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Segelmark, Mårten
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Publications (10 of 125) Show all publications
Appelgren, D., Puli, S., Hellmark, T., Pochard, P., Pers, J.-O., Ernerudh, J., . . . Segelmark, M. (2023). Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction. Clinical and Experimental Immunology, 213(2), 190-201
Open this publication in new window or tab >>Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction
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2023 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 213, no 2, p. 190-201Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
B-Lymphocytes, Regulatory; Cytokines; Granulomatosis with Polyangiitis; Humans; Inflammation; Interferon-gamma; azathioprine; CD24 antigen; CD27 antigen; chemokine; cyclophosphamide; cytokine; gamma interferon; interleukin 2 receptor; interleukin 2 receptor alpha; methotrexate; mycophenolate mofetil; myeloperoxidase; prednisolone; programmed death 1 ligand 1; rituximab; cytokine; gamma interferon; adult; aged; Article; autoimmunity; B lymphocyte; B lymphocyte subpopulation; cell function; cell population; cell proliferation; clinical article; coculture; comparative study; controlled study; cytokine production; disease activity; enzyme linked immunosorbent assay; female; flow cytometry; follow up; gene expression; gene frequency; human; human cell; immunoregulation; in vitro study; male; middle aged; peripheral blood mononuclear cell; phenotype; proliferation index; protein expression; regulatory B lymphocyte; regulatory mechanism; remission; T lymphocyte; T lymphocyte activation; treatment failure; vasculitis; Wegener granulomatosis; inflammation; metabolism
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-200766 (URN)10.1093/cei/uxad021 (DOI)001167051500001 ()36752779 (PubMedID)2-s2.0-85165521399 (Scopus ID)
Note

Funding Agencies|Ingrid Asps Foundation; Alfred Osterlunds Stiftelse; Reumafonden; Swedish Society of Nephrology; County Council of Ostergotland; Inga-Britt and Arne Lundberg's research foundation

Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2025-02-18
Uhlin, F., Szpirt, W., Kronbichler, A., Bruchfeld, A., Soveri, I., Rostaing, L., . . . Segelmark, M. (2022). Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study. Journal of the American Society of Nephrology, 33(4), 829-838
Open this publication in new window or tab >>Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study
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2022 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 33, no 4, p. 829-838Article in journal (Refereed) Published
Abstract [en]

Background The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treat-ment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis.& nbsp;Methods An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR < 15 ml/min per 1.73m(2). All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months.& nbsp;Results At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m(2). The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P < 0.001, Fishers exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug.& nbsp;Conclusions In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.

Place, publisher, year, edition, pages
AMER SOC NEPHROLOGY, 2022
Keywords
anti-GBM disease; endopeptidases; clinical trial; glomerulonephritis; Goodpasture syndrome
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-183877 (URN)10.1681/ASN.2021111460 (DOI)000767598900001 ()35260419 (PubMedID)2-s2.0-85128001625 (Scopus ID)
Note

Funding Agencies|Region Skane [2020-O000028]; Region Ostergotland [LIO-755 381]; Ingrid Asp Foundation [991602]; Hansa Biopharma [IMH-2016-00286]

Available from: 2022-03-30 Created: 2022-03-30 Last updated: 2025-02-18Bibliographically approved
Stevens, K. I., Frangou, E., Il Shin, J., Anders, H.-J., Bruchfeld, A., Schoenermarck, U., . . . Kronbichler, A. (2022). Perspective on COVID-19 vaccination in patients with immune-mediated kidney diseases: consensus statements from the ERA-IWG and EUVAS. Nephrology, Dialysis and Transplantation, 37(8), 1400-1410
Open this publication in new window or tab >>Perspective on COVID-19 vaccination in patients with immune-mediated kidney diseases: consensus statements from the ERA-IWG and EUVAS
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2022 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 37, no 8, p. 1400-1410Article, review/survey (Refereed) Published
Abstract [en]

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2022
Keywords
IgA nephropathy; immunology; immunosuppression; rituximab; vasculitis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-185854 (URN)10.1093/ndt/gfac052 (DOI)000804547600001 ()35244174 (PubMedID)
Available from: 2022-06-17 Created: 2022-06-17 Last updated: 2025-02-18Bibliographically approved
Caravaca-Fontan, F., Fernandez-Juarez, G. M., Floege, J., Goumenos, D., Kronbichler, A., Turkmen, K., . . . Bruchfeld, A. (2022). The management of membranous nephropathy-an update. Nephrology, Dialysis and Transplantation, 37(6), 1033-1042
Open this publication in new window or tab >>The management of membranous nephropathy-an update
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2022 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 37, no 6, p. 1033-1042Article in journal (Refereed) Published
Abstract [en]

In recent decades, several important advances have taken place in the understanding of the pathogenesis underlying membranous nephropathy (MN) that have sparked renewed interest in its management. Four landmark trials in MN and a fifth clinical trial-which was a pilot study-have been published in recent years. The results from some of these trials have had a significant impact on the recommendations included in the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases, representing a significant step forward compared with the previous guideline in several aspects, including diagnosis, disease monitoring and treatment strategies. However, considering the rapidly evolving advances in the knowledge of MN and the recent publication of the STARMEN and RI-CYCLO trials, several recommendations contained in the guideline warrant updates. This article provides a perspective of the Immunonephrology Working Group of the European Renal Association regarding the management of MN in native kidneys of adult patients.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2022
Keywords
calcineurin inhibitors; cyclophosphamide; membranous nephropathy; remission; rituximab
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-183935 (URN)10.1093/ndt/gfab316 (DOI)000767450600001 ()34748001 (PubMedID)
Note

Funding Agencies|ERA

Available from: 2022-04-01 Created: 2022-04-01 Last updated: 2025-02-18Bibliographically approved
Weiner, M., Goh, S. M., Mohammad, A. J., Hrušková, Z., Tanna, A., Sharp, P., . . . Segelmark, M. (2020). Effect of treatment on damage and hospitalization in elderly patients with microscopic polyangiitis and granulomatosis with polyangiitis. Journal of Rheumatology, 47(4), 580-588
Open this publication in new window or tab >>Effect of treatment on damage and hospitalization in elderly patients with microscopic polyangiitis and granulomatosis with polyangiitis
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2020 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 47, no 4, p. 580-588Article in journal (Refereed) Published
Abstract [en]

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, England, 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, rituximab, and corticosteroids the first three months was registered. Outcomes up to two years from diagnosis included vasculitis damage index (VDI), hospitalization, and cause of death.

RESULTS: Treatment data was available for 167 of 202 patients. At two years, 4% had no items of damage. There was a positive association between VDI score at two years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using cyclophosphamide or rituximab. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. MPO-ANCA positivity and lower creatinine levels decreased the odds for readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose.

CONCLUSION: Immunosuppressive treatment with cyclophosphamide or rituximab 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 three months was associated with treatment-related damage and fatal infections.

Place, publisher, year, edition, pages
J RHEUMATOL PUBL CO, 2020
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-161581 (URN)10.3899/jrheum.190019 (DOI)000578888800016 ()31308208 (PubMedID)
Note

Funding agencies: Ingrid Asp Foundation; Swedish Renal Foundation; National Institute for Health Research Imperial Biomedical Research Centre

Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2025-02-18
Anders, H.-J., Bruchfeld, A., Juarez, G. M., Floege, J., Goumenos, D., Turkmen, K., . . . Segelmark, M. (2020). Recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus 2 pandemic. Nephrology, Dialysis and Transplantation, 35(6), 920-925
Open this publication in new window or tab >>Recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus 2 pandemic
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2020 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 35, no 6, p. 920-925Article, review/survey (Refereed) Published
Abstract [en]

The coronavirus disease 2019 (COVID-19) pandemic has created major challenges for all countries around the globe. Retrospective studies have identified hypertension, cardiovascular disease, diabetes and older age as risk factors for high morbidity and mortality from COVID-19. There is a general concern that patients with immune-mediated kidney diseases, namely those on immunosuppressive therapies and/or those with more advanced kidney failure, could particularly be at risk for adverse outcomes due to a compromised antiviral immunity. Uncertainties exist on how management routines should be reorganized to minimize the risk of severe acute respiratory syndrome coronavirus 2 infection and what measures are necessary for infected patients. The aim of the present review of the Immunonephrology Working Group of the European Renal Association-European Dialysis and Transplant Association is to provide recommendations for the management of patients with immune-mediated kidney diseases based on the available evidence, similar circumstances with other infectious organisms and expert opinions from across Europe. Such recommendations may help to minimize the risk of encountering COVID-19 or developing complications during COVID-19 in patients with immune-mediated kidney disease.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2020
Keywords
COVID-19; glomerulonephritis; lupus; renal vasculitis; steroids
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-167680 (URN)10.1093/ndt/gfaa112 (DOI)000544176600006 ()32445573 (PubMedID)
Note

Funding Agencies|Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [AN372/24-1]

Available from: 2020-07-20 Created: 2020-07-20 Last updated: 2025-02-18
Paats, J., Adoberg, A., Arund, J., Dhondt, A., Fernström, A., Fridolin, I., . . . Ortiz, A. A. (2020). Serum Levels and Removal by Haemodialysis and Haemodiafiltration of Tryptophan-Derived Uremic Toxins in ESKD Patients. International Journal of Molecular Sciences, 21(4), Article ID 1522.
Open this publication in new window or tab >>Serum Levels and Removal by Haemodialysis and Haemodiafiltration of Tryptophan-Derived Uremic Toxins in ESKD Patients
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol. 21, no 4, article id 1522Article in journal (Refereed) Published
Abstract [en]

Tryptophan is an essential dietary amino acid that originates uremic toxins that contribute to end-stage kidney disease (ESKD) patient outcomes. We evaluated serum levels and removal during haemodialysis and haemodiafiltration of tryptophan and tryptophan-derived uremic toxins, indoxyl sulfate (IS) and indole acetic acid (IAA), in ESKD patients in different dialysis treatment settings. This prospective multicentre study in four European dialysis centres enrolled 78 patients with ESKD. Blood and spent dialysate samples obtained during dialysis were analysed with high-performance liquid chromatography to assess uremic solutes, their reduction ratio (RR) and total removed solute (TRS). Mean free serum tryptophan and IS concentrations increased, and concentration of IAA decreased over pre-dialysis levels (67%, 49%, -0.8%, respectively) during the first hour of dialysis. While mean serum total urea, IS and IAA concentrations decreased during dialysis (-72%, -39%, -43%, respectively), serum tryptophan levels increased, resulting in negative RR (-8%) towards the end of the dialysis session (p < 0.001), despite remarkable Trp losses in dialysate. RR and TRS values based on serum (total, free) and dialysate solute concentrations were lower for conventional low-flux dialysis (p < 0.001). High-efficiency haemodiafiltration resulted in 80% higher Trp losses than conventional low-flux dialysis, despite similar neutral Trp RR values. In conclusion, serum Trp concentrations and RR behave differently from uremic solutes IS, IAA and urea and Trp RR did not reflect dialysis Trp losses. Conventional low-flux dialysis may not adequately clear Trp-related uremic toxins while high efficiency haemodiafiltration increased Trp losses.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
uremic toxins; tryptophan; tryptophan-derived uremic toxins; indoxyl sulfate; indole-3 acetic acid; end-stage kidney disease; chronic kidney disease; haemodialysis; haemodiafiltration
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-165195 (URN)10.3390/ijms21041522 (DOI)000522524400349 ()32102247 (PubMedID)2-s2.0-85079893233 (Scopus ID)
Note

Funding Agencies|European Union through the European Regional Development FundEuropean Union (EU) [H2020-SMEINST-2-2017]; Estonian Ministry of Education and ResearchMinistry of Education and Research, Estonia [IUT 19-2]; Estonian Centre of Excellence in IT (EXCITE) - European Regional Development Fund; Njurfonden (2017), Sweden; Njurfonden (2018), Sweden; Programa Rio Hortega ISCIII FEDER funds; ISCIII-RETIC REDinREN [RD016/0009]; Sociedad Espanola de Nefrologia; Fundacion Renal Inigo Alvarez de Toledo (FRIAT)Fonds de la Recherche Scientifique - FNRS; Comunidad de MadridComunidad de MadridInstituto de Salud Carlos III [CIFRA2 B2017/BMD-3686]; OLDIAS2-Online Dialysis Sensor Phase2 project [767572]; ERA-PerMed-JTC2018 [KIDNEY ATTACK AC18/00064, PERSTIGAN AC18/00071]; FEDER fundsEuropean Union (EU); [PI19/00588]; [PI19/00815]; [DTS18/00032]

Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2025-02-18Bibliographically approved
Lu, Y., Jiang, H., Li, B., Cao, L., Shen, Q., Yi, W., . . . Chen, J. (2020). Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism. Annals of Translational Medicine, 8(6), Article ID 357.
Open this publication in new window or tab >>Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism
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2020 (English)In: Annals of Translational Medicine, ISSN 2305-5839, E-ISSN 2305-5847, Vol. 8, no 6, article id 357Article in journal (Refereed) Published
Abstract [en]

Background: Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism. Methods: We contrasted the release of neutrophil NETs from mice with telomere dysfunction, mice with DNA damage and wide-type mice. Neutrophil telomere length, the expression of LL37, and the formation of NETs were measured in SVV patients and healthy controls (HCs). The co-expression of gamma H2AX, LL37, and NETs were detected in SVV patients to evaluate the association of the immune aging of neutrophils and pro-inflammatory conditions. LL37 inhibitor was used to verify its key role in NETs release in SVV patients and DNA damage mice. Results: We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils. Conclusions: Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.

Place, publisher, year, edition, pages
AME PUBL CO, 2020
Keywords
Telomere dysfunction; DNA damage; small vessel vasculitis (SVV); LL37; neutrophil extracellular traps (NETs)
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-165184 (URN)10.21037/atm.2020.02.130 (DOI)000522784900100 ()
Note

Funding Agencies|National Basic Research Program of ChinaNational Basic Research Program of China [2012CB517603]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81470938, 81200546, 81300619]; Zhejiang Science and Technology Department [LQ19H050005, 2012C13G2010133]

Available from: 2020-04-20 Created: 2020-04-20 Last updated: 2021-05-01
Erdbrügger, U., Kielstein, J. T., Westman, K., Ma, J. Z., Xin, W., Bode-Böger, S. M., . . . De Groot, K. (2018). Higher levels of SDMA and not ADMA are associated with poorer survival of trial patients with systemic ANCA-associated vasculitis. European journal of rheumatology, 5(3), 153-159
Open this publication in new window or tab >>Higher levels of SDMA and not ADMA are associated with poorer survival of trial patients with systemic ANCA-associated vasculitis
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2018 (English)In: European journal of rheumatology, ISSN 2147-9720, Vol. 5, no 3, p. 153-159Article in journal (Refereed) Published
Abstract [en]

Endothelial dysfunction, increased cardiovascular events (CVE), and accelerated atherosclerosis have been described in patients with small vessel vasculitis and collagen vascular disease. Identifying predictors of cardiovascular risk will help to optimize short- and long-term care of patients with vasculitis. The present study investigates the predictive role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) for cardiovascular risk, all-cause mortality, and renal function in patients with anti-neutrophil-cytoplasmic antibodies-associated small vessel vasculitis (AASV) subjected to standardized treatment regimens in four European Vasculitis Study Group trials representing all stages of renal disease.

Place, publisher, year, edition, pages
AVES, 2018
National Category
Cardiology and Cardiovascular Disease
Identifiers
urn:nbn:se:liu:diva-155844 (URN)10.5152/eurjrheum.2018.17119 (DOI)30071927 (PubMedID)
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2025-02-10
Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V.-M., . . . Rosén, A. (2018). Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C. Proceedings of the National Academy of Sciences of the United States of America, 115(3), E478-E487
Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
Abstract [en]

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

Place, publisher, year, edition, pages
Washington, DC, United States: National Academy of Sciences, 2018
Keywords
CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
National Category
Basic Medicine Immunology in the medical area
Research subject
Economic Information Systems
Identifiers
urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)2-s2.0-85042104216 (Scopus ID)
Funder
Swedish Cancer Society
Note

Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2019-12-09Bibliographically approved
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