. Sag: None Declared, E. Ben-Chetrit: None Declared, M. Gattorno: None Declared, A. Gul: None Declared, P. Kone-Paut: None Declared, H. Lachmann: None Declared, E. Tsitsamis: None Declared, M. Twilt: None Declared, F. Introduction: The original reports of the deficiency of adenosine deaminase 2 DADA2 in emphasized early-onset lacunar strokes, livedoid rash, intermittent fevers and early-onset polyarteritis nodosa.

Since then, there have been reports of antibody deficiency, pure red cell aplasia, and cytopenias observed in DADA2 patients. All patients had biallelic germline mutations in ADA2. Serum ADA2 enzyme activity levels were obtained in 32 patients and revealed absent to low levels compared to age-matched controls. The 46 th patient, seen 5 years after bone marrow transplantation for presumed GATA2 deficiency, was not included in our summary calculations.

The average age at the time of the first stroke was 5. Stroke patients had an average of 3 strokes range of Liver biopsies revealed hepatoportal sclerosis in 5 patients and focal nodular regenerative hyperplasia in 2. Significant peripheral vasculopathy was seen in 4 patients, one requiring multiple amputations of gangrenous digits. Immunoglobulin replacement was required in 10 patients. Immune mediated neutropenia was observed in 12 patients.

Conclusion: The spectrum of DADA2 continues to expand to include ischemic and hemorrhagic strokes, cutaneous findings, portal and systemic hypertension, hematologic abnormalities, vascular pathology, immune deficiency and bone marrow failure. As the phenotypic presentation is likely to continue to expand, it is important to investigate any new complaints. The protein product pyrin is expressed in monocytes, neutrophils and eosinophils.

Acute inflammatory attacks are accompanied by a dramatic hepatic acute phase response. Methods: All patients were genotyped. Patient and HC monocyte apoptosis was compared. There was no difference in calprotectin concentrations between the different mutations and no correlation with levels of the hepatic acute phase response, CRP or SAA. Minimal monocyte and neutrophil cell surface expression was detectable. Introduction: PAPA syndrome is a very rare autoinflammatory condition.

Few data are nowadays available about the clinical characteristic, the response to treatment and the outcome of this disease. The patients were included in the study in the presence of mutations in the PSTPIP1 gene or, in genetically negative patients, in the presence of at least two of the following clinical manifestation: recurrent pyogenic arthritis, pyoderma gangrenousm or skin abscess with negative cultural tests.

Demographic data, clinical manifestations and response to treatment were analysed. Results: In may baseline and clinical information were available of near patients in the Eurofever registry. Of the 36 patients classified as PAPA syndrome, 2 were excluded from the study. At the time of enrolment, 15 patients were in the paediatric age, while 19 were adults.

The disease course was recurrent in 24 patients, while the other 10 presented a chronic disease course with periodic recrudesces. Joint and skin involvement were present at disease onset in 24 and 9 patients respectively. In other 12 patients skin involvement appeared over time. Five patients were treated with methotrexate with partial response. Etanercept was used in 6 patient with complete response in 2 and partial in 4, adalimumab in 4 patients 1 partial and 1 complete responders, 2 failure and anakinra in 9 patients 3 partial and 6 complete responders.

The unusual clinical manifestations and the lack of the clinical triad of the disease may be responsible for the under recognition of this disease. Between biologic drugs, IL-1 inhibitors were more effective in the analysed cohort of patients. Objectives: The aim of our study was to compare these new classification criteria for monogenic recurrent fever syndromes with the diagnoses of clinicians in a real-life setting. For this purpose we used the JIRcohort database, an international platform gathering data of patients with pediatric inflammatory disease.

Methods: Patients with recurrent fever syndrome and complete clinical and genetic data were enrolled to the study from the auto-inflammatory module of the JIRcohort database. Patients genotype were characterized with HRF pathogenicity classification. A score from 0 to 2, 0 no mutation , 1 non-confirmatory genotype and 2 confirmatory genotype was attributed to each gene screened in one patient. The new Genoa classification criteria were applied to all the patients and then compared to the diagnosis of the treating physician.

The treating physician diagnosis was considered as standard reference. Finally, for each criteria sensitivity and specificity were determined before an analytical study, describing true positive, false positive and false positive patients. Conclusion: This work is the first to study Genoa criteria, in real-life setting, in a cohort of patients seen with recurrent fever.

Genoa criteria showed tremendous performance for patients with confirmatory genotype and helped classifying patients with non-confirmatory genotype. Genoa classification criteria were less effective when patients did not display at least one genetic variant. The major limit of our study is the lack of a proper gold standard when genotype is not confirmatory.

Nevertheless our study shows that the new classification criteria are of a high risk of misclassification in patients displaying a recurrent fever syndrome without genetic test. Apart from the inhibiting mitosis in all cells, colchicine has an anti-inflammatory effect by inhibiting activation and migration of neutrophils. Colchicine is a safe drug at recommended doses, but it can cause rare side effects including hematological findings such as lymphopenia, thrombocytopenia and neutropenia.

Objectives: In this study we aimed to define the adverse effect of colchicine on platelet function and its clinical relevance. Methods: A total of FMF patients between June , followed at Hacettepe University Pediatric Rheumatology Department and were on colchicine treatment for at least one year, were included to the study. The mean age of these patients was The mean cumulative colchicine exposure was 5. Among these patients, 36 of them had prolonged bleeding time and impaired platelet aggregation test.

Patients who had abnormal platelet function tests the group with abnormal bleeding time were receiving higher colchicine doses median 0. Colchicine was not reduced in these patients and no life-threatening event was observed.

Conclusion: In our study, we have shown prolonged bleeding time for the first time in the literature. Colchicine may cause microtubule inhibition in platelets as well as in other cells and impair platelet function. Further prospective studies are needed to clarify the significance of this side effect. Introduction: A higher prevalence of autoimmune and autoinflammatory complications has been reported in patients with myelodysplastic syndrome MDS.

The exact cause of this remains to be elucidated. As part of their diagnostic workup, all patients had karyotype assessment and targeted genetic sequencing performed. Chi-squared test, Student t-test, analysis of variance ANOVA , univariate and multivariate logistic regression analyses were performed. Results: The average age was Conclusion: Autoinflammatory conditions were found to be more prevalent than expected in patients with MDS and were linked to a worse prognosis.

Transcription factor pathway gene mutations and an abnormal karyotype were also associated with autoinflammation. Autoinflammatory features were associated with malignant transformation, hinting at the possibility that treatment of the autoinflammation might play a role in preventing disease progression. Further studies are required to replicate our findings and study the effect of anti-inflammatory therapy on disease progression.

Introduction: Hereditary systemic autoinflammatory diseases SAIDs are rare genetic disorders characterised by recurrent, spontaneously resolving episodes of fever and systemic inflammation that predominantly involves serosal surfaces. AA amyloidosis is the most serious complication of SAIDs and is associated with proteinuric renal dysfunction that progresses to end stage renal failure and premature death. Objectives: To find a genetic cause in a large British family with a dominantly inherited autoinflammatory syndrome complicated by AA amyloidosis.

Methods: Initially the Next Generation Sequencing NGS targeting 20 autoinflammatory genes was performed in the index patient and his sister, both of whom have been diagnosed with AA amyloidosis. There was a clear autosomal dominant inheritance affecting three generations. Upon finding a genetic cause the DNA obtained from other affected family members were analysed by Sanger sequencing. Results: The index case was diagnosed with sJIA aged 7 and developed end stage renal failure in his early twenties.

He had haemodialysis for four years and underwent renal transplantation at the age of He reported suffering with fever accompanied by severe abdominal and chest pain, arthritis, erythema and night sweats from early life. Interestingly having been started on colchicine for post-transplant gout he felt significantly better.

Subsequently his sister developed nephrotic syndrome due to AA amyloidosis. She describes similar symptoms throughout most of her life. Their parents were of white British origin from a non-consanguineous kindred. Their father had died aged 52 years from complications immediately following a cadaveric renal transplantation.

The post-mortem examination of his renal biopsy revealed deposition of AA amyloid fibrils. The index case grandmother also suffered with cyclical episodic abdominal cramping and had a history of osteoarthritis. PL variant in exon 3. Subsequently this variant was confirmed by Sanger sequencing in all living affected members. The mutant allele was not identified in the unaffected cases. All symptomatic individuals were treated with colchicine which suppressed their FMF related inflammation.

Typically FMF is an autosomal recessive disorder, nonetheless very rare cases of dominantly inherited disease have previously been reported, namely caused by the deletion of methionine residue at position identified in British patients and three substitutions affecting threonine p. TN, p. TS and p. TA found in British, Turkish and Dutch patients respectively. Here we report a novel MEFV variant p. PL causing dominant FMF in three generations of a large British family and in three cases this was complicated by AA amyloidosis indicating a severe pathogenicity of this variant.

The relationship between MEFV mutations and Pyrin inflammasome regulations is still poorly understood. In parallel, a human monocyte cell line was engineered to modelize FMF and HD monocytes and assess the role of Pyrin phosphorylation and inflammasome components in cell death and cytokine release.

Results: Dephosphorylation of Pyrin was sufficient to trigger Pyrin inflammasome activation in monocytes from FMF patients while no inflammasome activation was observed in monocytes from healthy controls. Using a human monocyte cell line, we demonstrated that dephosphorylation of Pyrin was similar in cells expressing wild-type or mutated MEFV but that a mutated MEFV was necessary and sufficient to progress to active inflammasome upon PKC superfamily inhibition.

Finally, thanks to a cohort of FMF patients, we demonstrate that FMF patients can be efficiently and specifically diagnosed based on the response of their monocytes to PKC superfamily inhibitors. Conclusion: Our results demonstrate that Pyrin dephosphorylation is sufficient to trigger inflammasome activation in monocytes from FMF patients but not from healthy donors.

This indicates that in healthy donors, the progression to an active Pyrin inflammasome requires two independently-controlled steps and that the second mechanism of control is deficient in monocytes from FMF patients. Our study also demonstrates that monitoring inflammasome activation upon PKC superfamily inhibition in monocytes can discriminate FMF patients from patients with other inflammatory conditions opening the way to a fast functional test to diagnose FMF.

Fascinatingly, depending on the subunit affected, such genomic alterations result in the development of two seemingly distinct phenotypes, namely: i systemic autoinflammation or ii cognitive impairment. Herein, mutations of the 20S core particle subunits i.

By contrast, genetic disruption of the subunits of the 19S regulatory particle i. Methods: Peripheral blood mononuclear cells PBMC from subjects carrying 19S proteasome loss-of-function mutations diagnosed with syndromic ID as well as related control were collected and subjected to RNA isolation and protein extraction prior to quantitative PCR and western-blot analysis, respectively.

Interestingly, the strength of the IFN signatures in these patients correlated with the magnitude of the unfolded protein responses UPR initiated by proteasome dysfunction, suggesting a cause-and-effect relationship between endoplasmic reticulum ER stress and inflammation. Conclusion: In this work, we provide evidence on the association of 19S proteasome dysfunction with the generation of autoinflammation in subjects diagnosed with syndromic ID disorders.

From these data, we expect to convey a more integrated picture of the pathophysiology of syndromic ID and identify new therapeutic targets for the treatment of cognitive impairment. Proton pump inhibitors PPIs , commonly used as inhibitors of gastric acidproduction, also display anti-inflammatory properties, making them promising drugs in sepsis and in inflammatory disorders. Hystological analysis of all organs was evaluated by hematoxylin and eosin staining.

Amyloid deposition was quantified through Congo Red staining. These mice had systemic inflammation, with high levels of serum pro-inflammatory cytokines compared to WT controls. Hystological analysis revealed the presence of acute and chronic inflammatory cell infiltrates and amyloid deposits in spleen, liver and kidneys. PPIs treatment of KI mice showed a clear clinical impact with improvement of inflammatory conditions and regression of amyloid deposits.

The therapeutic effectiveness associated with lack oftoxicity indicates that PPIs could represent relevant adjuvants to the anti-IL-1 drugs in IL-1 driven diseases. Germline mutations in ARPC1B have been recently described in six unrelated patients, with clinical features of combined immunodeficiency, whose neutrophils and platelets but not T lymphocytes were studied.

Methods: Next-generation sequencing in 6 patients; flow cytometry, proliferation and migration, confocal and electron microscopy to characterize defects in T cells; lentiviral-mediated gene transfer for genetic correction of ARPC1B. In 2 patients normal ARPC1B levels in a fraction of lymphocytes were associated with in vivo somatic reversion and improved T cell migration in vitro.

Conclusion: Inherited ARPC1B deficiency alters T cell cytoskeletal dynamics and functions, contributing to the clinical features of combined immunodeficiency. Introduction: Adenosine Deaminase 2 Deficiency DADA2 is an autoinflammatory disease characterized by systemic vasculopathy, strokes and mild immunodeficiency, mainly affecting B cell compartment.

The defect is due to a loss of function mutation of ADA2 gene, coding for Adenosine Deaminase 2, a protein which regulates the catabolism of extracellular adenosine. Methods: 14 patients carrying loss of function mutations in ADA2 were examined.

They showed clinical history with livedo reticularis, fever, vasculitis and neurological symptoms. We analyzed peripheral B and T cell phenotype by flow cytometry, in vitro B-cell proliferation and differentiation to Immunoglobulin secreting cells in response to TLR9 agonist and T cell help. Simultaneously cytokine production from Tfh cells has been analyzed. Conclusion: Our findings suggest that ADA2 mutations could lead to an intrinsic defect in B cell function and to a reduced T cell dependent B cell response.

Introduction: Tonsillectomy is one of the most common surgical procedures in children and is performed typically for recurrent tonsillitis or obstructive sleep apnea OSA , and less frequently for periodic fever, aphthous stomatitis pharyngitis, cervical adenitis PFAPA syndrome.

Objectives: In order to understand the pathogenesis of these two disorders, we studied the immunologic profile of tonsils removed from children with PFAPA and OSA in comparision with control tonsils. Mononuclear cells from the tonsils were separated by standard methods and cells were analyzed by flow cytometry and gene expression with Nanostring. Cytokine production by isolated tonsillar mononuclear cells was measured by flow cytometry following phorbol myristate acetate PMA and ionomycin stimulation for 4 hours ex vivo.

Results: Tonsils from patients with PFAPA, which were removed during asymptomatic intervals, had evidence of germinal center suppression with significantly fewer T follicular helper cells, more T follicular regulatory cells, fewer plasma cells and reduced IgG class switching compared to tonsils from either OSA patients or controls. Gene expression analysis revealed downregulation of pro-inflammatory genes in tonsillar myeloid cells from patients with PFAPA. On the other hand, tonsils from patients with OSA, had significantly larger germinal center areas by histology compared to those from patients with PFAPA and controls.

During asymptomatic periods, PFAPA patients display myeloid cell and germinal center suppression in the tonsils, suggesting a compensatory response to inflammatory flares. We hypothesize that alternating periods of heightened immune activation and suppression lead to the periodicity of PFAPA. In comparison, tonsils from patients with OSA display relatively constant germinal center hypertrophy likely due to unchecked chronic T cell activation.

Further studies are necessary to understand the genetic and environmental risk factors for T cell activation in both of these disorders and why PFAPA patients may have cycling of inflammatory periods in the tonsils while OSA patients have chronic tonsillar inflammation. Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis PFAPA syndrome is a more frequent cause of recurrent fever in children.

The exact etiology of this pediatric disorder is still unknown. Palatine tonsils are sites where innate immunity leads to the onset of adaptive immunity, mediated by B and T lymphocytes. Natural killer NK cells, the most important effectors of the innate lymphoid cells ILCs , play a fundamental role in innate immune responses.

We tested whether specific infiltrating inflammatory cells in pediatric tonsils contribute to PFAPA pathogenesis. Phenotypic analysis of subpopulations of tonsil cell suspensions and tissues was performedby flow cytometry and immunohistochemistry. Results: During the asymptomatic phase of disease the number of monocytes did not differ between the PFAPA and control tonsils.

Accordingly, plasmacytoid dendritic cells, the main source of type I interferon cytokines, were significantly increased in PFAPA tonsils. Conclusion: These results suggest aninvolvement of NK cells in the pathogenesis of PFAPA and support the crucial role ofinnate immunity in the disease. Introduction: Adult-onset Still's disease AOSD is a rare autoinflammatory disease characterized by fever, arthritis, and multi-organ involvement.

The genetic predisposition to this rampant ILdriven inflammation remains nevertheless elusive. Previous studies failed to identify associations between polymorphisms in the genes encoding IL-1 and AOSD, thus pointing at more complex genetic mechanisms. Studies focusing on highly penetrant rare variants or different types of mutations i. Scope of this study was to unravel the combined mutational variation of a network of ILrelated receptors, pathways, counter-regulators, and cellular processes possibly involved in the pathogenesis of AOSD and ILmediated inflammation in general.

Methods: We collected clinical, demographic, and genetic data from a large cohort of 76 AOSD patients and developed an innovative platform based on molecular inversion probes MIP technology for performing highly multiplexed targeted-resequencing. This allows efficient sequencing of the coding sequence of 48 genes related to the ILpathway, and allows studying rare and common variants in one assay. We have also screened healthy controls, and s of samples with other disorders using the same assay.

Results: We identified rare and unique i. Whether any these are involved in a strong predisposition to AOSD is currently followed-up. Conclusion: Unraveling the genetic bases of inflammation in AOSD deepens our understanding of the human innate immunome.

Of note, this study platform may serve for the genetic analysis of other ILmediated conditions, including gout and other autoinflammatory diseases, whose genetic predisposition remains elusive. Equally important, the identification of pathways amenable to targeting with small molecules or biologics may translate into remarkable clinical implications. A few patients with constitutional trisomy 8 mosaicism and ulcerative disease have also been reported.

The spectrum of phenotypic abnormalities, inflammatory profiles, and treatment responses of patients with constitutional trisomy 8 are not well-characterized. Objectives: We analyzed the clinical and immunologic features of a cohort of patients with trisomy 8 mosaicism in order to understand the pathogenesis of the disorder. Methods: Whole blood gene expression was analyzed with the Nanostring Human Immunology panel.

Platelet electron microscopy was performed in a clinical laboratory. Results: Eleven patients with trisomy 8 mosaicism ranging in age from 5 to 37 years were recruited. Five patients reported genital, esophageal, or colonic ulcers.

Nine patients had cognitive or motor delay. Conclusion: We report the spectrum of clinical and immunologic manifestations in patients with trisomy 8 mosaicism, a disease we name trisomy 8-associated autoinflammatory disease TRIAD. Patient monocytes are elevated in number and have higher percentage of trisomy 8, indicating that an extra copy of chromosome 8 may confer a survival advantage preferentially to monocytes.

Like monocytes, megakaryocytes and platelets develop from a common myeloid progenitor suggesting that cell development in the myeloid lineage may be affected. Further studies are underway to better characterize the inflammatory and survival pathways in myeloid cells with trisomy 8. Introduction: Genetic defects in regulatory proteins of the cytoskeleton are known to cause different syndromes, mostly dominated by hematologic and immune phenotypes. Methods: We report the natural history, clinical manifestations, genetics, and immunohematological findings in 14 patients from 12 families with ARPC1B deficiency.

Results: Although consanguinity was not revealed by clinical history in five families, all cases carried homozygous mutations in ARPC1B. The mutations resulted in undetectable or reduced protein expression. Moderate thrombocytopenia was present in the majority of patients while overt bleeding tendency was absent after infancy.

Immunophenotyping showed a B-cell lymphocytosis and abnormalities in T- and NK-lymphocyte subsets. In vitro T- and B-lymphocyte proliferation and in vivo response to vaccination were normal. Most noticeable was the strongly reduced regulatory T-cell function in those patients tested. Conclusion: In conclusion, our cohort delineates the spectrum of clinical, hematological and immunological manifestations of subjects with ARPC1B deficiency.

The disease appears progressive in most cases and challenging to manage clinically with prophylactic measures and immunosuppression alone. Introduction: ARPC1B-deficiency is a rare paediatric genetic disorder identified in with autoinflammatory components. Primary symptoms include cutaneous vasculitis, increased susceptibility to infection, microthrombocytopenia, and colitis. Its expression is limited to the haematopoietic compartment, however its function in macrophages and B cells has not been characterised.

Cells were tracked individually and migration behaviour quantified using Volocity. Patient 1 has a null mutation c. Patients 2 and 3 are brothers with two SNPs c. LCLs were also derived from the parents of Patient 2 and 3, heterozygous for both mutations. Cell phenotype was assessed by immunoblotting, immunofluorescence, and flow cytometry. Results: ARPC1B-deficient zebrafish were significantly smaller, and monocytes migrated slower compared to WT fish in response to injury.

Patient 1 LCLs were unusually adherent in the absence of stimulation, suggesting constitutive activation. To measure activation, LCLs were stimulated with anti-IgG to measure calcium flux; Patient 1 had a statistically significant higher calcium flux peak compared to control. Introduction: Heterozygous mutations in COPA , encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy SAVI.

Mutations were originally described to cause endoplasmic reticulum ER stress and priming of a T helper 17 response. More recently, increased transcription of interferon IFN -stimulated genes ISGs was reported in blood circulating cells of affected individuals.

However, the precise pathophysiology of this disease remains unclear. Methods: We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in COPA. Introduction: It is assumed that monogenic interferonopathies are mediated by type I interferon IFN inducing autoinflammation. The corresponding mutation in humans also causes lung disease.

As read out we evaluated the mice for development of spontaneous inflammatory lung disease. In addition we generated bone marrow chimeric mice and examined severity of the lung disease and survival of the transplanted animals for days. Bone marrow transplantation experiments revealed that certain aspects of STING NS-associated disease are intrinsic to the hematopoietic system. Introduction: Deficiency of adenosine deaminase type 2 DADA2 is an autosomal recessive autoinflammatory disease and vasculitis, caused by loss-of-function mutations in ADA2.

This treatment may also not effectively treat bone marrow failure or the associated immunodeficiency. Transduced or non-transduced MDM from DADA2 patients and healthy controls were also cultured with endothelial cells, and CD62E expression marker of endothelial activation was examined with flow cytometry.

Next steps now include: 1. Introduction: Chimeric antigen receptor T-cell CAR-T therapy is a highly effective form of adoptive cell immunotherapy combining antigen specific targeting capabilities with T-cell based cytotoxicity. Results: In 52 subjects, 46 experienced CRS, of whom 37 All had resolution of HLH symptoms, except 1 who died from gram-negative rod sepsis complications prior to resolution.

Three had asymptomatic lab abnormalities that self-resolved median 14 days without intervention. Both regimens resolved HLH. Conclusion: Ferritin and cytokine profiling revealed HLH patients had a different inflammatory response independent of disease burden. Introduction: Cryopyrin-associated periodic syndrome CAPS is an autoinflammatory disease characterized by a hyperactive inflammasome leading to the overproduction of interleukin-1b IL-1b.

Assembly of the NLRP3 inflammasome is central to the CAPS disease process resulting in subsequent activation and prolific release of inflammatory cytokines, which further propagate inflammation and disease. While there are a number of new compounds in pre-clinical development that target NLRP3 directly, there is little data on the efficacy of these compounds in CAPS versus healthy controls.

Methods: Peripheral blood mononuclear cells from 7 CAPS patients with 6 different NLRP3 mutations and 4 healthy donor controls were isolated by gradient centrifugation, and monocytes were allowed to adhere for 4 hours prior to treatment and stimulation. Samples were obtained under an approved Institutional Review Board protocol for human subjects. Whole body and spleen weights were measured and blood was obtained for complete blood counts in treated and untreated mice.

Results: Robust inhibition of IL-1b release from C1 treated cells was shown with comparable activity across multiple human NLRP3 mutations and murine Nlrp3 mutant models. Compound efficacy and pharmacodynamics were also shown to be similar between CAPS mutant cells and cells from respective healthy donors or wild-type controls.

Introduction: Systemic autoinflammatory diseases SAIDs are characterized by abnormally increased inflammation affecting different organs. They are mediated predominantly by the cells and molecules of the innate immune system. Inflammasome activation represents the critical pathogenic mechanism shared by most SAIDs. Current treatment strategies are limited to downstream cytokine blockade.

Specific inflammasome inhibitors are not available so far. Objectives: To address this unmet medical need, we performed a high content screening of more than Methods: For the primary screen, we used a fluorescent murine inflammasome reporter cell line to detect ASC speck formation, a marker of inflammasome activation. Among these compounds were known anti-inflammatory drugs such as auranofin and a VEGFR2 tyrosine kinase inhibitor.

A similar inhibitory profile could be observed for the previously reported inflammasome inhibitor MCC, which was included in our assays as a reference substance. Moreover, compounds had similar efficacy in inflammasome inhibition PBMCs obtained from patients and healthy controls. Conclusion: Based on our results in murine and human cells in vitro , small molecule inflammasome inhibitors my complement current treatment options for SAIDs in the future.

Objectives: We aimed to investigate a 14 year-old boy from a consanguineous family in India with polyarthritis, parotitis, hepatosplenomegaly and colitis associated with anorectal fistula, but without skin manifestations or any history of severe infections. Methods: We performed whole exome sequencing to identify the genetic cause of the patient's phenotypes. SHARPIN deficient patient fibroblasts demonstrated enhanced apoptosis induced by FAS stimulation as compared to control cells, which parallels the enhanced apoptosis observed in the Sharpin deficient mice.

Introduction: Deubiquitinase enzymes DUBs function in the removal of poly-ubiquitin chains from substrate proteins to regulate their activity and degradation by the ubiquitin-proteasome system UPS. Through whole exome sequencing analysis WES , we identified a novel homozygous missense mutation c. The patient presented with early-onset recurrent fevers, rash, subcutaneous skin nodules, lipodystrophy, and prominent arthritis, and this phenotype was suggestive of the CANDLE syndrome.

We aimed to study the disease-causing mechanism underlying this novel mutation, EK, as well as the biological function and targets of USP Immunoprecipitation and immunoblot, luciferase assays, serum and plasma cytokine profiling, immunofluorescence, real-time PCR, and flow cytometry were used to investigate abnormalities in patient-derived cells.

Results: We found that the novel USP43 mutation leads to an upregulation in interferon signaling and causes an impairment in the proteasome-mediated protein degradation pathway. This cellular phenotype was rescued by transfection with wild-type USP43, which suggests that this mutation is loss-of-function. Similarly, transient knockout of USP43 in T cells led to increased levels of ubiquitinated proteins. PSMB8 encodes the catalytic subunit of the immunoproteasome.

Conclusion: Our data suggest that the loss-of-function mutation in USP43 decreases immunoproteasome activity and causes an upregulation in type I interferon signaling, similar to what is observed in patients with CANDLE. Treatment with a JAK inhibitor has been very effective in controlling the disease activity in this patient. To our knowledge, this is the first report of a human disease caused by mutation in USP Introduction: Despite continuous advances in the identification of novel causative genes, several patients with a clinical autoinflammatory phenotype remain unclassifiable.

Objectives: to describe a novel hematological and autoinflammatory disorder in three unrelated patients caused by a de novo missense mutation of CDC Methods: Whole exome sequencing was used to identify the novel variant. The functional impact of altered CDC42 function on hematopoiesis and inflammation was assessed through patient peripheral blood and bone marrow analyses, protein behavior and immune and non-immune cell functioning through in vitro biochemical and functional assays and in vivo C.

Disease features included n eonatal- o nset c ytopenia with dyshematopoiesis, a utoinflammation, r ash, and h emophagocytosis collectively termed NOCARH syndrome Table. An altered hematopoietic compartment prevalence of early differentiation elements and substantially decreased clonogenic progenitors was demonstrated. Complementary assays documented the unique consequences of this mutation on CDC42 localization and function, and its disruptive effect on cell behavior and developmental processes, possibly linked to actin dysregulation.

Conclusion: The p. RC amino acid substitution in CDC42 underlies a novel, unique syndrome where CDC42 functional dysregulation has pleiotropic effects, causing hematopoietic disturbance, hyperinflammation, and immune impairment. We describe here a 3-year-old female patient with clinical features evocative of PRAAS in whom no mutations have been found using our 62 gene panel sequencing that includes known PRAAS genes.

Objectives: The aim of the study was to identify the molecular cause responsible for the PRAAS phenotype in this patient. Methods: We performed a trio-based whole exome sequencing WES in the patient and her parents. Functional assays were conducted to confirm the pathogenic effect of the mutated candidate gene. Results: The patient is a 3-year-old female patient of Algerian descent, born to related parents. She developed a cutaneous rash on the 7 th day of life and became febrile at the age of one year.

The rash was polymorphic, annular shaped and predominantly periorbital She failed to thrive and has long-lasting hepatosplenomegaly. She has an emaciated face, a distinctive nose, and long and gracile fingers. She had elevated acute phase reactants, microcytic anemia and hypertriglyceridemia. She exhibited partial response to steroid and methotrexate treatment and relapsed when the doses were lowered. WES revealed a homozygous missense mutation in the candidate gene PSMB10 , located in the N-terminal part of protein which is cleaved in the mature form.

This variant is absent from the GnomAD cohort, and predicted to be pathogenic according to in silico bioinformatic tools. This is the third and last immunoproteasome subunit involved in this disease, and this new gene responsible for PRAAS expands the number of genes involved in this spectrum.

Introduction: Use of NGS in patients with unclassifiable disease lies a possible approach to the identification of novel disease causing genes. Objectives: We report a patient with an early onset inflammatory bowel disease with granulomatous lesions and recurrent HLH episodes carrying a missense mutation in the WNT6 gene. Results: Ten years old Caucasian boy affected by early onset pan-colitis from 9 months of age.

Since the disease onset the patient is on glucocorticoid treatment with amino acidic enteral nutrition and oligo antigenic diet. Because of recurrent disease relapses at any attempt of glucocorticoid withdrawal, azathioprine and cyclosporine treatments were also added. At 2 years of age he received total colectomy with ileostomy.

Because of insufficient disease control, treatment with a TNF-inhibitor infliximab was started with apparent improvement of intestinal symptoms. However, persistent granulomatous inflammatory disease of the distal portion of the ileus-rectal anastomosis persisted. Moreover, the patient presented recurrent HLH episodes that required high dose of glucocorticoid and cyclosporine-A treatment.

Except one HLH episode related to a varicella zoster infection, the other HLH events were most likely triggered by his underlying inflammatory condition. Considering the early disease onset, primary immunodeficiency and early intestinal bowel disease onset were genetically ruled out as well as chronic granulomatosis diseases through extensive NGS panels. The patient is now partially controlled on low dose of oral glucocorticoid 0.

Conclusion: WNT signalling has been primarily described as a regulatory pathway in ontogeny and homeostatic processes. Schaale at al. Moreover, they found that the transcription factor c-Myc is significantly induced in murine macrophages by WNT6. This identifies WNT6 as a novel factor driving macrophage polarization toward an M2-like phenotype, suggesting a role for WNT6 in macrophage differentiation.

Our case suggests defective function of WNT6 might be involved in the development of a granulomatous disease. WNT6 role in macrophage differentiation and polarization might also be important in the activation of the IFN-gamma pathway and in recurrent HLH episodes. Schaale et al. J Immunol ; Bracaglia: None Declared, D. Knafelz: None Declared, F. Bracci: None Declared, A. Insalaco: None Declared, G. Marucci: None Declared, M. Pardeo: None Declared, G.

Prencipe: None Declared, I. Caiello: None Declared, A. Pascarella: None Declared, M. Niceta: None Declared, F. Pantaleoni: None Declared, A. Ciolfi: None Declared, B. Papadatou: None Declared, M. Tartaglia: None Declared, G.

Torre: None Declared, F. Introduction: Juvenile idiopathic arthritis JIA is the most common of the childhood rheumatic diseases. JIA is characterized as juvenile-onset persistent arthritis with no defined cause. A high degree of clinical heterogeneity is observed within the JIA group of diseases, thought to reflect a diversity in genetic and environmental factors and mechanistic drivers. The recent success in identifying monogenic causes of autoinflammatory diseases suggests that monogenic causes may also underlie a subset of JIA patients.

Objectives: NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans. Methods: Here we characterized a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry.

Parallel studies were performed in a mouse model. Results: The patients inherited a novel p. The mutant form of NFIL3 demonstrated reduced stability in vitro. Introduction: The multi-subunit phagocyte nicotinamide adenine dinucle- otide phosphate oxidase generates reactive oxygen species and is crucial for host defence.

Deficiencies in individual subunits gp91phox, p22phox, p47phox, p67phox, and p40phox cause chronic granulomatous disease CGD , but some patients with CGD do not have mutations in these genes. We recently found that Eros, a hitherto undescribed protein, is essential for the generation of reactive oxygen species because it is necessary for protein but not mRNA expression of the gp91phox-p22phox heterodimer, which is almost absent in Eros-deficient mice.

Neither clone expressed detectable EROS protein. Knockout of EROS in cell lines or primary human ips derived macrophages results in abswnt gp91phox-p22phox expression and aboloishges the phagocyte respiratory burst. However, EROS also regulates the expression of other proteins. Introduction: Early onset cold-induced urticarial rash with systemic inflammatory symptoms are hallmarks of hereditary autoinflammatory diseases caused by gene mutations of the innate immune pathway, e. However, in many cases genetic tests are negative, suggesting the existence of unrecognized genetic variants.

Methods: We studied eight members of a four-generation family, four of whom were affected. Genetic analysis involved exome sequencing followed by targeted Sanger sequencing. Functional analyses included immunoblotting, mononuclear cell stimulation and immunohistochemistry.

We generated recombinant protein variants and assessed cytokines and proteins in plasma and skin. Results: Affected patients had cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identified a novel deleterious variant in gene F12 TA , resulting in p.

Occurrence of the mutation segregated with disease status. Furthermore, we observed contact system activation with reduced plasma prekallikrein and profound cleavage of high molecular weight kininogen, representing bradykinin production.

Skin and blood neutrophils were found to be a prominent source of FXII. In accordance with these findings, treatment with icatibant bradykinin-B2-antagonist or anakinra interleukinantagonist reduced disease activity in patients. Conclusion: We identified a novel autoinflammatory syndrome characterized by a substitution in the F12 gene resulting in activation of the contact system and cytokine-mediated inflammation. Most of DADA2 patients reveal systemic vasculopathy consistent with polyarteritis nodosa and large phenotypic variability has been reported [1, 2, 3].

However, pathogenesis of DADA2 remains unclear. Objectives: The objective of this study is to reveal clinical and genetic characteristics of Japanese DADA2 patients, and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. Low levels of IgG and IgM were revealed in 3 There were two We identified 6 previously described and 4 novel variants in ADA2 , which included two that we reported before [3]. Overexpression of ADA2 variant constructs in HEK cells showed that some variants had comparable protein expression levels to wild-type in cell lysate but most of them were not secreted and all the variants had low or absent ADA2 enzyme activities.

In multi-omics analysis, differentially expressed DE genes were analyzed at the mRNA and protein levels. We found 64 and 58 genes that were differentially expressed in acute phase vs control and remission phase vs control in common at the transcriptome and proteome levels respectively.

Gene ontology analysis of these datasets revealed constitutive up-regulation of type 1 and type 2 interferon pathway. Some genes were common to both datasets. Using multi-omics analysis, we also have found differentially expressed genes in DADA2 patients. Some genes were consistently up-regulated even in the remission period. This may provide further insights into the pathogenesis of DADA2. Objectives: In this study, we performed a multicenter survey investigating HA20 patients found in Japan and characterized immunological profile.

Methods: We summarized the detailed clinical manifestations, genetic analyses and several immunological parameters of Japanese patients with HA Multicolor flowcytometry analysis was performed. Results: A total 32 patients from 10 independent families were enrolled in this study. Age of onset was 0 to 20 years. All these mutations were evaluated to be functionally pathogenic by several in vitro assays.

In the detailed analysis of lymphocyte subsets including T, B and NK cells, regulatory T cells Treg were increased in all analyzed patients. The increase of double-negative T DNT and T helper 17 cell Th17 cells were observed in 7 and 3 out of 18 analyzed patients, respectively. In addition, follicular helper T cells Tfh were significantly increased especially in younger patients.

Memory B cells were decreased in most of analyzed patients. The immune dysregulation derived from the defect of A20 may cause the increase of the autoimmune related T cell subsets and the secondary Treg expansion as well as the phonotype of the previously reported A20 knockout mice. Conclusion: Our study revealed unexpected variation in phenotypes of HA20 including autoimmunity.

In the analysis of lymphocyte subsets for HA20 patients, the characteristic findings such as the increase of Treg and the decrease of memory B cells were observed. Introduction: Monogenic Interferonopathies represent a rare group of inflammatory diseases with difficulties in early diagnosis.

Methods: Eight patients with genetically confirmed monogenic Interferonopathies were included. Clinical data, classical inflammatory markers and blood count were obtained by patients file. Results: All patients showed homozygous mutations. Mean age of patients was 12 years min. Five patients showed abnormalities on brain MRI, like periventricular calcifications or corpus callosum thinning. Two patients homozygous for IFIH-1 mutation were diagnosed with Singleton-Merten-Syndrome presenting abnormal ossification of extremities and dental anomalies.

One patient with homozygous TREX1 mutation presented with postnatal glaucoma, microcephaly, developed sensorimotor polyneuropathia and suffered from recurrent fever with persistent chilblain lesions. In six patients elevated SIGLEC1 expression showed dysregulation of the type 1 interferon pathway prior to genetic testing. In three patients with unclear disease phenotype measuring expression of SIGLEC1 contributed to establish the right diagnosis.

Therefore, SIGLEC1 qualifies as an easy accessible and cheap diagnostic marker with short turnaround time to screen patients with suspected Interferonopathy. Patients usually present in childhood, but age of onset, disease severity, and organ involvement of DADA2-associated vasculitis is highly variable.

To further assess the pathogenicity of identified variants on a functional level, ADA2 activity was determined on available serum samples of patients with PAN. Results: Nine of patients with PAN 7. Four patients 3. The remaining variant, PS, is a rare variant predicted to be damaging to protein function by in silico algorithms.

ADA2 activity of three of the four available serum samples on monoallelic carriers was not reduced, confirming the non-pathogenicity of T65M, MI, and VI. The serum sample on the individual carrying the pathogenic variant YC showed ADA2 activity in the range of carriers. ADA2 enzyme activity testing of the remaining serum samples revealed one additional individual with strongly reduced ADA2 activity levels as well as five individuals with enzymatic activity in the range of carriers.

Sanger sequencing of the ADA2 gene in these individuals did not identify any pathogenic variants and indicates the presence of cryptic mutations undetectable by conventional sequencing. Introduction: in recent years several genetic diseases linked to pathologic activation of type 1 interferon IFN pathway have been described. Objectives: To identify type I interferonopathies in a cohort of children with early-onset rheumatic disease and to report the long-term efficacy and side effect of pathway-specific treatment with a Janus Kinase JAK inhibitor.

Methods: Patients were selected based on the presence of any of the following: i early onset infancy or before puberty inflammatory SLE-like symptoms; ii vasculopathy skin ulcers, chilblains, strokes iii panniculitis with or without lipodystrophy iv persistent or recurrent systemic inflammation with or without lung involvement v polyarthritis with lung involvement.

In selected patients, molecular analysis was performed using Sanger sequencing, a NGS panel of 41 inflammatory-related genes or whole exome sequencing. Off label therapy with the JAK inhibitor Ruxolitinib was considered in patients with a definitive genetic diagnosis and incomplete disease control by standard treatment.

Results: We screened patients evaluated in the rheumatology unit of our Institute. Based on the clinical presentation and the result of the IFN signature we further analyzed a subset of patients for an underline genetic defect. In 6 patients we identified pathogenic mutations affecting TMEM p. VM in one patient and p. RH genes were identified. Therapy with Ruxolitinib was started in 4 patients and allowed to partially control disease manifestations and reduce or stop steroids, however, we observed the following limitation: the patient with DNASE1L3 mutations and a severe kidney involvement at therapy onset, despite the control of his systemic symptoms progressed to kidney failure; one patient with SAVI and a severe lung involvement experienced severe recurrent viral lung infections requiring intensive care and extracorporeal membrane oxygenation ECMO in one episode; the patient with DNASE2 mutationsexperienced a Herpes Zoster infection controlled with antiviral therapy and decreasing Ruxolitinib dosage.

Conclusion: Patients with type 1 interferonopathies might present with symptoms overlapping pediatric rheumatic diseases. The combination of type 1 interferon pathway activation assessment and NGS is an effective strategy for the diagnosis of this heterogeneous class of diseases and can guide the choice for targeted therapies.

JAK inhibitors represent a therapeutic resource in controlling these difficult-to-treat patients, however further studies are needed to assess their efficacy and long-term safety. Introduction: DADA2 is phenotypically heterogenous in its presentation, even within families with the same mutation, and the absence of a murine ortholog has placed emphasis on the study of known cases of the disease.

Objectives: We conducted an E-Delphi study to explore consensus on the diagnosis, investigations and management of those with suspected disease. Actors are not nested within one level but cross over into other levels or arenas without there necessarily being any clarity as to their authority or links back to their original level.

In other words the degree to which we can sustain our analysis in terms of distinct levels may be open to question. Accountability is a broad term that reflects a range of understandings rather than a single paradigm. Until recently, accountability was not a term in common use, nor did it figure as a term of art outside the financial contexts of accountancy and audit. In the context of a democratic state, the key accountability relationships in this core sense are those between citizens and the holders of public office, and within the ranks of office holders, between elected politicians and bureaucrats.

In a delegation model of accountability, relationships are established as a means of carrying out the delegation of tasks and the communication of expectations. Accountability can be construed as an important organizing principle of democracy resting upon specific standardized procedures.

Accountability forces power to speak the truth, at least in ideal terms. However, its evocative powers make it also a very elusive concept because it can mean many different things to different people, as anyone studying accountability will soon discover Bovens Bovens has defined accountability as a social relationship between an actor and a forum, in which the actor explains his conduct and gives information to the forum, in which the forum can reach a judgment or render an assessment of that conduct, and on which it may be possible for some form of sanction formal or informal to be imposed on the actor.

The attractiveness of this definition for many of those working on accountability related issues is that it provides a clear procedural and organizational framework with a focus on the relationship between the actor, potentially any actor including for example actors that can never be understood as agents, such as networks and an accountability forum, potentially any kind of accountability forum it can be legal, administrative, financial as well as the more obviously political.

In addition it limits the focus of accountability to the ex post and to those mechanisms that provide in some manner for the imposition of sanctions or consequences in a looser, not strictly legal, sense. The more limited understanding of accountability as a social relationship between an actor and a forum is an excellent way of linking actors, any actors and accountability forums, irrespective of the grand constitutional design. Moreover the fact that accountability is given a precise definition makes it possible to operationalise it in very specific institutional contexts and to study empirically the practices of accountability with regard to various forums courts, parliaments, auditors, ombudsmen, etc.

Quite a number of those working on accountability in the EU context take the Bovens definition as their point of departure precisely because it enables them to take account of actors and forums that are not necessarily in any delegation relationship Benz ; Papadopoulous ; Harlow and Rawlings The Richness of CONNEX Research in a Nutshell 25 This has been a useful way forward, making it possible to focus how accountability practices are actually institutionalised in practice in the European multilevel polity.

Accountability practices in the EU multi-level governance context The most interesting finding from our work on EU multi-level governance systems relates to the wide variety of actors that can be studied in terms of their relationship as a matter of legal, institutional and empirical practice with a wide variety of accountability forums. They vary from very formal and institutionalised actors to much less institutionalised forums for example networks.

One finding that arose out of the study of the practices of accountability in the context of various EU level actors was that we must not only focus on accountability practices of European level institutions at the level of the EU political system itself but also at the level of the national political systems. But national principal-agent relationships are still in place in a number of national systems and that this part of the accountability equation can in any event not be discounted.

As a matter of fact, governments must negotiate on their mandates with parliaments and this is usually done under discretion at the expense of transparency Auel Carol Harlow and Richard Rawlings show that not only courts and ombudsmen institutions play today an important role in ensuring the accountability of rules in multi-level systems, but also that for accountability to operate efficiently this requires the establishment of networks of accountability enabling exchange of information and cooperation between the EU and the national levels.

In addition it is emerging that the EU is developing an autonomous role in defending the rule of law where the international legal order fails to do so, in the interests of individuals whose rights and interests have been affected as for example is the case with regard to freezing of assets of terrorists legislation adopted by the UN Security Council in the aftermath of 11 September Our experience has highlighted the need for — and the interest in — even more intense inter-disciplinary collaboration between political scientists and public lawyers of all levels.

Without being able here to systematically review all the interesting results from the work of RG2, the innovative empirical research that was conducted indicated the empirical limits of the classic concept of democratic accountability and led the group to a more refined approach on the way accountability operates in what is a complex and multi-level system of governance.

Researchers concentrated on data based analyses to explore the effects of enlargement on the cohesion and distinctiveness of European parties and party groups in the European Parliament and also on electoral participation in EP elections.

They investigated if the European public sphere meets the necessary conditions for competitive EP elections and to what extend the EP electoral process is structured by EU issues. Do levels of mutual trust vary over time and across countries? They are more distinct than national parties and equally cohesive. The major dimension on which EP party groups are distinct is the left-right dimension, although there are also systematic differences in how party groups position themselves on the integration-independence dimension.

Enlargement did not affect cohesiveness and distinctiveness of EP groups on either the left-right or the EU dimension, but big differences exist on libertarian issues. The impact of enlargement on the heterogeneity of the European electorate When looking at the distributions of electoral participation, the diversity of the European electorate seems to have increased with the enlargement of the EU.

Such a straightforward comparison cannot be made for party choice, as the set of competing parties is unique for each of the member states. Similarly, we also find strong differences in terms of other characteristics that are known to be important for electoral participation and party choice: citizens in new member states identify much less frequently with a political party than those in the older member states, etc.

Schmitt At first sight, then, one might be inclined to say that the enlargement has increased the heterogeneity of the European electorate Schmitt Yet, such a conclusion would be misleading for two reasons. In terms of turnout, for example, Cyprus and Malta look more similar to Belgium, Italy and Luxembourg than that they resemble, e. But they do not indicate that these citizens are of a different nature, or that the factors that determine their behaviours and choices are different.

Euro sceptic political parties seem to drive some of this increase so in a sense the conditions for a competitive election are emerging. To what extent is the EP electoral process structured by EU issue concerns? Furthermore, in most EU countries there has been broad consensus about integration between the main parties.

There are significant exceptions to the general conclusion, most notably in the case of Denmark. It is also true that in Euro-sceptic and even outright anti-EU parties won their best results ever. Even so, it was as clear in as it was in that the results of EP elections could be predicted very effectively from the national circumstances of the contending national parties Schmitt First, and most notably, in as much as national competition is, perhaps increasingly, influenced by EU issues then there is an EU influenced structure to national competition which will be reflected in EP elections.

There are ways in which EU issues generate conflict which overlap with traditional cleavages: the immigration issue is a case in point. There are also EU issues which may cut across old left right divides, but they, too, can be part of national level competition Schmitt Secondly, there is evidence that EU concerns have motivated a minority of voters to switch allegiances between national and EP elections.

Enlargement has had some impact on the answer to this question in as much as the parameters of a second order election model seem to be different in the new accession countries, at least taken as a whole. It also seems clear that in at least some of them, the EU issue is a highly salient one for electoral competition. Even so, EP election results can still be predicted reasonably well from national ones Marsh First, the willingness of EU citizens to accept all other citizens of the enlarged Union as their fellow citizens and to accept that all EU-citizens are therefore entitled to all rights that come with the citizenship of the Union.

A second indicator of an emerging political community is the extent to which people do consider themselves as citizens of the European Union. A third indicator is mutual trust. In general people from the older member states are more inclined to accept the consequences of European citizenship, i. However, it is unlikely that this is a direct consequence of the duration of membership.

In general the people from the new member states in Central and Eastern Europe are less inclined to see themselves as European citizens than people in the older member states, but this is not a uniform pattern. The differences between some of the founding member states are as large as between any other pair of countries Thomassen Whereas the European Commission and the Council of Ministers faced declining trust between and , but recovered fast, the European Parliament continuously gained support.

However, there is a dramatic drop in trust between the Spring and Autumn of This development coincided with the Eastern enlargement and the signing of the Constitutional Treaty in Rome in October of that year. In the period from to Spring , trust in national institutions was higher than in European ones in no more than four of the fifteen member states. From the Autumn of trust in both national parliaments and the European Parliament increased somewhat whereas trust in national governments increased tremendously.

This revival of trust in national institutions is probably due to enlargement and the discussion about the European Constitution. It seems to be a stable pattern that citizens in the new member states trust European institutions more than do citizens in the old member states. In contrast, trust in national institutions is considerably lower in new than in older member states. Also, since trust in national governments in the new member states has dramatically declined, making the gap between new and old member states even wider Thomassen This is not simply a consequence of the changing composition of EU or the latest accession wave.

In fact, this sort of pattern is characteristic of most waves of accession. In looking to explain these variations we find that utilitarian considerations matter. Direct utilitarian benefits in terms of trade and transfer payments are associated with variation, as are changes in national economic performance, with the EU seemingly rewarded for good times.

A very simple, purely utilitarian, model is quite good at explaining the cyclical pattern at an aggregate level. Such an explanation is also consistent across different accession waves and not only the latest enlargement round. Only two countries prove to be major exceptions to the utilitarian model of support for EU policies. One is the Netherlands, where the gradual disenchantment with the benefits of membership since the early s is not reflected in the underlying material changes.

A more striking exception, and the most striking negative result, is the case of the UK. There, support has fallen since the early s, and fallen sharply from the relative heights achieved in the early s. Predictions from the model suggest support should have risen steadily, rather than fallen steadily from around Consequently, interest groups and civil society are well established on the social science research agenda but dealt with by different research communities.

Furthermore, empirical research was for a long time scattered across disciplinary and policy specific research fields with little cross-cutting intellectual exchange. Therefore, RG4 engaged in a concerted effort to link the debate on the alleged biased representation of interest groups in the EU with research on the promised benefits of civil society involvement in EU governance. RG4 did not shy away from methodological challenges but took up the thorny issue of measuring influence and aimed at making sense of the divergent concepts of civil society and the diverse functional roles attributed to civil society in EU governance.

Biased representation in the EU It is a common criticism that the EU is plagued by biased representation and that economic interests enjoy privileged influence on EU policies. But on closer scrutiny there is little agreement on the kind of empirical data that is needed to support or refute the common supposition.

If empirical evidence supports the assumption, how do we explain the persistence of biased representation? Empirical research on European trade policy gives evidence that civil society organisations of all different kinds have gained access to policy- makers. However, these representatives of general interests have largely failed to shift policy outcomes in their favour. This does not result from the overwhelming presence of focused producer interests since numbers do not necessarily count in international negotiations.

The explanatory factor is neither the lack of expert knowledge but a lack of resources in terms of not being able to diminish or enhance the chances of political actors to be re- elected or re-appointed. In order to draw a full picture of interest representation and influence, researchers further have to take into account that interest groups aim not only at policy influence but also at maintaining their organization.

Thus, while much lobbying could easily be viewed as ineffective in terms of shaping policy outcomes, this may underestimate the usefulness of the lobbying effort from the perspective of maintaining the organisation. Is civil society a remedy to the perceived legitimacy crisis of the EU? The positive image of civil society has many roots: the legacy of civil society in the peaceful transformation to democracy in Central and Eastern Europe, the recourse to NGOs as active representatives of general values and of rights based interests in global governance, the dissemination in academia of theories which attribute to civil society a key role in rejuvenating democracy such as public sphere and deliberate democracy theories and comparative associationalism.

The EU is no exception Michel : The discourse on civil society draws, mostly implicitly, on many divergent concepts and, consequently, promises the cure of all kind of deficiencies. However, institutional factors and the reality of associational life in Europe channel how these ideas are put into practise. It is widely acknowledged that the diversity in political cultures, languages and national allegiances in Europe are obstacles to the emergence of a trans-national civil society.

Less noticed are the effects of civil society changes at member state level. As the Scandinavian model is even in decline in the countries of origin, we can hardly expect its re-invigoration in the EU. Rather, the EU is faced by a pluralist system of highly professional organisations in which value and rights based civil society organisations compete with a wide range of social and economic interests groups Kohler-Koch a.

When trying to assess the democratic value of civil society engagement, we have to take into account that normative benchmarks vary with theoretical approaches. The discourse on EU-civil society relations was heavily influenced by normative theories advocating deliberative democracy and the value of a European public sphere.

Involving civil society: A contribution to participatory democracy? How did it translate the high principles of European governance - openness, participation, transparency, and accountability — in strategies and instruments? Since the turn of the century, EU institutions, above all the Commission, have been active to provide citizens with more opportunities to participate effectively in policy-making. In close cooperation with NGOs and the Commission researchers investigated the variety of approaches, the different uses of instruments and the divergent effects at different levels of government.

Notwithstanding all these efforts, equal representation has not been achieved, neither in terms of types of interests nor in relation to territorial origin Persson Furthermore, the commitment of the Commission to evidence based decision-making gives preference to expert knowledge and puts political, value oriented debates second.

However, the participatory discourse has clearly raised the awareness for the need of input legitimacy. Comparing the first with the second pillar of the EU, it is evident that civil society involvement in foreign and security policies is less in the spot light but research reveals that it is still very present.

The way in which the demands and arguments of civic groups are taken into account evolves in the course of this interaction. Furthermore, detailed case studies reveal a two way effect: civil society involvement changes the perception of the responsible General Directorate of its own role in such public participation exercises and it contributes to the Europeanisation of involved interest groups. Empirical research reveals that the EU has not a clear conception of civil society when it sets out to promote democracy in third states by empowering civil society.

A comparative investigation of the choice of instruments and partners documents that the EU is often trapped by the dilemma of having to choose between societal organisations which are closely associated with government and organisations in opposition to the authoritarian government. Apparently, this is a choice between, on the one hand, short term political stability and a possibly long-term transition to democracy and, on the other hand, a more conflict prone process that may bring about change more rapidly but with the risk of instability and political turmoil.

Irrespective of all the differences that accrue from different national situations, democracy promotion through civil society support turned out to be a fly-by-night instrument that was used with ever greater hesitation over time. The first group addressed the topic of social capital and governance in old and new EU-member states, paying special attention to national elites and their trans-European networks.

The second examined the question of civil society and multi-level governance focussing on a possible move from national toward international linkages, and the third investigated the EU contributions to civil society development in Central and Eastern Europe. To what extent has there been an Europeanization of Civil Society? The combination of various research perspectives and approaches demonstrated that the linkages in the European multi-level system are characterised by national features and developments and that voluntary associations have a very limited capacity to enhance meaningful political linkages between the EU and its citizens.

The linkages are heavily influenced by national elites who play a key gatekeeper role to exert top-down control. The Europeanisation process in terms of civil society actors adapting to the European political space has been somewhat uneven. Engagement with, and confidence in, the EU compared to national institutions is relatively weak exactly among the group of citizens that the social capital model predicts would be highest — members of voluntary associations. Attitudes towards Europe and European institutions among activists are not much more positive than those found among the general populations.

Consequently, because support for the EU is weak among citizens active at the local level bottom-up engagement at the EU level is unlikely to emerge. Thus, the social capital being generated in EU democracies is nation-centred: i. Combining various perspectives made clear that linkages in the European multi-level system are: i evidently characterised by national features and developments, ii only, in rather restricted ways, ascertained by voluntary associations, and iii heavily influenced by national elites who are able to control top-down linkages.

In contrast to the empirical findings on the local level, other RG5 research indicated an increasing interest in European affairs among civic organizations organised on trans-national trans-European level. Adam The transformation of civil society organizations on the European level into advocacy groups Research findings in Research Group 5 and other CONNEX groups chart the apparently inexorable trend towards the professionalization of representation.

However, from the group perspective it is a necessary response to trans-nationalisation processes and the multi-level policy-making system of the EU. Professionalization and bureaucratization appear to be inevitable if NGOs are to effectively represent their interests and influence outcomes.

These developments may ultimately result in a segmented and hierarchically structured civil society offering decreasing levels of political linkage and leading to the development of new civil society elite. A new market niche has been opened for such organisations - providing practical expertise and knowledge. It was agreed that comparative European studies would benefit from bringing the activities of trans-national NGOs more into focus.

Different strategies for the promotion of civil society in external states can be observed and the EU akin to other external actors faced significant problems in adequately taking the local contexts into account. There were problems with regard to the funding programmes and democratization instruments. EU funding of civil society tended to privilege a few large and well-connected NGOs and smaller and geographically dispersed organizations became the poorer relatives. These developments are likely to lead to greater hierarchy and stratification within civil society Susan Stewart How can one assess the crucial role of experts of all kinds in EU policy making?

How democratically legitimate are soft modes of governance? To what extend are new modes of governance EU-specific? Concerning the significance of the emergence and development of NMG it has been open to debate whether they suggest the demise of the old system or whether they simply represent a fist step of a new era of EU governance.

Equally disputed is the need of and possible mechanisms to supply democratic legitimacy. Although in-depth analyses concerning the concrete operation of the Community Method have been lacking, the basic principles are clearly identified. One of the most remarkable elements of this international regime has been its stability: 50 years on, despite a significant enlargement of the number of member countries and several treaty revisions, it may be argued that the key features of the system have remained unchanged.

New modes of governance provide a near-perfect mirror-image of all of these elements. Uniformity is perceived as unduly burdensome: flexibility is the new buzzword. For the same reason, non-binding instruments are preferred. The development of NMG could, therefore, easily be seen and is often presented as a sign of the obsolescence of the Community method. However, the study of EU policies conducted in the framework of RG6 suggests that the opposition of these two models is somewhat artificial.

Similarities are about as manifold as the differences. As a rule, EU policies are less centralised than those conducted in many Member States. Being the product of a consensus, they are often bound to be fairly flexible — hence the frequent resort to techniques such as minimum harmonization or opt outs. It is applied today in a larger number of areas than fifteen years ago and there has been no substantial decline of the volume of legislative initiatives, even after the enlargement Dehousse, Legal integration has not stopped, even in areas where the need for diversity is acutely felt, such as social policy Pochet In other words, the development of new modes of governance does not announce a demise of the Community method.

Assessing the crucial role of experts in EU policy-making Another recurrent theme in various workshops organized by RG 6 has been the limited role of political actors in most day-to-day decisions taken at the EU level. Scientific experts are crucial actors in risk governance, whether at the level of the regulatory decision-making process or at the level of the courts, and the powers of the EU in this field have been growing steadily Vos, Also, the problems linked to the tendency of law-makers to delegate part of their powers to different actors whether these be administrative agencies or private bodies have been addressed in several research teams.

Clearly, this increasing polycentricism is not specific to EU policy- making. At the domestic level as well, policy-making is characterized by an ever-wider array of decision structures. This trend has been partly described in the existing literature on policy networks. The web of EU committees has also been analyzed along these lines.

It is evident that the role of non-political actors experts and bureaucrats in EU policy-making has implications on the way Europe is perceived by its citizens. Given the weakness of partisan cleavages at the European level, decision-making appears to be dominated by technocratic elements. The complex lines of command that exist in the EU makes it often nearly impossible for ordinary citizens to identify who is responsible for a given decision.

Given the prevalence of the parliamentary model in the European political culture, it is not surprising to find that even technocrats may feel uncomfortable with this Borras, Moreover, the de- politicization of EU policy-making may create incentives for shifting responsibility for sensitive decisions to the European level in order to avoid political tensions at the domestic level Palier, Clearly, discussions within RG6 have shown the need for a regular dialogue between policy studies specialists and scholars working on accountability issues or on national and European politics.

The democratic legitimacy of New Modes of Governance While the normative qualities of soft governance arrangements are usually seen in their alleged higher effectiveness in attaining policy goals, serious concerns remain regarding their democratic legitimacy.

Therefore, they may imply, entail or legitimise an authoritative allocation of values, which makes their democratic legitimacy a valid concern. The Richness of CONNEX Research in a Nutshell 45 The research group identified the need to take into account the diverse nature of soft modes of governance, as well as the necessity to assess the democratic legitimacy of these governance arrangements against different theoretical concepts of democracy: On the one hand, new modes of governance might be considered as problematic from a liberal standpoint since they often bypass parliamentarian procedures and lack in transparency and accountability.

On the other hand, the participatory nature of many soft governance arrangements can be an important source of democratic renewal since they might constitute alternative sources of legitimacy for the EU from the standpoint of deliberative conceptions of democracy. Thus, the discussion of the democratic legitimacy of soft modes of governance depends both, on the particular policy instrument at hand and the conception of democracy that is employed.

Is the EU still unique? Finally, discussions within RG6 quite often stumbled upon the same question: to what extent are new modes of governance EU-specific? Nonetheless, in the social sciences, comparisons are often indispensable to draw conclusions of a general nature. The responses to this question were somewhat mixed.

Clearly, from a governance perspective, the EU is not unique since, in terms of policy- making, agenda-setting, decision-making, and evaluation, it looks like a political system like any other. However, the EU undoubtedly has some original features. Like all federal systems, it attempts to strike a balance between unity and diversity, even if the areas in which uniformity is sought are not always the same. All this may explain why in governance debates so much importance has been attached to the accountability of EU institutions.

Is it? VOS, Ellen Ed. As regards newer history, we may say that bilateral diplomacy constituted the first executive order at the European level: After the Thirty Years War, diplomacy became more regularised, with resident ambassadors among the smaller states. The Napoleonic Wars brought another institutional innovation at the European level; namely the coming about of multilateral diplomacy. Together with the growth of sectoral and functional international governmental organisations IGOs from the second part of the In particular, the increasing number of specialised IGOs with a permanent secretariat and a fixed location came to involve a huge number of non-diplomatic personnel from national sectoral ministries and agencies that made the European administrative space considerably more dense, multi-faceted and routinised.

States remained the primary building blocks of the order, and the principle of territorial organisation survived as the basic way of structuring IGOs, as reflected in the superior role of the Council of Ministers. The Second World War may have triggered an additional institutional innovation at the European level.

In organisational terms, the invention of the High Authority of the European Coal and Steel Community was indeed remarkable, since for the first time at this level a separate executive body with its own leadership and mandate had been erected outside the Council of Ministers. Arguably, this was the first step in a process that placed the development of the executive order in Europe on a radically different trajectory than before.

This route can be seen as leading to a third executive order, characterised by institutions that are able to partly reframe executive politics at the European level, so that a multi-dimensional pattern of conflict and cooperation is discernible.

The critical juncture represented by WWII might have been a necessary condition for decision-makers to accept what they under normal circumstances would not have accepted. So, inter alia, the availability of entrepreneurs, like Jean Monnet, and the narrowness of the mandate coal and steel have to be taken into consideration. It seems to have been easier to form parliamentary assemblies and courts of justice.

If we take a quick glance on how federal states were forged, the same pattern is discernable: In the United States of America, the Congress and the Court were both well established in Washington before a federal executive attained adequate capacity to act on a broader scale.

Such administrative capacity did not emerge automatically, but had to be extorted from already established institutional structures, in particular from the constituent states. A new and separate executive centre at the federal level emerged only gradually during the following years. Two quite general research questions can be raised in relation to institutions such as the Commission: 1 Under what circumstances will an institution that is thought to challenge the existing power structure be established?

RG1 has focused on the second question in this respect. It seems as if the Commission over time and in many respects has become more independent of those who erected it in the first place: the national governments. There are several organisational factors that might have been conducive to such a development. Most important has been perhaps the sectoral and functional division of labour at the very top of the institution, which means that politics at the Commission to a considerable degree tends to be politics among sectoral portfolios rather than among nation-states.

The fact that the Commission has a monitoring role in this respect does not in itself change this division of labour between levels of governance. Indirect implementation portrays the Union as a system in which the constituent states are integrated into a larger whole as coherent entities. Not surprisingly then, indirect implementation exposes common policies to considerable influence from national politics and administrative traditions and capabilities.

These two developments have triggered quite peculiar centrifugal forces within national governments; forces that could probably not have occurred if there was simply a combination of a classical IGO and internally integrated governments. Such bodies may be found among national agencies that are already somewhat detached from their respective ministerial departments. Arguably, profound integration at a higher system level presupposes some disintegration at the lower level, and vice versa.

Within the historical period covered in this paper, the emergence of a new executive order does not seem to have replaced the former order. Bilateral diplomacy among EU countries has not declined over the last couple of decades and it has been strengthened in relation to new member states.

And, in general, IGOs seem to flourish more than ever. Thus, executive orders are co-existing in Europe. This accumulated executive order consists of qualitatively new elements that transcend the inherited intergovernmental order. The persistence of diplomacy and IGOs represents at the same time recognition and reproduction of a system of states.

Notes 1 This paper is to a considerable degree based on D. Curtin and M. Thus, more elaborated arguments and literature references might be found there. However, the new literature tended to focus principally on the Commission as a political actor.

Pollack , Franchino , there was little change in its principal concerns. As a consequence, a series of important questions remained unanswered. First, how the Commission defines its preferences tended to be disregarded. How the availability and mobilization of the organizational resources at the disposal of the Commission offers possibilities for, but also imposed constraints upon Commission action, was a second question that was left unaddressed.

A third was the extent to which the Commission is organizationally independent. The degree to which it has a free hand in recruiting and promoting its staff, but beyond that its influence over the rules and procedures that govern its use of human and financial resources, as well as the shape of its internal structures, was unexplored.

A fourth concerned the identity of officials and their socialisation experiences within a multinational organization. The significance of national identity, the extent to which officials consider that their primary loyalty lies with the Commission, and the content and shaping of their beliefs are three important aspects.

A final unaddressed question concerned how the Commission manages its relations with other organizations in the performance of its functions in Brussels and beyond. In short, preoccupation with the Commission as a political actor led to a neglect of the Commission as an organization and administration. These themes have attracted considerably more interest in the recent past. Indeed, much of the research in which the participants of the CONNEX Research Group 1 RG1 have been engaged and which they have presented in workshops over the past four years has addressed exactly these themes.

They have considerably advanced our knowledge and understanding of the Commission and more broadly of the EU as a political system in significant ways. With respect to personnel and recruitment, Egeberg has examined the internalisation of recruitment and appointment processes concerning top officials, Wille a, b the end of national flags, and Balint et al the declining politicisation of higher management and degree of openness of career system.

In relation to nationality, Egeberg a has examined the role perception of Commissioners and the primary importance of their portfolio responsibilities in College decision making. Second, Dimitrakopoulos and Kassim , and Kassim and Dimitrakopoulos , used the Convention on the Future of Europe and the two intergovernmental conferences that followed as cases to investigate processes of preference formation within the Commission. Third, organizational change has been a concern of several researchers within the group, especially in the wake of the Kinnock reforms undertaken between and Finally, with respect to coordination, Kassim et al examines intra-organizational coordination.

It looks at how and to what extent the Commission manages interdepartmental relations effectively and the extent to which it achieves policy coherence. Similarly, Kassim considers the role of the Secretariat General. On inter-institutional relations, Christiansen and Vanhoonaker have investigated the Council Secretariat, Duke and Vanhoonaker administrative governance in the CFSP, and Egeberg and Trondal , Martens , and Thatcher and Coen the role of agencies and networks. Whilst the group through the aforementioned publications has made an important contribution to scholarship, several elements of a new research agenda and new possibilities for future research have come into view.

First, there are areas where knowledge of the Commission is still limited and which remain relatively unexplored. Second, there is a need for large-scale studies. Much of the existing work has been based on relatively small numbers. Third, new conceptualizations have been introduced that need to be tested and explored.

While the former needs to be further refined and linked to theoretical perspectives in the existing literature, the latter is an important achievement, but needs to be empirically validated by the charting of links and interconnections, to examine extent to which the administration is differentiated vertically and horizontally, and to explaining differences across policy domains. Finally, there are benefits to be gained from approaching the Commission in comparative perspective.

Egeberg b and Curtin and Egeberg have demonstrated the value of such an approach in regard to implementation and accountability. Bauer and Knill have done the same in relation to administrative reform, while Trondal has reflected on the study of the Commission from a public administration perspective. However, there is still surprising little research on the Commission as an international administration, the extent to which it embodies and exemplifies the ideal as set out in the international relations literature, and how it responds to challenges comparable to those faced by other international organizations.

Comparisons with national administrative bodies are also relatively scarce, leaving broad scope for the possibility of generating new insights from the comparative bureaucracies literature. There is limited empirical knowledge about individual Commission officials, how they work, and what, if anything, is distinctive about them. In all four areas, there are considerable research opportunities. Bauer, Michael W. A portrait of the Commission of the E. Delors: The Politics of Shared Leadership.

Dimitrakopoulos, Dionyssis G. Basingstoke: Macmillan Franchino, F. Kassim, Hussein and Dimitrakopoulos, Dionyssis G. Beach and T. Metcalfe, L. Studies associated with this latter perspective generally refer to what has been called Europeanization of domestic structures. Notwithstanding an ever- growing number of studies in this area, the analysis of Europeanization effects still suffers from far-reaching weaknesses. Although most these problems are well-known, they have not been sufficiently addressed so far.

In view of this constellation, it is the central purpose of this short paper to develop modest suggestions for overcoming the most important research deficits in this field of inquiry and hence to advance our understanding of Europeanization. The first weakness inherent to the concept of Europeanization is that the term is "over-stretched". There exist almost as many definitions of the concept as there are authors publishing in this research field, which implies that Europeanization refers to highly different phenomena.

This definition is certainly not very useful, as it simply reinvents the wheel, creating terminological confusion Lenschow , Others refer to the role of the EU in facilitating horizontal policy transfer across member states Bomberg and Peterson ; Radaelli A third definition is linked to a top-down perspective, focusing on the domestic impact of developments at the European level.

In addition to the confusion about the analytical scope of the concept, further complexities emerge from different definitions with regard to its geographical scope Eising , Should Europeanization be restricted to the domestic impact of the EU on member states or future member states only or should the term also cover all other countries that are potentially affected by the activities of the EU?

The second problem of Europeanization research emerges from the fact that not only the phenomenon as such is conceptualized rather vaguely, but also the independent and dependent variables that are typically identified in Europeanization studies. On the one hand, the most prominent and also most heatedly debated independent variable — the fit or misfit of European and domestic arrangements — is operationalized in very different and rather inconsistent ways.

Looking at the concrete indicators for operationalization, we again find almost as many different approaches as scholars in the field. Against this backdrop, it is hardly surprising that there is not much common theoretical ground so far. On the other hand, similar problems apply to the specification of the dependent variables. There are big differences across various studies how domestic policy or institutional change is measured.

Basically, this variety as such constitutes a strength rather than a weakness. This holds only true, however, as long as differences in the operationalization of independent and dependent variables are explicitly acknowledged — which is unfortunately rarely the case. A final problem refers to the fact that Europeanization studies typically suffer from a selection bias.

Mostly, the focus is exclusively on EU member or applicant states. As long as countries outside the EU are excluded from the country sample under investigation, it is hardly possible to control for potential effects that cannot be attributed to EU membership or conditionality. Of course some of the above-mentioned problems can also be found in other areas of political science and hence are not unique features of Europeanization studies.

Moreover, these problems are hardly new and have long been named by various scholars in the field. Nevertheless, not so much progress has been made so far to overcome them. In the following, I will hence develop some ideas that might constitute promising ways for future research on Europeanization. In this context, my basic suggestion might sound not only provocative, but also paradoxical: To improve our understanding of Europeanization, we should give up the concept.

In view of the vague and contradictory definitions of Europeanization, the concept has lost its analytical grip. Instead, it is a more promising approach to be more specific about the channels through which Europeanization operates. In which ways or mechanisms does European integration trigger domestic changes?

It makes a big difference, whether Europeanization effects emerge from legal harmonization, from political imposition or conditionality, from regulatory competition in the Common market, or from learning processes triggered by intensified communication and information exchange in supranational policy networks. First, theoretical explanations of Europeanization processes can be more precise and focused. It makes a big difference whether we look for theories that seek to explain Europeanization processes of every kind or whether we are looking for explanations that account for different domestic effects of legal harmonization, regulatory competition or transnational communication.

It is obvious that each of these Europeanization channels and the list of channels is certainly not complete or exclusive might operate differently, implying that there are different factors that account for potential variance in domestic impacts. Looking at legal harmonization, for instance, effects might vary with the degree of legal specification of European law.

Competition effects, by contrast, might vary with the extent to which domestic markets are actually exposed to international or European competition. For communication effects again different variables might play a role, such as the interaction density in European policy networks or the mere number of states that have already adopted a certain policy. Space does not allow me to go into detail with regard to these factors.

But the examples should be sufficient to underline the central point of my argument: The explanation of Europeanization effects varies with the concrete channel through which European integration might trigger domestic change. Rather than analyzing Europeanization as such it is hence theoretically more promising to focus on the specific mechanisms of Europeanization or modes of European governance.

This more precise analytical focus implies a second advantage. It is easier to avoid the selective focus on EU member states and to link Europeanization studies to the broader scientific debate, in particular to the analysis of domestic effects of internationalization and globalization or studies on the international diffusion and convergence of policies.

Also in this debate, emphasis is placed on effects of international harmonization or regulatory cooperation, regulatory competition, and transnational communication. From this perspective, it would hence be possible to analyze whether and to what extent the EU makes a difference compared to, for instance, effects of other international organizations or regimes and the growing integration of international markets. This way, not only the selection bias inherent to many Europeanization studies could be overcome.

It would also be possible to strengthen the development of general theories to explain the varying effects of the external environment be it European or global on national policies and institutions. Finally, a more differentiated analytical focus on distinctive causes or channels of Europeanization would also help to reduce the high degree of ambiguity that currently exists with regard to specification and operationalization of dependent and independent variables.

Although the mentioned perspectives for future research on Europeanization research will certainly not avoid all problems and research deficits encountered, they nevertheless might help to move some modest steps ahead in order to improve our understanding of this phenomenon. References Bomberg, E. Eising, R. Jachtenfuchs and B.

Knill, C. Ladrech, R. Lenschow, A. Richardson eds. Radaelli, C. Risse, T. Cowles, J. Caporaso and T. One of the most remarkable elements of that international regime has been its stability. Fifty years on, despite a significant enlargement of the number of member countries and several treaty revisions, it may be argued that the key features of the system have largely remained unchanged.

The European Parliament has gradually acquired significant prerogatives, but there has been an attempt to prevent this evolution from altering the initial balance of power.

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Pediatric Rheumatology volume 17Article number: 18 Cite this article.

Dirk syndram kontakt torrent Introduction: Chimeric antigen receptor T-cell CAR-T therapy is a highly effective form of adoptive cell immunotherapy combining antigen specific targeting capabilities with T-cell based cytotoxicity. Contrary to the rule applied to other European policies, which are implemented by national bodies, it was in fact the Commission that was check this out with applying the general principles defined by the Treaty of Rome in matters of competition. One of the most remarkable elements of this international regime has been its stability: 50 years on, despite a significant enlargement of the number of member countries and several treaty revisions, it may be argued that the key features of the system have remained unchanged. She describes similar symptoms throughout most of her life. Another central focus of Research Group 1 was on the domestic impact of EU level institutions on respective structures, political processes and policies in the member states. Importantly, all these effects were reversed to normal levels by restoring protein prenylation using geranylgeraniol the missing lipid metabolite dirk syndram kontakt torrent for protein prenylation. It is assessed that chronic inflammation, perpetuated by pro-inflammatory cytokines, may exert a role on bone metabolism leading, in the long run, at the onset of osteoporosis OP.
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