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Heinig K.,Max Delbrück Center for Molecular Medicine | Gatjen M.,Max Delbrück Center for Molecular Medicine | Cseresnyes Z.,Max Delbrück Center for Molecular Medicine | Anagnostopoulos I.,Charité - Medical University of Berlin | And 16 more authors.
Cancer Discovery | Year: 2014

In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell–like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin–β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin–β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma–leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor–stroma cross-talk. © 2014 American Association for Cancer Research.


Poddubnyy D.,Charité - Medical University of Berlin | Conrad K.,Charité - Medical University of Berlin | Haibel H.,Charité - Medical University of Berlin | Syrbe U.,Charité - Medical University of Berlin | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To investigate the role of serum vascular endothelial growth factor (VEGF) as a predictor of radiographic spinal progression in patients with axial spondyloarthritis (axSpA). Methods: Altogether, 172 patients with definite axSpA (95 with ankylosing spondylitis and 77 with non-radiographic axSpA) were included in this study. Spinal radiographs obtained at baseline and after 2 years of follow-up were scored independently by two trained readers in a concealed and randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) scoring system and for the presence of syndesmophytes. Radiographic spinal progression after 2 years was defined as (1) mSASSS worsening by ≥2 units, and (2) new syndesmophyte formation or formation of a bridging syndesmophyte from two single syndesmophytes. Serum VEGF levels were detected at baseline. Results: Mean baseline VEGF values were significantly higher in patients with mSASSS worsening by ≥2 units after 2 years (n=22) than in those without progression (562±357 vs 402±309 pg/mL, respectively, p=0.027) and in patients with syndesmophyte formation (n=18) again as compared with those without new bone formation (579±386 vs 404±307 pg/mL, respectively, p=0.041). VEGF as a predictor of radiographic spinal progression performed especially well in patients who were already at high risk for such a progression due to the presence of syndesmophytes at baseline (n=48). In these patients, a VEGF serum level of >600 pg/mL had a sensitivity of 53%, a specificity of 97% and an OR=36.6 (95% CI 3.9 to 341.5) as a predictor of mSASSS worsening by ≥2 units. For syndesmophyte formation, elevated VEGF demonstrated a sensitivity of 47%, a specificity of 94% and an OR=13.6 (95% CI 2.4 to 78.3). Conclusions: An elevated serum level of VEGF (>600 pg/mL) is highly specific as a predictor of radiographic spinal progression in patients with axSpA, especially in patients who are at high risk for further progression due to the presence of syndesmophytes. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.


Poddubnyy D.A.,Charité - Medical University of Berlin | Marker-Hermann E.,Dr Horst Schmidt Hospital | Kaluza-Schilling W.,University Hospital | Zeidler H.,Hannover Medical School | And 4 more authors.
Journal of Rheumatology | Year: 2011

Objective. In a pilot study, a distinct T cell cytokine pattern associated with HLA-B27 status and a tumor necrosis factor-α (TNF-α) promoter gene polymorphism was found at -308 (TNF-308). The objective of our study was to assess these associations in a different cohort of patients with ankylosing spondylitis (AS) and to evaluate any effect on clinical measurements. Methods. Peripheral T cell cytokine production of patients with AS (n = 121) from the German Spondyloarthritis Inception Cohort was assessed by flow cytometry and correlated with HLA-B27, TNF-238, and TNF-308, and with clinical measurements. Results. In HLA-B27-positive, anti-TNF-naive patients with AS, the percentages of TNF-α-producing (5.02%) and interleukin 10-producing (0.31%) CD8+ cells were significantly lower in comparison to HLA-B27-negative patients (9.52%, p = 0.048, and 0.46%, p = 0.037, respectively). A non-significant trend was found for a lower production of TNF-α by CD4+ and interferon-γ by both CD4+ and CD8+ T cells, as compared to HLA-B27-negative patients with AS (p > 0.05 for all comparisons). The A allele at TNF-308 was associated with a lower percentage of TNF-α-producing CD4+ T cells. No significant correlations were found between clinical or radiological measurements and cytokine production or with TNF-α promoter gene polymorphisms. Conclusion. Modulation of T cell cytokines by HLA-B27 might play a role in AS pathogenesis in B27-positive individuals. No conclusive data were obtained for the TNF-308 polymorphism on cytokine production, and no effect of cytokines or genetic polymorphisms on clinical manifestations was observed. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Conrad K.,Charité - Medical University of Berlin | Wu P.,Deutsches Rheumaforschungszentrum | Sieper J.,Charité - Medical University of Berlin | Syrbe U.,Charité - Medical University of Berlin
Arthritis Research and Therapy | Year: 2015

Introduction: Innate immune responses, including monocyte functions, seem to play an important role in the pathogenesis of axial spondyloarthritis (axSpA). Therefore, we characterized the phenotype and functional state of monocytes of patients with axSpA. Methods: Fifty-seven patients with axSpA, 11 patients with rheumatoid arthritis (RA), and 29 healthy controls were included in the study. We determined the percentage of classic, intermediate, and non-classic monocytes according to CD14 and CD16 expression and the expression of Toll-like receptor (TLR) 1, 2, and 4 in whole blood by flow cytometry. The percentage of monocytes producing interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNFaα), IL-12/23p40, and IL-1 receptor antagonist (IL-1ra) was detected by flow cytometry after stimulation of whole blood without and with different TLR and nucleotide-binding oligomerization domain ligands-i.e., lipopolysaccharide (LPS), fibroblast-stimulating lipopeptid-1, PAM3CSK4, and muramyl dipeptide (MDP)-for 5 h. IL-10 production was measured after 18 h of stimulation in supernatants by enzyme-linked immunosorbent assay. Results: In patients with axSpA but not patients with RA, we found higher frequencies of classic monocytes than in controls (median of 90.4 % versus 80.4 %, P < 0.05), higher frequencies of monocytes spontaneously producing IL-1beta and IL-1ra (P < 0.05), and a higher percentage of monocytes producing IL-1beta after MDP stimulation (P < 0.05). Elevated cytokine production was confined to axSpA patients under conventional therapy (non-steroidal anti-inflammatory drugs) and not found in patients under TNFaα inhibitor treatment. The LPS-induced production of IL-6 and IL-10 was lower in axSpA patients compared with controls (P < 0.05). Monocytic TLR expression was unaffected in patients with axSpA. Conclusion: Enhanced spontaneous and MDP-induced cytokine secretion by monocytes suggests in vivo pre-activation of monocytes in axSpA patients under conventional therapy which is reverted under TNF inhibitor treatment. © 2015 Conrad et al.


Appel H.,Charité - Medical University of Berlin | Wu P.,Charité - Medical University of Berlin | Scheer R.,Charité - Medical University of Berlin | Kedor C.,Charité - Medical University of Berlin | And 5 more authors.
Journal of Rheumatology | Year: 2011

Objective. Regulatory T cells are characterized by expression of the transcription factor FoxP3 and are thought to be involved in the pathogenesis of autoimmune diseases. We determined the frequency and phenotypic characteristics of CD4+FoxP3+ T cells in the blood and synovial fluid (SF) of patients with inflammatory joint diseases. Methods. SF from 10 patients with ankylosing spondylitis (AS), 20 patients with other spondyloarthritides or with peripheral arthritis (pSpA), and 12 patients with rheumatoid arthritis (RA), and peripheral blood (PB) from 22 patients with AS, 19 with pSpA, 15 with RA, and 12 healthy controls were stained for CD4, FoxP3, CD25, and CD127 and different effector cytokines and then analyzed by flow cytometry. Methylation pattern of the Treg-specific demethylated region (TSDR) was determined after bisulfite treatment by quantitative polymerase chain reaction. Results. In all groups of patients we observed higher frequencies of Foxp3+ cells/CD4+ T cells within SF compared to PB. The frequency of synovial Foxp3+ cells/CD4+ T cells was significantly higher in patients with pSpA (18.79% ± 6.41%) compared to patients with AS (9.69% ± 4.11%) and patients with RA (5.95% ± 2.21%). CD4+FoxP3+ T cells were CD25+ and CD127- and lacked effector cytokine production in any of the different patient groups. The majority of the CD4+CD25+CD127- T cells showed demethylation of the TSDR within the Foxp3 locus, confirming its regulatory phenotype. Conclusion. Our data show accumulation of Foxp3+ T cells within inflamed joints. These Foxp3+ T cells are mainly of stable T regulatory phenotype. The high frequency of Foxp3+ T cells in pSpA might contribute to the spontaneous resolution and remitting course of arthritis in pSpA as compared to the more persistent joint inflammation in RA. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Syrbe U.,Charité - Medical University of Berlin | Callhoff J.,Deutsches Rheumaforschungszentrum | Conrad K.,Charité - Medical University of Berlin | Poddubnyy D.,Charité - Medical University of Berlin | And 6 more authors.
Arthritis and Rheumatology | Year: 2015

Objective Adipokines have metabolic and inflammatory functions but can also affect bone metabolism. The purpose of this study was to determine the relationship between serum levels of adiponectin, resistin, and visfatin and markers of inflammation, disease activity, and radiographic spinal progression in patients with ankylosing spondylitis (AS). Methods Levels of adiponectin, resistin, and visfatin in the serum of 86 AS patients and 25 healthy controls were measured by enzyme-linked immunosorbent assay at baseline. Radiographic spinal progression was determined by the scoring of radiographs of the spine obtained at baseline and after 2 years. Results Mean (±SD) baseline levels of resistin and visfatin were significantly higher in AS patients than in healthy controls (11.6 ± 10.6 ng/ml versus 6.6 ± 3.2 ng/ml [P = 0.01] for resistin, and 20.9 ± 48.3 ng/ml versus 3.4 ± 2.6 ng/ml [P = 0.001] for visfatin). Adipokine serum levels did not correlate with disease activity or functional indices. Only resistin serum levels correlated with markers of inflammation. Baseline levels of visfatin, but not resistin or adiponectin, were significantly higher in patients with worsening of the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) by ≥2 units after 2 years (n = 19) as compared to patients without mSASSS worsening (37.7 ± 57.8 ng/ml versus 16.1 ± 44.6 ng/ml; P = 0.029) and in patients with syndesmophyte formation/progression (n = 22) as compared to patients without such progression (37.1 ± 55.3 ng/ml versus 15.3 ± 44.8 ng/ml; P = 0.023). Visfatin levels of >8 ng/ml at baseline were predictive of subsequent radiographic spinal progression (adjusted odds ratio 3.6 for mSASSS progression and 5.4 for syndesmophyte formation/progression). Conclusion Serum levels of resistin and visfatin are elevated in AS patients. Elevated visfatin levels at baseline are predictive of subsequent progression of radiographic damage in AS patients. Copyright © 2015 by the American College of Rheumatology.


Riedel O.,TU Dresden | Klotsche J.,Deutsches Rheumaforschungszentrum | Forstl H.,TU Munich | Wittchen H.-U.,TU Dresden
Journal of Geriatric Psychiatry and Neurology | Year: 2013

Despite the wide use of clock drawing tests (CDTs) for screening cognitive impairment, their use in patients having Parkinson disease (PD) with dementia has not been systematically investigated until date. In this cross-sectional study, neurological and neuropsychiatric statuses of 1449 outpatients having PD with and without dementia were comprehensively assessed. The CDT revealed cognitive impairment in 42.7% of the 1383 patients whose drawings were available. Overall, CDT sensitivity and specificity were 70.7% and 68.9%, respectively. The positive and negative predictive values were 48.0% and 85.3%, respectively. In patients with depression, CDT specificity dropped significantly to 55.8% (71.3% in nondepressed patients, P <.001). Classification performance was not impacted by motor symptoms. The estimated classification performances and predictive values correspond to those reported previously for non-PD populations. Our results indicate that CDT is a suitable screening instrument in patients with PD, but test results from patients with depression warrant careful consideration. © The Author(s) 2013.


Tornack J.,Max Planck Institute for Infection Biology | Seiler K.,Stanford University | Grutzkau A.,Deutsches Rheumaforschungszentrum | Grun J.R.,Deutsches Rheumaforschungszentrum | And 3 more authors.
PLoS ONE | Year: 2013

The transcription factors SCL/Tal-1 and AML1/Runx1 control the generation of pluripotent hematopoietic stem cells (pHSC) and, thereby, primitive and definitive hematopoiesis, during embryonic development of the mouse from mesoderm. Thus, Runx1-deficient mice generate primitive, but not definitive hematopoiesis, while Tal-1-deficient mice are completely defective. Primitive as well as definitive hematopoiesis can be developed "in vitro" from embryonic stem cells (ESC). We show that wild type, as well as Tal-1-/- and Runx1-/- ESCs, induced to differentiation, all expand within 5 days to comparable numbers of Flk1+ mesodermal cells. While wild type ESCs further differentiate to primitive and definitive erythrocytes, to c-fms+Gr1+Mac1+ myeloid cells, and to B220+CD19+ B- and CD4+/CD8+ T-lymphoid cells, Runx1-/- ESCs, as expected, only develop primitive erythrocytes, and Tal-1-/- ESCs do not generate any hematopoietic cells. Retroviral transduction with Runx1 of Runx1-/- ESCs, differentiated for 4 days to mesoderm, rescues definitive erythropoiesis, myelopoiesis and lymphopoiesis, though only with 1-10% of the efficiencies of wild type ESC hematopoiesis. Surprisingly, Tal-1-/- ESCs can also be rescued at comparably low efficiencies to primitive and definitive erythropoiesis, and to myelopoiesis and lymphopoiesis by retroviral transduction with Runx1. These results suggest that Tal-1 expression is needed to express Runx1 in mesoderm, and that ectopic expression of Runx1 in mesoderm is sufficient to induce primitive as well as definitive hematopoiesis in the absence of Tal-1. Retroviral transduction of "in vitro" differentiating Tal-1-/- and Runx1-/- ESCs should be a useful experimental tool to probe selected genes for activities in the generation of hematopoietic progenitors "in vitro", and to assess the potential transforming activities in hematopoiesis of mutant forms of Tal-1 and Runx1 from acute myeloid leukemia and related tumors. © 2013 Tornack et al.


Riedel O.,Leibniz Institute for Prevention Research and Epidemiology | Riedel O.,TU Dresden | Klotsche J.,Deutsches Rheumaforschungszentrum | Wittchen H.-U.,TU Dresden
Parkinsonism and Related Disorders | Year: 2014

Introduction: Clinical Global Impression of Severity (CGIS) is a common measure in clinical research on Parkinson's disease (PD). However, patient features that contribute to the impression of the physician remain unclear. In particular, the impact of cognitive impairment and depression is understudied. Methods: In a nationwide study on 1449 outpatients with PD, examined by 315 office-based neurologists, PD severity was documented with the Unified Parkinson's Disease Rating Scale (UPDRS-I, II, and IV). All patients were screened with the Montgomery-Asberg Depression Rating Scale (MADRS) for depression. The diagnosis of dementia was based on Diagnostic and Statistical Manual of Mental Disorders IV Text Revision criteria. Each patient was rated on the CGIS. Results: CGIS ratings were available for 1438 patients, of which 50.8% were rated as "borderline" to "moderately ill" and 49.2% as "markedly" to "extremely ill." Worse ratings were associated with higher age (p<0.001), longer PD duration (p<0.001), and female sex (p<0.001). The impact of patient and physician variables on CGIS rating was calculated with three regression models (A: single bivariate regression; B: multivariate regression; and C: multivariate, multilevel regression, including physician variables). In all models, higher UPDRS-II scores and longer disease duration of PD were the strongest predictors for a worse CGIS rating. In the multivariate models (B and C), neuropsychiatric symptoms were unrelated to the CGIS rating. Conclusion: The additional burden of dementia and depression was underestimated in the CGIS rating, suggesting that they are possibly relativized against the motor impairment. © 2014 Elsevier Ltd.


Kneitz C.,Klinik F. Innere Medizin II | Strangfeld A.,Deutsches Rheumaforschungszentrum | Kruger K.,Praxiszentrum
Zeitschrift fur Rheumatologie | Year: 2014

In general, the risk of serious infections increases with age, mainly explained by immunosenescence and accumulation of comorbidities. Those patients with rheumatoid arthritis who are of advanced age and require treatment with immunosuppressive agents are at particular risk to develop an infectious disease. Actual requirement and kind of treatment on the one hand, and risk of infection on the other hand, have to be considered carefully for each patient. For example, in high-risk patients, it is important to use glucocorticoids in a minimal way, i.e. in low doses and as short as possible. Vaccination, especially against influenza and pneumococci, plays an essential role in preventing infectious diseases, particularly in the elderly. Nevertheless, in cases of suspected bacterial infection, empiric antibiotic therapy should be started promptly. Due to the burden of drugs taken by patients of advanced age, the benefits and possible side effects as well as potential drug interactions have to be carefully considered. In summary, drug treatment of the elderly requires bearing in mind the complete health status of the individual patient. © 2014 Springer-Verlag Berlin Heidelberg.

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