| 1. |
- 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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| 2. |
- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
- 2022
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Ingår i: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
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Tidskriftsartikel (refereegranskat)abstract
- Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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| 3. |
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| 4. |
- Eriksson, Per, 1958-, et al.
(författare)
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Systemisk vaskulit
- 2018. - 6
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Ingår i: Internmedicin. - Stockholm : Liber. - 9789147113262 ; , s. 939-949
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Geetha, Duvuru, et al.
(författare)
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Rituximab for treatment of severe renal disease in ANCA associated vasculitis
- 2016
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Ingår i: JN. Journal of Nephrology. - : Springer. - 1121-8428 .- 1724-6059. ; 29:2, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking.MethodsWe conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events.ResultsA total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed.ConclusionsThis study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC.
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| 6. |
- Karlsson, Maths, 1978, et al.
(författare)
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Quasielastic neutron scattering of hydrated BaZr0.90A0.10O2.95 (A = Y and Sc)
- 2009
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Ingår i: Solid State Ionics. - : Elsevier BV. - 0167-2738. ; 180:1, s. 22-28
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Tidskriftsartikel (refereegranskat)abstract
- Proton motions in hydrated proton conducting perovskites BaZr 0.90 A 0.10 O 2.95 (A = Y and Sc) have been investigated using quasielastic neutron scattering. The results reveal a localized motion on the ps time scale and with an activation energy of ~ 10-30 meV, in both materials. The temperature dependence of the total mean square displacement of the protons shows an onset of this motion at a temperature of about 300 K. The low activation energy, much lower than the activation energy for the macroscopic proton conductivity, suggests that this motion is not the rate-limiting process for the long-range proton diffusion, i.e. it is not linked to the two materials significantly different proton conductivities. In fact, a comparison of the QENS results with density functional theory calculations indicates that for both materials the observed motion may be ascribed to intra-octahedral proton transfers occurring close to a dopant atom. © 2008 Elsevier B.V. All rights reserved.
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| 7. |
- Karlsson, Maths, 1978, et al.
(författare)
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Using Neutron Spin-Echo To Investigate Proton Dynamics in Proton-Conducting Perovskites
- 2010
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Ingår i: Chemistry of Materials. - : American Chemical Society (ACS). - 1520-5002 .- 0897-4756. ; 22:3, s. 740-742
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Tidskriftsartikel (refereegranskat)abstract
- The applicability and potential of neutron spin-echo (NSE) to study proton dynamics in proton-conducting ceramics was studied. The experiment was performed on hydrated BaZr 0,90 Y 0.10 O 2.95 (10Y:BZO), a cubic perovskite with a relatively high proton conductivity. The NSE experiment was performed at the IN15 spectrometer at Institut Laue-Langevin (ILL) in Grenoble, France. The relaxation rate for two Q-values for the temperature 563 K was determined. The first-principles calculations were carried out within the framework of density functional theory (DFT). The calculated diffusion harriers far from Y-dopants are found to he 0.20 and 0.18 eV for the proton transfer and hydroxyl rotation motion, respectively. The binding energy to a Y-dopant is 0.16 eV, and the influence of the Y-dopant on the energetics for the proton is quite extended in space, including both the first and the second coordination shells.
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| 8. |
- Karlsson, Maths, 1978, et al.
(författare)
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Vibrational Properties of Protons in Hydrated BaInxZr1-xO3-x/2
- 2005
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Ingår i: Physical Review B - Condensed Matter and Materials Physics. - 2469-9950 .- 2469-9969. ; 72, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the local proton dynamics in the proton conducting hydrated perovskite system BaInxZr1-xO3-x/2 (x=0.25-0.75) using infrared spectroscopy and first-principles calculations. We show that oxygen vacancies and dopant atoms in the vicinity of the proton tilt the proton toward a neighboring oxygen creating strongly hydrogen-bonded configurations. This is manifested as a strong redshift of the O-H stretch band in the infrared absorption spectrum. We also find considerable fluctuations of the nearest and next-nearest oxygen-proton distances with time, resulting in additional spectral broadening. By comparing the frequencies of computed O-H stretch modes we can relate specific local configurations to different parts of the broad O-H stretch band. Even though hydrogen-bonded configurations favor proton transfer they hinder the long-range migration by decreasing the reorientational rate. Thus, in order to optimize the proton mobility it is important to avoid extreme configurations caused by either oxygen vacancies or dopant atoms in the perovskite structure.
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| 9. |
- Weiner, Maria, 1987-, et al.
(författare)
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Effect of Treatment on Damage and Hospitalization in Elderly Patients with Microscopic Polyangiitis and Granulomatosis with Polyangiitis
- 2020
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 47:4, s. 580-588
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown. Methods. Consecutive patients from Sweden, the United Kingdom, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide (CYC), rituximab (RTX), and corticosteroids the first 3 months was registered. Outcomes up to 2 years from diagnosis included Vasculitis Damage Index (VDI), hospitalization, and cause of death. Results. Treatment data were available for 167 of 202 patients. At 2 years, 4% had no items of damage. There was a positive association between VDI score at 2 years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using CYC or RTX. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. Myeloperoxidase-antineutrophil cytoplasmic antibody positivity and lower creatinine levels decreased the odds of readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose. Conclusion. Immunosuppressive treatment with CYC or RTX in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first 3 months was associated with treatment-related damage and fatal infections.
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| 10. |
- Weiner, Maria, 1987-
(författare)
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The Importance of Demographic and Geographical Factors on the Incidence and Outcome of Systemic Small Vessel Vasculitis Associated with Anti-Neutrophil Cytoplasmic Antibodies
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) comprise microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Two serotypes are recognized: myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA. Renal involvement is a common and severe manifestation associated with increased mortality. The incidence varies geographically, but studies are difficult to compare due to heterogeneous methodology and inclusion criteria. AAV is commonly found in the elderly, but there are little data on outcome and optimal treatment in the highest age groups. This thesis focuses on the epidemiology of AAV: incidence, geographical distribution, and outcome.In Paper I annual incidence rates and outcome were compared between nephritis in AAV and nephritis in systemic lupus erythematosus (SLE) in two geographically defined populations in Sweden. Even though SLE is twice as common as AAV, ANCA-associated nephritis outnumbered lupus nephritis by three to one, and was significantly more severe in terms of mortality and development of end stage renal disease.In Paper II associations between ANCA serotype and geographical and demographic factors were investigated in a large multi-centre study of 1408 patients with renal biopsy-proven AAV. PR3-ANCA was associated with male gender, younger age and higher glomerular filtration rate. PR3-ANCA was also associated with higher latitude and lower ultraviolet radiation levels, but analyses of subgroups suggested that genetic rather than environmental explanations might be more important for this geographical gradient.In Paper III a consecutive cohort of 151 elderly patients with MPA and GPA was studied with a focus on treatment, mortality and renal survival. Patients who had received immunosuppressive treatment with cyclophosphamide or rituximab had better survival rates compared to less intensively treated or untreated patients. Severely impaired renal function at diagnosis was associated with worse outcome in terms of both patient and renal survival.In Paper IV the elderly cohort was extended to 202 patients. In this study we found that treatment with cyclophosphamide or rituximab was associated with the development of less permanent organ damage, and not with higher utilization of in-hospital care. However, high doses of glucocorticoids were associated with fatal infections and treatment-related damage.
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