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Träfflista för sökning "AMNE:(MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Urologi och njurmedicin) ;pers:(Hellmark Thomas)"

Sökning: AMNE:(MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Urologi och njurmedicin) > Hellmark Thomas

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  • AbdGawad, Mohamed, et al. (författare)
  • Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.
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  • Carlsson, Malin, et al. (författare)
  • Pseudomonas aeruginosa in cystic fibrosis: Pyocyanin negative strains are associated with BPI-ANCA and progressive lung disease
  • 2011
  • Ingår i: Journal of Cystic Fibrosis. - : Elsevier Science B.V., Amsterdam.. - 1569-1993 .- 1873-5010. ; 10:4, s. 265-271
  • Tidskriftsartikel (refereegranskat)abstract
    • The clinical consequence of chronic Pseudomonas aeruginosa colonization in cystic fibrosis (CF) varies between individuals for unknown reasons. Auto-antibodies against bactericidal/permeability increasing protein (BPI-ANCA) are associated with poor prognosis in CF. We hypothesize that there is a correlation between the presence of BPI-ANCA, the properties of the colonizing bacteria and the clinical conditions of the host. We compared isolates of P. aeruginosa from BPI-ANCA positive CF patients who have deteriorating lung disease with BPI-ANCA negative CF patients who are in stable clinical conditions. Epithelial cells (A549) and isolated polymorphonuclear granulocytes (PMNs) were stimulated with the isolates and cell death was analyzed with flow cytometry. We found that the ANCA associated strains in most cases showed pyocyanin negative phenotypes. These strains also induced less inflammatory response than the non-ANCA associated strains as shown by apoptosis and necrosis of epithelial cells and neutrophils. Our results suggest that colonization with strains of P. aeruginosa that induce a weak inflammatory response is associated with unfavorable outcome in CF. We speculate that inadequate control of pathogen proliferation through an insufficient inflammatory response results in a slowly increasing number of bacteria and accumulation of dying PMNs in the airways, contributing to progression in CF lung disease.
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4.
  • Hellmark, Thomas (författare)
  • Molecular dissection of the Goodpasture epitope
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Goodpasture disease is a prototype autoimmune disease that is characterized by a rapidly progressive glomerulonephritis, with or without lung haemorrhage, associated with autoantibodies against the glomerular basement membrane. The major antigen has previously been shown to be the non-collagenous domain of the a3 chain of type IV collagen, one of the six known a chains of type IV collagen. On average, one percent of the total IgG fraction from the patients is comprised of anti-type IV collagen autoantibodies. Ninety percent of these antibodies are a3(IV)-specific and the remaining ten percent are low-affinity antibodies, showing cross-reactivity with the other a(IV) chains. Furthermore, the epitope specificity seems to be limited, as shown by monoclonal antibody inhibition. To test the hypothesis that only antibodies against certain epitopes are nephrotoxic, clinical and serological data from 77 anti-GBM positive patients were retrieved. The results showed that the anti-a3(IV) titre, and especially the antibodies that can be blocked using a monoclonal antibody, correlated with the outcome, in terms of kidney survival. Thus, the study strongly indicates the pathogenic role of the circulating autoantibodies. Epitope mapping of the anti-GBM antibodies has been done using overlapping synthetic peptides. The epitope specificity of the autoantibodies from one patient with anti-a1(IV) antibodies was revealed, and reactivity in ELISA was successfully blocked using a four-amino-acid-long peptide from the a1(IV) sequence. The same approach did not show any reactivity with the anti-a3(IV) autoantibodies. By using recombinant antigens expressed in a human cell line as chimeric proteins, where the a3(IV) sequence was exchanged for the corresponding sequence from the a1(IV) chain, we could show that only autoantibodies against the N-terminal third of the a3(IV) chain correlated with disease. The reactive sequence was further narrowed down to nine discontinuous amino acid residues. A chimeric protein comprised of a1(IV), but with these nine positions expressed as a3(IV), bound the toxic autoantibodies with approximately the same affinity as native a3(IV). These studies provide evidence that only autoantibodies against a very limited region of the a3(IV) chain carry a toxic potential. Furthermore, epitope spreading is relatively limited, thus indicating a possibility for new forms of therapy, including epitope immunomodulatory treatment. In the future, therapy might be adjusted for each individual patient, on the basis of diagnostic tests, e.g., regarding the fine specificity and titre of the autoantibodies, thereby minimising unnecessary discomfort caused by the side effects of immunosuppressive treatment.
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  • Hellmark, Thomas, et al. (författare)
  • Eosinophils in anti-neutrophil cytoplasmic antibody associated vasculitis
  • 2019
  • Ingår i: BMC Rheumatology. - : Springer Science and Business Media LLC. - 2520-1026. ; 3:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).Methods: The expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.Results: Both GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).Conclusions: The percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.
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  • Tyrberg, Linnéa, et al. (författare)
  • Using imlifidase to elucidate the characteristics and importance of anti-GBM antibodies produced after start of treatment
  • 2023
  • Ingår i: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 39:1, s. 45-54
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Autoantibodies are common in glomerulonephritis, but the clinical benefit of rapid elimination has not been determined, even in anti-glomerular basement membrane (GBM) disease. Even less is known about the importance of autoantibody characteristics, including epitope specificity and immunoglobulin G (IgG) subclass distribution. We aimed to address this by characterizing the autoantibody profile in anti-GBM patients: we utilized samples from the GOOD-IDES-01 (treating GOODpastures disease with Imunoglobulin G Degrading Enzyme of Streptococcus pyogenous) ( identifier: NCT03157037) trial , where imlifidase, which cleaves all IgG in vivo within hours, was given to 15 anti-GBM patients.Methods: In the GOOD-IDES-01 trial, plasmapheresis was (re)started if anti-GBM antibodies rebounded. Serum samples were collected prospectively for 6 months and analyzed for anti-GBM epitope specificity using recombinant constructs of the E-A and E-B epitopes, IgG subclass using monoclonal antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). The results were correlated with clinical data.Results: Patients with a rebound (n = 10) tended to have lower eGFR at 6 months (11 vs 34 mL/min/1.73 m(2), P = .055), and patients with dialysis at 6 months had a higher E-B/E-A ratio at rebound (0.8 vs 0.5, P = .047). Moreover, two patients demonstrated increasing epitope restriction and several patients displayed a shift in subclass distribution at rebound. Six patients were double positive for ANCA. ANCA rebound was seen in 50% of patients; only one patient remained ANCA positive at 6 months.Conclusions: In this study, rebound of anti-GBM antibodies, especially if directed against the E-B epitope, was associated with a worse outcome. This supports the notion that all means should be used to eliminate anti-GBM antibodies. In this study ANCA was removed early and long-term by imlifidase and cyclophosphamide.
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9.
  • Bryland, Anna, et al. (författare)
  • Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions.
  • 2012
  • Ingår i: Diabetes & Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 9:1, s. 42-51
  • Tidskriftsartikel (refereegranskat)abstract
    • Hyperglycaemia and glucose degradation products (GDPs) are closely associated with oxidative stress and inflammation in diabetic patients, a condition that leads to endothelial dysfunction and cardiovascular problems. We evaluated the effect of citrate and gluconate on glucose- and GDP-induced endothelial inflammation by measuring changes in viability, inflammation and function in primary human umbilical vein endothelial cells (HUVECs). The extent of apoptosis/necrosis was measured by flow cytometry and visualised with confocal microscopy by staining with annexin V or propidium iodide, respectively. Protein kinase C-βII (PKC-βII) activation was evaluated with Western blotting. Incubation with glucose (30 mM) and GDP (50 µM) significantly increased PKC-βII expression, endothelial cell death and inflammation. The addition of citrate decreased hyperglycaemia-induced apoptosis (p = 0.021), necrosis (p = 0.04) and reduced PKC-βII expression (p = 0.021) down to background levels. Citrate improved endothelial function by reducing the inflammatory markers(p = 0.01) and by decreasing neutrophil diapedesis (p = 0.012). These results suggest that citrate may have therapeutic potential by reducing hyperglycaemia-induced endothelial inflammation and abolishing endothelial dysfunction.
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