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Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.ORCID iD: 0000-0003-3522-1842
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
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2021 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 599647Article in journal (Refereed) Published
Abstract [en]

Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF(lo) B cells. Consistent with this, a majority of light and dark zone GC B cells were DAF(lo) and susceptible to complement-dependent phagocytosis, as compared with DAF(hi) GC B cells. We could also show that the DAF(hi) GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021. Vol. 11, article id 599647
Keywords [en]
human B cell development, germinal center (GC), decay accelerating factor (DAF), complement-mediated phagocytosis, complement regulating proteins
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-179577DOI: 10.3389/fimmu.2020.599647ISI: 000608470700001PubMedID: 33469456Scopus ID: 2-s2.0-85099651060OAI: oai:DiVA.org:umu-179577DiVA, id: diva2:1525693
Funder
NIH (National Institute of Health), U19AI142777-01Swedish Research Council, 2016-06598Available from: 2021-02-04 Created: 2021-02-04 Last updated: 2024-01-17Bibliographically approved
In thesis
1. Life and death of human B cells in health and disease
Open this publication in new window or tab >>Life and death of human B cells in health and disease
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cells provide one of the key mechanisms of immunological memory, which is theproduction of neutralising antibodies. How B cells respond to infections and vaccinationgives clues to how the development of the immunological memory is facilitated, and canthus lead to a deeper understanding of why the immune system sometimesmalfunctions. This thesis focuses on the human B cell responses in three differentsettings: Acute viral infection, mechanisms involved in germinal centre responses, andvaccination upon interrupted B cell depletion therapy in patients with multiple sclerosis(MS). We have found that during acute Puumala-orthohantavirus (PUUV) infection, Bcells activate on a large scale and derive a phenotype similar to previous observations inautoimmune diseases and chronic infections. Patients with PUUV infection also haddecreased expression of the complement regulatory protein Decay-Accelerating Factor(DAF) at an early stage in the disease. Here, we hypothesised that this might be a resultof a robust B cell response, and therefore we continued to assess B cells at the peripheralsites of their maturation. We found that B cells downregulated the complementinhibitory protein during the germinal centre reaction, which also primed the cells forphagocytosis. This finding shed light to the mechanisms that control B cell homeostasis.Finally, we assessed the B cell responses towards vaccination in patients with MS afterinterruption of their B cell depletion therapy. Here we showed that the patients yieldedexpansion of vaccination-specific memory B cells. However, these memory B cells didnot comprise expansion of DAFlo cells, in contrast to the non-MS control individuals.We speculated that the B cell depletion might have an impact on the formation of B cellmemory after interrupted treatment. Taken together, this thesis contributes to theoverall understanding of the life cycle of B cells, in the context of infection, vaccination,and homeostasis.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2022. p. 84
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2202
Keywords
b cells, antibody, hantavirus, germinal centre, phagocytosis, selection, DAF, vaccination, rituximab
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-199289 (URN)978-91-7855-883-4 (ISBN)978-91-7855-884-1 (ISBN)
Public defence
2022-10-07, 5B Stora hörsalen, Målpunkt P, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2022-09-16 Created: 2022-09-12 Last updated: 2022-09-14Bibliographically approved

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Dernstedt, AndyLeidig, JanaHolm, AnnaKerkman, PriscillaAhlm, ClasHenriksson, JohanHultdin, MagnusForsell, Mattias N. E.

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Dernstedt, AndyLeidig, JanaHolm, AnnaKerkman, PriscillaAhlm, ClasHenriksson, JohanHultdin, MagnusForsell, Mattias N. E.
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Department of Clinical MicrobiologyOtorhinolaryngologyDepartment of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)Pathology
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