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  • Abonia, J Pablo, et al. (författare)
  • Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung
  • 2006
  • Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 108:5, s. 1588-1594
  • Tidskriftsartikel (refereegranskat)abstract
    • Normal mouse lungs lack appreciable numbers of mast cells (MCs) or MC progenitors (MCp's), yet the appearance of mature MCs in the tracheobronchial epithelial surface is a characteristic of allergic, T-cell-dependent pulmonary inflammation. We hypothesized that pulmonary inflammation would recruit MCp's to inflamed lungs and that this recruitment would be regulated by distinct adhesion pathways. Ovalbumin-sensitized and challenged mice had a greater than 28-fold increase in the number of MCp's in the lungs. In mice lacking endothelial vascular cell adhesion molecule 1 (VCAM-1) and in wild-type mice administered blocking monoclonal antibody (mAb) to VCAM-1 but not to mucosal addressin CAM-1 (MadCAM-1), recruitment of MCp's to the inflamed lung was reduced by greater than 75%. Analysis of the integrin receptors for VCAM-1 showed that in beta7 integrin-deficient mice, recruitment was reduced 73% relative to wild-type controls, and in either BALB/c or C57BL/6 mice, mAb blocking of alpha4, beta1, or beta7 integrins inhibited the recruitment of MCp's to the inflamed lung. Thus, VCAM-1 interactions with both alpha4beta1 and alpha4beta7 integrins are essential for the recruitment and expansion of the MCp populations in the lung during antigen-induced pulmonary inflammation. Furthermore, the MCp is currently unique among inflammatory cells in its partial dependence on alpha4beta7 integrins for lung recruitment.
  • Abrahamsson, Anna, et al. (författare)
  • Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study.
  • 2014
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 124:8, s. 1288-1295
  • Tidskriftsartikel (refereegranskat)abstract
    • There is consensus that young patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens, but optimal treatment of elderly patients as well for as patients with limited or indolent disease is not defined. Our aim was to evaluate and compare outcome in relation to prognostic factors and first-line treatment in patients with MCL in a population-based data set. Data were collected from the Swedish and Danish Lymphoma Registries from the period of 2000-2011. A total of 1389 patients were diagnosed with MCL. During this period, age-standardized incidence MCL increased, most prominently among males. Furthermore, male gender was associated with inferior overall survival (OS) in multivariate analysis (HR 1.36; p=0.002). Forty-three (3.6%) patients with stage I-II disease received radiotherapy with curative intent, showing a 3 year OS of 93%. Twenty-nine (2.4%) patients followed a watch-and-wait approach and showed a 3 year OS of 79.8%. Among patients receiving systemic treatment, rituximab (n=766; HR 0.66; p=0.001) and autologous stem cell transplant (ASCT) (n=273; HR 0.55; p=0.004) were independently associated with improved overall survival in multivariate analysis. Hence, by a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.
  • Agar, Cetin, et al. (författare)
  • beta(2)-Glycoprotein I: a novel component of innate immunity
  • 2011
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 117:25, s. 6939-6947
  • Tidskriftsartikel (refereegranskat)abstract
    • Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis. Lipopolysaccharide (LPS), one of the major constituents of the outer membrane of Gram-negative bacteria, plays a major role in activating the host's immune response by binding to monocytes and other cells. Several proteins are involved in neutralization and clearance of LPS from the bloodstream. Here, we provide evidence that beta(2)-glycoprotein I (beta(2)GPI) is a scavenger of LPS. In vitro, beta(2)GPI inhibited LPS-induced expression of tissue factor and IL-6 from monocytes and endothelial cells. Binding of beta(2)GPI to LPS caused a conformational change in beta(2)GPI that led to binding of the beta(2)GPI-LPS complex to monocytes and ultimately clearance of this complex. Furthermore, plasma levels of beta(2)GPI were inversely correlated with temperature rise and the response of inflammatory markers after a bolus injection of LPS in healthy individuals. Together, these observations provide evidence that beta(2)GPI is involved in the neutralization and clearance of LPS and identify beta(2)GPI as a component of innate immunity. (Blood. 2011;117(25):6939-6947)
  • Agar, Cetin, et al. (författare)
  • beta(2)-Glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome
  • 2010
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 116:8, s. 1336-1343
  • Tidskriftsartikel (refereegranskat)abstract
    • The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed that beta(2)GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome. (Blood. 2010; 116(8): 1336-1343)
  • Agathangelidis, Andreas, et al. (författare)
  • Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies
  • 2012
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 119:19, s. 4467-4475
  • Tidskriftsartikel (refereegranskat)abstract
    • Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset. (Blood. 2012;119(19):4467-4475)
  • Ahamed, Jasimuddin, et al. (författare)
  • Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1
  • 2005
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 105:6, s. 2384-2391
  • Tidskriftsartikel (refereegranskat)abstract
    • Tissue factor (TF) triggers upstream coagulation signaling via the activation of protease-activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor 1 (TFPI-1) is the physiologic inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TF-mediated signaling through PARs. In endothelial cells transduced with TF to mimic exacerbated TF expression in vascular cells, TF-VIIa-Xa ternary complex-dependent activation of PAR1 remained intact when TF-mediated Xa generation was blocked with 2.5 to 5 nM recombinant TFPI-1 (rTFPI-1). Concordantly, inhibition of signaling in PAR1-expressing Chinese hamster ovary (CHO) cells required about 30-fold higher rTFPI-1 concentrations than necessary for anticoagulation. Studies with proteoglycan-deficient CHO cells document a crucial role of accessory receptors in supporting the anticoagulant and antisignaling activities of rTFPI-1. Coexpression of PAR2 with TF enhanced rTFPI-mediated inhibition of TF-VIIa-Xa-mediated PAR1 signaling, suggesting an unexpected role of PAR2 in the inhibitory control of TF signaling. These experiments are of potential significance for the limited therapeutic benefit of rTFPI-1 in systemic inflammation and recommend caution in using anticoagulant potency as a measure to predict how efficacious TF-directed inhibitors block cell signaling during initiation of coagulation.
  • Ahnström, Josefin, et al. (författare)
  • Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue
  • 2011
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 117:24, s. 6685-6693
  • Tidskriftsartikel (refereegranskat)abstract
    • Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the omega-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is gamma-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca2+ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693)
  • Albert, Michael H, et al. (författare)
  • X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options.
  • 2010
  • Ingår i: Blood. - 1528-0020. ; 115:16, s. 3231-3238
  • Tidskriftsartikel (refereegranskat)abstract
    • A large proportion of patients with mutations in the Wiskott-Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Whereas stem cell transplantation at an early age is the treatment of choice for patients with WAS, therapeutic options for patients with XLT are controversial. In a retrospective multicenter study we defined the clinical phenotype of XLT and determined the probability of severe disease-related complications in patients older than 2 years with documented WAS gene mutations and mild-to-moderate eczema or mild, infrequent infections. Enrolled were 173 patients (median age, 11.5 years) from 12 countries spanning 2830 patient-years. Serious bleeding episodes occurred in 13.9%, life-threatening infections in 6.9%, autoimmunity in 12.1%, and malignancy in 5.2% of patients. Overall and event-free survival probabilities were not significantly influenced by the type of mutation or intravenous immunoglobulin or antibiotic prophylaxis. Splenectomy resulted in increased risk of severe infections. This analysis of the clinical outcome and molecular basis of patients with XLT shows excellent long-term survival but also a high probability of severe disease-related complications. These observations will allow better decision making when considering treatment options for individual patients with XLT.
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