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Mice Producing IgM Unable to Activate Complement Have Impaired Endogenous Feedback Regulation but Increased Antigen Trapping in Follicles
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-8871-0079
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
Keyword [en]
complement-activating IgM, marginal zone B cells, follicular dendritic cells, antigen trapping
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-310226OAI: oai:DiVA.org:uu-310226DiVA: diva2:1078555
Available from: 2017-03-05 Created: 2017-03-05 Last updated: 2017-03-08
In thesis
1. IgG3 Complements IgM in the Complement-Mediated Regulation of Immune Responses
Open this publication in new window or tab >>IgG3 Complements IgM in the Complement-Mediated Regulation of Immune Responses
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An intact complement system is essential for the initiation of a normal antibody response. Antibodies can regulate their own production against the antigens that they are specific for. Both IgG3 and IgM are able to enhance the antibody response via complement. Here, we have compared the fate of OVA-TNP (ovalbumin-2,4,6-trinitrophenyl) administered intravenously to mice either alone or in complex with monoclonal IgG3 anti-TNP. IgG3-antigen complexes bind to marginal zone (MZ) B cells via complement receptors 1 and 2 (CR1/2) and are transported into splenic follicles. The majority (50% - 90%) of the antigens is deposited on follicular dendritic cells (FDC) and the antigen distribution pattern is strikingly similar to peripheral dendrites/processes of FDC already 2 h after immunization. The development of germinal centers (GC) induced by IgG3-antigen complexes is impaired in mice lacking CR1/2. Experiments on bone marrow chimeric mice show that CR1/2 expression on both MZ B cells and FDC is required for optimal IgG3-mediated enhancement of antibody responses. Complement factors C3 and C1q are essential for OVA-TNP delivery and deposition on splenic FDC. The production of IgG anti-OVA is abrogated in mice lacking CR1/2, C1q, and C3. Further, IgG3-antigen complexes dramatically upregulate the memory response against OVA-TNP by inducing OVA-specific memory cells. Besides small protein OVA, IgG3 can also upregulate humoral responses against large soluble keyhole limpet hemocyanin.

To further study the role of MZ B-cells and CR1/2 in enhancement of antibody responses, a knock-in mouse strain, Cμ13, was used. IgM in this mouse strain is unable to activate complement due to a point mutation in the constant µ-heavy chain. Cμ13 mice have a higher proportion of MZ B cells, with higher CR1/2 expression, than wild-type mice. More IgG3-immune complexes are captured by MZ B cells and deposited on FDC in Cμ13 than in WT mice. In spite of this, IgG3 did not enhance the primary antibody response more efficiently in Cμ13 mice. The existence of endogenous IgM-mediated feedback regulation was suggested by the observation that GC development and antibody responses, after priming and boosting with suboptimal doses of SRBC, was lower in Cμ13 than in WT mice.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1310
Keyword
IgG3, IgM, marginal zone B cells, follicular dendritic cells, complement receptors 1 and 2, C1q, C3, antigen transport
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-316618 (URN)978-91-554-9843-6 (ISBN)
Public defence
2017-04-27, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-04-04 Created: 2017-03-08 Last updated: 2017-04-18

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