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Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-6212-002X
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0001-6048-5300
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). (Andrea Puhar)ORCID iD: 0000-0002-1653-9639
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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. Vol. 10, article id e1313
Keywords [en]
antibodies, atypical B cells, B cells, haemorrhagic fever with renal syndrome, hantavirus, plasmablasts
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-186401DOI: 10.1002/cti2.1313ISI: 000680165000010Scopus ID: 2-s2.0-85111325845OAI: oai:DiVA.org:umu-186401DiVA, id: diva2:1582132
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_3Available from: 2021-07-28 Created: 2021-07-28 Last updated: 2022-12-09Bibliographically 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
2. Role of extracellular ATP in immune mechanisms against infections
Open this publication in new window or tab >>Role of extracellular ATP in immune mechanisms against infections
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Roll av extracellulär ATP i immunmekanismer mot infektioner
Abstract [en]

Inflammation is driven either by infection with pathogens or sterile stimuli, such as tissue damage or autoimmune diseases. Upon tissue damage, ATP is released passively from the dead or compromised cells. During stress, ATP can be secreted from the cells. Extracellular ATP (eATP) acts as an endogenous danger signal. An increase in eATP is sensed by cell surface purinergic receptors and regulates the onset and resolution of inflammation. Extracellular ATP is an important inflammatory mediator during sterile inflammation. On the other hand, the role of eATP is poorly studied during infection, both bacterial and viral. In this thesis, I present the molecular mechanisms underlying ATP secretion during bacterial infections and the role of eATP in human hantaviral infections.

During infection with certain enteropathogenic Gram-negative bacteria, intestinal epithelial cells secrete ATP via connexin hemichannels as an alert signal to activate the immune system, which triggers acute inflammation in the gut. However, neither what triggers ATP secretion nor the molecular mechanisms of ATP secretion were known. Pharmacological, genetic, and microscopy-based evidence shows that during invasive bacterial infections, the plasma membrane ruffles act as mechanical immune stimuli and activate the inherently mechanosensitive plasma membrane channel PIEZO1. Mechanically activated PIEZO1 leads to the influx of Ca2+ ions and concurrent ATP secretion. In addition, PIEZO1 also activates protective transcriptional responses. Thus, PIEZO1 acts as a sensor for invasive infection using mechanical stimuli, unlike the so-far-described immune sensors of infection, which all recognize microbial components by chemical interaction.

During human hantavirus infection, the humoral immune responses are poorly studied. Our collaborators found that atypical B cells, which do not have the surface marker CD27, show increased frequency in a cohort of hantavirus-infected patients. CD27 shedding in murine lymphocytes had been previously linked to eATP-dependent activation of a purinergic receptor7. To test whether ATP levels in the circulation of hantavirus-infected patients are elevated, an approach to perform same-day eATP quantifications in human plasma was developed. This assay was used to establish the normal eATP concentration in plasma in a cohort of healthy volunteers and to show that eATP levels are elevated in the acute and convalescent stages of hantavirus infection. Further, the addition of ATP to isolated human B cells recapitulated the observed CD27 shedding via a metallomatrix proteinase-8-dependent (MMP8) mechanism. Together, these projects provide evidence for the importance of eATP in bacterial and viral infectious diseases.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2022. p. 44
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2216
Keywords
Extracellular ATP, invasive bacteria, Shigella, Listeria, plasma membrane ruffle, PIEZO1, infection, immune response, Hanta virus
National Category
Microbiology in the medical area Infectious Medicine
Research subject
molecular cell biology
Identifiers
urn:nbn:se:umu:diva-200913 (URN)978-91-7855-932-9 (ISBN)978-91-7855-933-6 (ISBN)
Public defence
2022-12-02, Atrium Betula, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2022-11-11 Created: 2022-11-09 Last updated: 2023-10-05Bibliographically approved

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Kerkman, PriscillaDernstedt, AndyTadala, LalithaDannborg, MirjamTuiskunen-Bäck, AnneWigren Byström, JuliaOcaya, PaulineThunberg, TheresePuhar, AndreaAhlm, ClasForsell, Mattias N. E.

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Kerkman, PriscillaDernstedt, AndyTadala, LalithaDannborg, MirjamSundling, ChristopherTuiskunen-Bäck, AnneWigren Byström, JuliaOcaya, PaulineThunberg, ThereseJangra, Rohit KKlingström, JonasPuhar, AndreaAhlm, ClasForsell, Mattias N. E.
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Department of Clinical MicrobiologyUmeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Medicine)
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Clinical & Translational Immunology (CTI)
Infectious MedicineMicrobiology in the medical area

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