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IgG3 Complements IgM in the Complement-Mediated Regulation of Immune Responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-8871-0079
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 [en]
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: urn:nbn:se:uu:diva-316618ISBN: 978-91-554-9843-6 (print)OAI: oai:DiVA.org:uu-316618DiVA: diva2:1079601
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
List of papers
1. Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles
Open this publication in new window or tab >>Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles
2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 4, 1681-1689 p.Article in journal (Refereed) Published
Abstract [en]

Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2(+) MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23.

Keyword
antigen transport, marginal zone B cells, complement receptors 1 and 2
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-233024 (URN)10.4049/jimmunol.1400331 (DOI)000341139300019 ()
Available from: 2014-10-06 Created: 2014-09-29 Last updated: 2017-03-08
2. IgG3-Antigen Complexes Are Deposited on Follicular Dendritic Cells in the Presence of C1q and C3
Open this publication in new window or tab >>IgG3-Antigen Complexes Are Deposited on Follicular Dendritic Cells in the Presence of C1q and C3
(English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Other academic) Submitted
Keyword
follicular dendritic cells, C1q, C3, memory response
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-316615 (URN)
Available from: 2017-03-05 Created: 2017-03-05 Last updated: 2017-03-08
3. Mice Producing IgM Unable to Activate Complement Have Impaired Endogenous Feedback Regulation but Increased Antigen Trapping in Follicles
Open this publication in new window or tab >>Mice Producing IgM Unable to Activate Complement Have Impaired Endogenous Feedback Regulation but Increased Antigen Trapping in Follicles
(English)Manuscript (preprint) (Other academic)
Keyword
complement-activating IgM, marginal zone B cells, follicular dendritic cells, antigen trapping
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-310226 (URN)
Available from: 2017-03-05 Created: 2017-03-05 Last updated: 2017-03-08

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