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Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-3328-5060
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.ORCID iD: 0000-0002-3555-7162
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.ORCID iD: 0000-0001-9456-2044
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2242Article in journal (Refereed) Published
Abstract [en]

In mice, B1 and marginal zone (MZ) B-cells play an important role in prevention of autoimmunity through production of regulatory cytokines and natural antibodies. There is limited knowledge about the human counterparts of these cells. We therefore investigated functions of MZ-like B-cells and the frequency of circulating MZ-like and Bl-like B-cells in healthy controls (HC), as well as in patients with autoimmune vasculitis to learn more about the role of these cells in autoimmune disease. After stimulation with CpG oligodeoxynucleotides (ODN) of class B in vitro, MZ-like B-cells were the main producers of IgM whereas switched memory B-cells primarily produced IgG and IgA. TNF and IL-10 were produced by both MZ-like and switched memory B-cells. Neither antibody nor TNF/IL-10 production by the B-cell subsets differed between patients and HC. Patients with autoimmune vasculitis, irrespective of disease activity, had lower percentage and absolute numbers of circulating MZ-like B-cells, and lower absolute numbers of B1-like B-cells. The percentage of B1-like B-cells was reduced during active disease. These findings remained significant when the analysis was confined to active treatment-naive patients (disease onset).Our results suggest that human innate-like B-cells might have a physiological role in prevention of autoimmunity.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2018. Vol. 9, article id 2242
Keywords [en]
marginal-zone (MZ) B-cells; B1 B-cells; innate-like B-cells; natural antibodies; T-cell-independent antibodies; IgM; autoimmunity; anti-neutrophil cytoplasmic autantibody (ANCA) associated vasculitis
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-152056DOI: 10.3389/fimmu.2018.02242ISI: 000446095400001OAI: oai:DiVA.org:liu-152056DiVA, id: diva2:1259444
Note

Funding Agencies|Ingrid Asps Foundation; Swedish Society of Nephrology; Swedish Renal Foundation

Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2020-01-16
In thesis
1. The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis
Open this publication in new window or tab >>The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic. 

In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells) in addition to cells of innate immunity can release ET-like structures, in this case consisting of mitochondrial (mt) DNA. mtDNA can act as a damage-associated pattern molecule (DAMP) and promote inflammation, and increased levels of mtDNA has been observed in AAV. Our finding broadens our perspective of the possible roles of T and B cells in immunological responses, and should be further investigated in AAV. In paper IV, we observed reduced frequencies of MZ-like B cells, considered to be innate-like B cells that produce natural antibodies, and of the proposed regulatory B (Breg) cell populations CD24highCD27+ and CD25+CD27+ B cells in patients, particularly in those with active disease. We also observed the phenotypes of these different Breg cell populations to be different from the corresponding cells in HC.

We hypothesize that the increased activation potential by neutrophils in AAV to produce ROS and undergo NETosis/necrosis contribute to the excessive inflammation as well as an increased antigen load of PR3 and MPO, and that this in combination with dysregulation of innate-like B cells and Breg cells could lead to break of tolerance to these antigens and production of pathogenic autoantibodies. ANCA can in turn activate neutrophils to release NETs, suggesting a vicious circle in disease development.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. p. 91
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1545
National Category
Immunology in the medical area Urology and Nephrology
Identifiers
urn:nbn:se:liu:diva-132327 (URN)10.3384/diss.diva-132327 (DOI)9789176856598 (ISBN)
Public defence
2016-12-01, Berzeliussalen, Campus US, Linköping, 13:00 (English)
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Available from: 2016-11-01 Created: 2016-11-01 Last updated: 2019-12-09Bibliographically approved

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Appelgren, DanielEriksson, PerErnerudh, JanSegelmark, Mårten
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Division of Drug ResearchFaculty of Medicine and Health SciencesDivision of Neuro and Inflammation ScienceDepartment of RheumatologyDepartment of Clinical Immunology and Transfusion MedicineDepartment of Nephrology
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