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Life and death of human B cells in health and disease
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. (Mattias Forsell)
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 [en]
b cells, antibody, hantavirus, germinal centre, phagocytosis, selection, DAF, vaccination, rituximab
National Category
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-199289ISBN: 978-91-7855-883-4 (print)ISBN: 978-91-7855-884-1 (electronic)OAI: oai:DiVA.org:umu-199289DiVA, id: diva2:1694939
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
List of papers
1. Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings
Open this publication in new window or tab >>Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings
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2021 (English)In: Clinical & Translational Immunology (CTI), E-ISSN 2050-0068, Vol. 10, article id e1313Article in journal (Refereed) Published
Abstract [en]

Objective: Human hantavirus infections can cause haemorrhagic fever with renal syndrome (HFRS). The pathogenic mechanisms arenot fully understood, nor if they affect the humoral immune system. The objective of this study was to investigate humoral immune responses to hantavirus infection and to correlate them to the typical features of HFRS: thrombocytopenia and transient kidney dysfunction.

Methods: We performed a comprehensive characterisation of longitudinal antiviral B-cell responses of 26 hantavirus patients and combined this with paired clinical data. In addition, we measured extracellular adenosine triphosphate (ATP)and its breakdown products in circulation and performed in vitro stimulations to address its effect on B cells.

Results: We found that thrombocytopenia was correlated to an elevated frequency of plasmablasts in circulation. In contrast, kidney dysfunction was indicative of an accumulation of CD27-IgD- B cells and CD27/low plasmablasts. Finally, we provide evidence that high levels of extracellular ATP and matrix metalloproteinase 8 can contribute to shedding of CD27 during human hantavirus infection.

Conclusion:  Our findings demonstrate that thrombocytopenia and kidneydysfunction associate with distinctly different effects on the humoral immune system. Moreover, hantavirus-infectedindividuals have significantly elevated levels of extracellular ATP incirculation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
antibodies, atypical B cells, B cells, haemorrhagic fever with renal syndrome, hantavirus, plasmablasts
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-186401 (URN)10.1002/cti2.1313 (DOI)000680165000010 ()2-s2.0-85111325845 (Scopus ID)
Funder
Swedish Foundation for Strategic ResearchSwedish Society of Medicine, SLS-787091Region Västerbotten, VLL-579011, VLL-850681Knut and Alice Wallenberg Foundation, KAW 2015.0225NIH (National Institutes of Health), R01AI132633Swedish Research Council, 2018-02646_3
Available from: 2021-07-28 Created: 2021-07-28 Last updated: 2022-12-09Bibliographically approved
2. Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
Open this publication in new window or tab >>Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis
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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
Keywords
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:nbn:se:umu:diva-179577 (URN)10.3389/fimmu.2020.599647 (DOI)000608470700001 ()33469456 (PubMedID)2-s2.0-85099651060 (Scopus ID)
Funder
NIH (National Institute of Health), U19AI142777-01Swedish Research Council, 2016-06598
Available from: 2021-02-04 Created: 2021-02-04 Last updated: 2024-01-17Bibliographically approved
3. Variable immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis after rituximab treatment interruption
Open this publication in new window or tab >>Variable immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis after rituximab treatment interruption
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-199293 (URN)
Available from: 2022-09-12 Created: 2022-09-12 Last updated: 2023-07-03

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Citation style
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