Norbert Blank

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (62)214 Total impact

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    ABSTRACT: Abstract Objective: To identify risk factors for serum amyloid-A (AA) amyloidosis in patients living in Germany. Methods: Clinical and genetic data were obtained from 71 patients with AA amyloidosis. SAA1 genotypes were analyzed in 231 individuals. Control groups comprised 45 patients with long-standing inflammatory diseases without AA amyloidosis and 56 age-matched patients without any inflammatory disease. Results: The most frequent underlying diseases of AA amyloidosis were familial Mediterranean fever (FMF) (n = 24, 34%) and inflammatory rheumatic diseases (n = 30, 42%). Patients without any known underlying disease (n = 11, 16%) were considered as having idiopathic AA amyloidosis. Patients with FMF were significantly younger at disease onset and younger at diagnosis of AA amyloidosis compared with patients with rheumatic diseases. Patients with idiopathic AA amyloidosis were older than patients with definite rheumatic diseases. Patients with FMF and high penetrance MEFV gene mutations had a relative risk of 1.73 for AA amyloidosis. Patients with FMF or a rheumatic disease and the SAA1 α/α genotype had a relative risk of 4.86 and 2.53, respectively, for developing an AA amyloidosis. The prevalence of this risk genotype was 36% in German patients without an inflammatory disease, 92% in German patients with AA amyloidosis and 100% in German patients with idiopathic AA amyloidosis. Conclusions: Risk factors for AA amyloidosis are the presence of a hereditary autoinflammatory or chronic rheumatic disease, elevated C-reactive protein and SAA serum levels, a long delay of a sufficient therapy, an advanced age and the SAA1α/α genotype.
    Amyloid. 11/2014;
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    ABSTRACT: Objective: B-cells with immunoregulatory properties have been described in mice (Breg) but their role in control of human immune responses is ill defined. We recently identified a population of human activated FSC(hi) B-cells which exhibited regulatory activity towards T-helper (Th)-cells. Our aim was to test such induced Breg (iBreg) in autoimmune disease. Methods: purified CD19+FSC(hi) B-cells of patients with Systemic Lupus Erythematosus (SLE) or healthy donors (ND), activated via their B-cell receptor, were cocultured with CD3-stimulated SLE- or ND-CD4+Th-cells. 3H-Thymidine incorporation, flow cytometry and ELISA were used for proliferation, cytokine secretion and surface marker expression. Results: Although under costimulatory conditions FSC(hi) SLE-B-cells supported ND-T-cell proliferation like ND-B-cells, their regulatory function was significantly diminished in B-cell suppressor-assays. Similar effects were measured when SLE-T-cells were used, confirming that SLE-T-cells were equally susceptible to iBreg signals like ND-T-cells and that SLE-iBreg defects were independent of T-cell origin. B-cell viability and expression of surface markers (CD25, CD80, B7-H1) or cytokines (IL-6, TNFα, IL-10) were comparable between both B-cell populations. There was no correlation between extent of iBreg-induced inhibition and disease activity. CD19+FSC(hi) B-cells from another systemic autoimmune disease, Granulomatosis with Polyangiitis (GPA), exhibited no regulatory defects, suggesting that iBreg defects were SLE-specific and not a general consequence of autoimmunity or inflammation. Conclusion: iBreg from SLE patients but not GPA patients are less effective in control of Th-cell proliferation, supporting the findings of a skewed B-cell repertoire in SLE. The malfunctioning SLE-iBreg might allow an overstimulation of immune responses and contribute to initiation and/or perpetuation of disease. © 2014 American College of Rheumatology.
    Arthritis & rheumatology (Hoboken, N.J.). 06/2014;
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):564-564. · 9.11 Impact Factor
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    ABSTRACT: Whereas the association between sarcoidosis and malignant diseases has been well described, it remains controversial whether this association is merely a coincidence or the consequence of a common pathophysiologic mechanism. We investigated the incidence of malignancies in a large cohort of patients with sarcoidosis from a German University Hospital. Patients with a malignant disease were identified in a retrospective analysis of a cohort of 425 patients with sarcoidosis at the Medical Center of the University of Heidelberg. The type of malignancies and the onset before, concomitant or after sarcoidosis were analyzed. Sixty-one patients with a malignant disease were identified in our cohort of 425 patients with sarcoidosis. Among them, there were 18 patients with malignant lymphoma, 13 with breast cancer and 5 with cervical cancer. Malignant lymphoma was diagnosed up to 30 years after sarcoidosis with a median of 6.9 years. Breast or cervical cancers were diagnosed up to 20 years before or after sarcoidosis, and the median was 0.0 years. A high prevalence of B-cell lymphoma, breast and cervical cancers was found in our sarcoidosis cohort. In most patients, B-cell lymphoma was diagnosed many years after chronic sarcoidosis. In contrast, the diagnosis of breast or cervical cancer was evenly distributed before, around and after the diagnosis of sarcoidosis. Our hypothesis is that the immune dysregulation which persists during or after chronic sarcoidosis might represent a contributing factor for the development of B-cell lymphoma.
    Rheumatology International 03/2014; · 2.21 Impact Factor
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    ABSTRACT: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies.These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    01/2014;
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    ABSTRACT: Objective. Patients with RA suffer from a higher risk of periodontal attachment loss and increased oral inflammation. We hypothesize that there are pathogenetic and immunological interactions between these diseases that go beyond impaired manual dexterity accompanying advanced RA. The primary objective of the present study was to determine whether a loss of alveolar bone can be detected in RA patients during the early course of the disease.Methods. In this cross-sectional, epidemiological case-control study, 22 patients with early RA (ERA) were compared with 22 matched healthy controls. Oral and periodontal status, clinical activity, and socio-demographic parameters were determined. Oral microbiota were analysed using real-time quantitative PCR specific for leading oral pathogens.Results. More advanced forms of periodontitis were found in ERA patients compared with controls. ERA patients had a greater number of missing teeth [ERA 5.7 (s.d. 5.0), controls 1.9 (s.d. 1.0), P = 0.002], deeper periodontal pockets [clinical attachment level: ERA 3.4 (s.d. 0.5 mm), controls 2.7 (s.d. 0.3 mm), P < 0.000], and greater bleeding on probing [ERA 18.6% (s.d. 9.0%), controls 10.5% (s.d. 5.1%), P = 0.001] despite comparable oral hygiene. Tannerella forsythia (6.77-fold, P = 0.033) subgingivally and Streptococcus anginosus (3.56-fold, P = 0.028) supragingivally were the characteristic pathogens in ERA.Conclusion. Increased loss of periodontal attachment and alveolar bone can be detected in patients with ERA, therefore we propose that the consulting rheumatologists inform the patients that they have a higher risk of periodontal disease. It would be beneficial if these patients were referred directly for intensive dental care.
    Rheumatology (Oxford, England) 11/2013; · 4.24 Impact Factor
  • N Blank, H M Lorenz
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    ABSTRACT: History and admission findings: A 66-year-old patient presented in our clinic with increasing painful swelling of his hands, whole body stiffness, weight loss and dyspnoea upon exercise.Examinations: The physical examination revealed a marked skin sclerosis of hands, extremities and the face. Fist closure was impossible. Pulmonary CT scan showed lung fibrosis and ground glass opacities. Antinuclear antibodies and antibodies against Scl70 were positive. CRP, LDH, NT-Pro-BNP were elevated.Diagnosis, treatment and course: A diffuse cutaneous systemic sclerosis with an active interstitial pneumonia and lung fibrosis was diagnosed. Three pulses of cyclophosphamide 1.4 g every three weeks were ineffective to halt the progression of skin sclerosis, joint contractures and decline of pulmonary function. Mobilisation chemotherapy was initialized and blood stem cells were harvested. Blood stem cells were reinfused after myeloablative chemotherapy with melphalan. A maintainance therapy with mycophenolic acid was initiated after recovery of hematopoiesis. Six months after blood stem cell transplantation a decrease of skin sclerosis and an increasing recovery of joint mobility and physical strength was observed.Conclusion: Patients with a progressive systemic sclerosis and further risk factors should be treated with high-dose chemotherapy with blood stem cell transplantation before organ function is severely compromised. In cases with contraindications against cyclophosphamide or anti-thymocyte-globulin melphalan can be discussed as an alternative.
    DMW - Deutsche Medizinische Wochenschrift 09/2013; 138(37):1824-7. · 0.65 Impact Factor
  • N Blank, S O Schönland
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    ABSTRACT: Systemic AA amyloidosis is a severe complication of chronic inflammatory diseases. Renal involvement is the predominant organ manifestation. Patients who are at risk for developing AA amyloidosis should be screened for microalbuminuria. The goal of therapy is an effective control of the acute phase reaction. A well controlled blood pressure and nephroprotective treatment contribute to the maintenance of renal function. In case of progressive amyloidosis dialysis is required. Renal transplantation can be performed if the underlying disease is well controlled.
    DMW - Deutsche Medizinische Wochenschrift 09/2013; 138(37):1835-8. · 0.65 Impact Factor
  • Pediatric Rheumatology 01/2013; 11(Suppl 2):P214. · 1.47 Impact Factor
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    ABSTRACT: Objective: To characterize patients with familial Mediterranean fever (FMF) with and without AA amyloidosis living in Germany. Method: Clinical and genetic data from 64 FMF patients were analysed for amyloidosis risk factors. Results: Fifty-five patients (85%) were of Turkish or Armenian origin. Thirty-one patients (48%) developed FMF symptoms before the age of 16 years. Sixteen patients (26%) became symptomatic after age 20. Symptoms reported were peritonitis (95%), fever (78%), pleuritis (59%), arthralgia (60%), arthritis (32%), erysipelas-like erythema (23%), and vasculitis (8%). FMF diagnosis was delayed for a median of 8.0 years. Genetic analysis confirmed M694V as the most prevalent Mediterranean fever (MEFV) gene mutation in 46 out of 59 patients (78%). M694V homozygosity was associated with an earlier FMF onset (median age 5.5 years, p = 0.0001) and a higher prevalence of peritonitis (p = 0.007) and pleuritis (p = 0.0007) compared to patients without an M694V mutation. AA amyloidosis was detected in 16 patients (25%) at a median age of 36.5 years and tended to be associated with a higher age at disease onset (p = 0.062) and a higher FMF activity score (p = 0.093). AA amyloidosis was significantly associated with a higher age at FMF diagnosis (p = 0.0022). Conclusions: Clinical symptoms of FMF-affected migrants living in Germany resemble those observed in their home country. In particular, patients with an onset of FMF symptoms after age 20 and a later FMF diagnosis have a high risk of AA amyloidosis. Symptomatic patients who originate from countries with a higher FMF prevalence should be screened for FMF and proteinuria.
    Scandinavian journal of rheumatology 11/2012; · 2.51 Impact Factor
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    ABSTRACT: The clearance of apoptotic cells occurs in a non-inflammatory context. Defects in this clearance process have been linked to the emergence of human autoimmune diseases like systemic lupus erythematosus (SLE). A characteristic of apoptotic cell death is the shedding of membrane coated vesicles from the cellular surfaces. Those vesicles have recently been recognized as mediators of intercellular communication or as adjuvant in the pathogenesis of autoimmune diseases. We analyzed the interactions between these apoptotic cell-derived membrane vesicles and professional antigen presenting cells. These vesicles were engulfed by monocyte-derived dendritic cells (mDC) and stimulated their maturation towards a phenotype comprising an upregulation of CD80, CD83, CD86, and a remarkable downregulation of MHC class II molecules. We observed only a minor release of proinflammatory cytokines from these mDC when compared to LPS stimulation. mDC stimulated by apoptotic vesicles did not cause significant T-cell expansion. Interestingly, when compared to normal healthy donors SLE patients-derived dendritic cells showed a significantly different phenotype lacking the downregulation of MHC class II, which correlated to disease activity.
    Journal of Autoimmunity 09/2012; · 8.15 Impact Factor
  • Dr. R. Max, N. Blank, H.M. Lorenz
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    ABSTRACT: Entzündlich-rheumatische Erkrankungen können in jedem Lebensalter auftreten. Erstmanifestationen im jungen Erwachsenenalter finden sich v. a. bei den Spondyloarthritiden und beim systemischen Lupus erythematodes (SLE), der zur Gruppe der Kollagenosen gehört. Entzündlicher Rückenschmerz, HLA-B27, Veränderungen der Iliosakralfugen in der Bildgebung sowie extraartikuläre Manifestationen sollten vom primär aufgesuchten Hausarzt oder Internisten bedacht werden, damit Patienten mit einer vermuteten Spondyloarthritis frühzeitig einer fachärztlichen Betreuung zugeführt werden können. Gleiches gilt für die Haut- und Organmanifestationen, allen voran die Lupusnephritis, sowie das Autoantikörperscreening, insbesondere auf antinukleäre und Anti-dsDNA-Antikörper bei Verdacht auf einen SLE. Die Patienten stehen häufig am Beginn ihres Berufs- und Familienlebens. Nur bei rascher Diagnosestellung kann zeitnah eine adäquate Therapie eingeleitet werden, die längerfristige Einschränkungen verhindert bzw. minimiert.
    Der Internist 09/2012; 53(9). · 0.33 Impact Factor
  • R Max, N Blank, H M Lorenz
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    ABSTRACT: Inflammatory rheumatic diseases can occur at any age. In young adulthood spondyloarthritis and systemic lupus erythematosus in particular present the first symptoms. General practitioners and internists are the first to be contacted by patients. They should be familiar with inflammatory back pain, HLA B27, inflammatory signs in the sacroiliac joints on imaging and extra-articular manifestations in order to transfer patients suspected of having spondyloarthritis to a rheumatologist. The same applies to skin and organ involvement, especially lupus nephritis, in patients with suspected systemic lupus erythematosus, as well as antibody screening in particular for antinuclear antibodies and anti-double stranded DNA (dsDNA) antibodies. Patients are often at the beginning of their professional and family career, therefore, early diagnosis is necessary to initiate an adequate therapy and prevent or minimize long-term damage.
    Der Internist 08/2012; 53(9):1038-46. · 0.33 Impact Factor
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    ABSTRACT: The objective of this prospective study was to assess short- and long-term efficacy of exercise training (ET) as add-on to medical therapy in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-APAH). Patients with invasively confirmed CTD-APAH received ET in-hospital for 3 weeks and continued at home for 12 weeks. Efficacy parameters have been evaluated at baseline and after 15 weeks by blinded-observers. Survival rate has been evaluated in a follow-up period of 2.9 ± 1.9 years. Twenty-one consecutive patients were included and assessed at baseline, and after 3 weeks, 14 after 15 weeks. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 67 ± 52 meters after 3 weeks (p < 0.001) and by 71 ± 35 meters after 15 weeks (p = 0.003), scores of quality of life (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET. The 1- and 2-year overall-survival rates were 100%, the 3-year survival 73%. In one patient lung transplantation was performed 6 months after ET. ET as add-on to medical therapy is highly effective in patients with CTD-APAH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further randomized controlled studies are needed to confirm these results. ClinicalTrials.gov: NCT00491309.
    Arthritis research & therapy 06/2012; 14(3):R148. · 4.27 Impact Factor
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    Arthritis care & research. 03/2012; 64(3):459-64.
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    ABSTRACT: Amyloidosen sind seltene Proteinfaltungskrankheiten, bei denen sich Proteine infolge einer Konformationsänderung als unlösliche fibrilläre Aggregate ablagern. Dies kann systemisch oder lokalisiert erfolgen. Systemische Amyloidosen sind lebensbedrohliche Komplikationen monoklonaler Gammopathien oder chronischer Entzündungen oder treten im Rahmen einer familiären Erkrankung auf. Die kausale Behandlung der Amyloidosen besteht in der Reduktion der amyloidbildenden Proteine durch Chemotherapie, antientzündliche Behandlung oder Lebertransplantation. Die Frühdiagnose der Erkrankung ist essenziell, um die Patienten effektiv behandeln zu können und eine weitere Funktionsverschlechterung der Organe zu verhindern. Amyloidoses are rare protein folding disorders, in which proteins are deposited as insoluble fibrillar aggregates due to a conformational change. This can occur in a local or systemic form. Systemic amyloidoses are life-threatening complications of monoclonal gammopathy, chronic inflammatory diseases or within hereditary diseases. The causative treatment of amyloidosis is the reduction of the amyloid precursor protein by chemotherapy, anti-inflammatory treatment, or liver transplantation. Early diagnosis of the disease is essential in order to effectively treat patients and avoid further deterioration of organ functions. SchlüsselwörterAmyloidose–Proteinfaltungskrankheiten–Klassifikation–Monoklonale Gammopathien–Transplantation KeywordsAmyloidosis–Protein folding disorders–Classification–Monoclonal gammopathies–Transplantation
    Der Internist 01/2012; 53(1):51-64. · 0.33 Impact Factor
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    ABSTRACT: Amyloidoses are rare protein folding disorders, in which proteins are deposited as insoluble fibrillar aggregates due to a conformational change. This can occur in a local or systemic form. Systemic amyloidoses are life-threatening complications of monoclonal gammopathy, chronic inflammatory diseases or within hereditary diseases. The causative treatment of amyloidosis is the reduction of the amyloid precursor protein by chemotherapy, anti-inflammatory treatment, or liver transplantation. Early diagnosis of the disease is essential in order to effectively treat patients and avoid further deterioration of organ functions.
    Der Internist 01/2012; 53(1):51-64. · 0.33 Impact Factor
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    ABSTRACT: In the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry. Sera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion. Antinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged. This study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients.
    Arthritis research & therapy 10/2011; 13(5):R172. · 4.27 Impact Factor
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    ABSTRACT: Five years ago a 52-year-old patient presented with arthritis of the small and large joints. Further symptoms were relapsing fever, unspecific gastrointestinal complaints with meteorism but no diarrhea, fatigue and impaired concentration. Subsequently increasing lower back pain developed. A lumbar-disc lesion was already known. Inflammatory markers were elevated including leucocytosis. Gastroscopy with intestinal biopsies and colonoscopy remained without pathologic findings. Whipple's disease was excluded, but unspecific lymphozyte infiltration of the duodenal mucosa was described. Magnetic resconance imaging of the lumbar spine showed spondylodiscitis in L3/4 which was punctured, and polymerase chain reaction revealed Tropheryma whipplei DNA. Retrospectively, this was also found in the intestinal biopsies of three years ago. After initial exclusion of Whipple's disease an unspecific systemic inflammatory disease had been presumed, and the patient had been treated with immunomodulatory therapies in alternating combinations. Steroids improved the symptoms but an increasing dosage of steroids was required. After the detection of Tropheryma whipplei and diagnosis of Whipple's disease the patient received ceftriaxon for a period of two weeks, subsequently cotrimoxazol for one year. Inflammatory activity decreased but unspecific symptoms remained almost unaffected. The differential diagnosis in patients with fever, elevated inflammatory markers and gastrointestinal symptoms must include Whipple's disease. A Tropheryma whipplei PCR from duodenal biopsies should be performed because of its higher sensitivity compared to histology alone.
    DMW - Deutsche Medizinische Wochenschrift 08/2011; 136(33):1656-9. · 0.65 Impact Factor

Publication Stats

787 Citations
214.00 Total Impact Points

Institutions

  • 2005–2012
    • Universität Heidelberg
      • • Medical University Clinic and Polyclinic
      • • University Hospital of Internal Medicine
      • • Department of Rheumatology
      Heidelburg, Baden-Württemberg, Germany
  • 2008
    • Harvard Medical School
      • Department of Medicine
      Cambridge, MA, United States
  • 2006
    • Yale University
      New Haven, Connecticut, United States
  • 2001–2003
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Rheumatology and Immunology Clinic
      • • Department of Clinical and Molecular Virology
      Erlangen, Bavaria, Germany