| 1. |
- AbdGawad, Mohamed, et al.
(författare)
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Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:3
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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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| 2. |
- AbdGawad, Mohamed, et al.
(författare)
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Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression
- 2010
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Ingår i: Clinical and Experimental Immunology. - Chichester, West Sussex, United Kingdom : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 161:1, s. 89-97
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Tidskriftsartikel (refereegranskat)abstract
- Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
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| 3. |
- AbdGawad, Mohamed, et al.
(författare)
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Increased neutrophil membrane expression and plasma level of proteinase 3 in systemic vasculitis are not a consequence of the - 564 A/G promotor polymorphism.
- 2006
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 145:1, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- Several findings link proteinase 3 (PR3) to small vessel vasculitis. Besides being a major target of anti-neutrophil cytoplasm antibodies (ANCA), previous findings have shown increased circulating levels of PR3 in vasculitis patients, increased levels of neutrophil membrane-PR3 (mPR3) expression and a skewed distribution of the − 564 A/G polymorphism in the promotor region of the PR3 gene. In this study we elucidate how these three findings relate to each other. The plasma concentration of PR3 was measured by enzyme-linked immunosorbent assay (ELISA), mPR3 expression by fluorescence activated cell sorter (FACS) and the gene polymorphism by real-time polymerase chain reaction (PCR). We compared results from 63 patients with ANCA-associated systemic vasculitis (AASV) with 107 healthy blood donors. In accordance with previous reports, AASV patients had increased plasma concentrations of PR3 compared to healthy controls (mean 224 µg/l versus 155 µg/l, P < 0·0001). They also showed an increased number of mPR3-positive neutrophils (60% versus 42%, P < 0·001). However, contrary to a previous report, we found no skewed distribution of the polymorphism in PR3 gene. There was a weak correlation between mPR3 mean fluorescence intensity (MFI) and plasma PR3 among healthy controls and myeloperoxidase–ANCA (MPO–ANCA)-positive patients (r = 0·24, P = 0·015 and r = 0·52, P = 0·011, respectively). In conclusion, increased plasma PR3 and high expression of mPR3 are associated with small vessel vasculitis, but neither of them is a consequence of the − 564 A/G polymorphism of the PR3 gene promotor.
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| 6. |
- Appelgren, Daniel, 1985-, et al.
(författare)
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Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction
- 2023
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press. - 0009-9104 .- 1365-2249. ; 213:2, s. 190-201
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.
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| 7. |
- Armstead, Sumiko I, et al.
(författare)
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A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin.
- 2013
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Ingår i: Case reports in transplantation. - : Hindawi Limited. - 2090-6943 .- 2090-6951. ; 2013:Dec 2
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Tidskriftsartikel (refereegranskat)abstract
- Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.
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| 8. |
- Askman, Sandra, et al.
(författare)
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Decreased neutrophil function in newly diagnosed multiple myeloma patients is restored with lenalidomide therapy
- 2024
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Ingår i: EUROPEAN JOURNAL OF HAEMATOLOGY. - 0902-4441 .- 1600-0609.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesBacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls.MethodsPhagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay.ResultsPMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment.ConclusionOur results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.
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| 9. |
- Audard, Vincent, et al.
(författare)
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A 59-kd renal antigen as a new target for rapidly progressive glomerulonephritis
- 2007
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Ingår i: American Journal of Kidney Diseases. - : Elsevier BV. - 1523-6838 .- 0272-6386. ; 49:5, s. 710-716
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Tidskriftsartikel (refereegranskat)abstract
- Anti-glomerular basement membrane (anti-GBM) antibodies are the hallmark of anti-GBM disease, which is characterized by rapidly progressive glomerulonephritis. We describe the case of a 58-year-old woman who presented with rapidly progressive glomerulonephritis with typical anti-GBM staining found by means of direct immunofluorescence microscopy, associated with linear immunoglobin G deposits on tubules. Serum analysis showed circulating anti-tubular basement membrane antibodies, but failed to detect anti-GBM antibodies. Immunoblotting showed that serum antibodies reacted with a 59-kd antigen found along both the GBM and tubular basement membrane.
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| 10. |
- Bahnan, Wael, et al.
(författare)
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A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function
- 2023
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 15:2, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.
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