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Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic 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.
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.

Place, publisher, year, edition, pages
2014. Vol. 193, no 4, 1681-1689 p.
Keyword [en]
antigen transport, marginal zone B cells, complement receptors 1 and 2
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-233024DOI: 10.4049/jimmunol.1400331ISI: 000341139300019OAI: oai:DiVA.org:uu-233024DiVA: diva2:752885
Available from: 2014-10-06 Created: 2014-09-29 Last updated: 2017-12-05
In thesis
1. Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies
Open this publication in new window or tab >>Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibodies can enhance or suppress the immune responses against their specific antigens. This phenomenon is known as antibody-mediated feedback regulation. We have studied the mechanisms underlying IgE-, IgM-, and IgG3-mediated enhancement of immune responses in mouse models using intravenous immunization. We attempted to answer the following questions: 1) Which cell type presents IgE-complexed antigens to CD4+ T cells? 2) Is complement activation required for specific IgM to enhance antibody responses? 3) Does IgM enhance CD4+ T-cell responses? 4) How are IgG3-antigen complexes transported into B-cell follicles?

We found that CD23+ B cells transporting IgE-antigen complexes into B-cell follicles were not required to prime the antigen-specific CD4+ T cells in vivo, whereas CD11c+ cells were indispensable. After examining the three most common subpopulations of CD11c+ cells in the spleen, we determined that it was CD8α- conventional dendritic cells migrating into the T-cell zone following immunization that presented IgE-complexed antigens to CD4+ T cells.

Next, we showed that specific IgM from Cµ13 mice, which is unable to activate complement, failed to enhance either antibody or germinal center responses whereas wild-type IgM enhanced both responses. Therefore, specific IgM must activate complement to enhance humoral responses. In addition, wild-type IgM did not up-regulate CD4+ T-cell responses.

Finally, we showed that IgG3-antigen complexes were transported by marginal zone B cells into B-cell follicles via binding to complement receptors 1 and 2 (CR1/2) on those cells. The immune complexes were captured by follicular dendritic cells as early as 2 h after immunization. Germinal center responses were also enhanced by IgG3. Using bone marrow chimeric mice, we found that CR1/2 expression was required on both marginal zone B cells and follicular dendritic cells to provide an optimal enhancement of antibody responses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1061
Keyword
IgE, IgM, IgG3, antibody responses, T-cell responses, antigen transportation, antigen presentation, complement, complement receptors 1 and 2
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-237337 (URN)978-91-554-9129-1 (ISBN)
Public defence
2015-02-12, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-01-19 Created: 2014-12-01 Last updated: 2015-03-09Bibliographically approved
2. Modulation of B cell access to antigen by passively administered antibodies: an explanation for antibody feedback regulation?
Open this publication in new window or tab >>Modulation of B cell access to antigen by passively administered antibodies: an explanation for antibody feedback regulation?
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibody responses can be up- or down-regulated by passive administration of specific antibody together with antigen. Depending on the structure of the antigen and the antibody isotype, responses can be completely suppressed or enhanced up to a 1000-fold of what is seen in animals immunized with antigen alone.

IgG suppresses primary antibody responses against erythrocytes. Suppression works well in mice lacking Fc-receptors for IgG, C1q, C3, or complement receptor 1 and 2 (CR1/2). Here, we demonstrate that IgG anti-NP given to mice together with NP-conjugated sheep erythrocytes, suppresses the generation of NP-specific extra-follicular antibody-secreting cells, NP-specific germinal center B cells, induction of memory and long-lived plasma cells. IgG increases antigen clearance but this does not explain the suppressed antibody response. It is demonstrated that IgG-mediated suppression of IgG responses is epitope specific, suggesting that epitope masking is the dominant explanation for IgG-mediated suppression of antibody responses.

Both IgE and IgG3 can enhance antibody responses against soluble antigens. IgE-antigen complexes bind to recirculating B cells expressing CD23, an Fc-receptor for IgE.  Thirty minutes after intravenous administration, IgE-antigen is found in splenic follicles. Subsequently, germinal center responses, antigen-specific T cell proliferation, and antibody responses are enhanced. We show that also antigen conjugated to anti-CD23 can bind to CD23+ B cells and be transported to splenic follicles. CD11+ spleen cells, rather than CD23+ B cells, present IgE-antigen complexes to T cells. Here, it is demonstrated that CD8α conventional dendritic cells is the CD11c+ cell population presenting IgE-antigen to T cells.

IgG3-mediated enhancement is dependent on CR1/2. We find that IgG3-antigen complexes, administered intravenously to mice, bind to marginal zone B cells via CR1/2. These cells then transport IgG3-antigen into splenic follicles and deposit antigen onto follicular dendritic cells. Mice treated with FTY720, a drug which dislocates marginal zone B cells from the marginal zone, impairs this transport. Studies in bone marrow chimeric mice show that CR1/2 on both B cells and follicular dendritic cells are crucial for IgG3-mediated enhancement.

In summary, these observations suggest that antibodies can feedback regulate antibody responses by modulating the access of antigen to the immune system. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1255
Keyword
IgG, IgG3, IgE, suppression, enhancement, epitope masking, antigen transport, antigen presentation, follicular B cells, marginal zone B cells
National Category
Immunology Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-302780 (URN)978-91-554-9697-5 (ISBN)
Public defence
2016-12-01, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-09 Created: 2016-09-09 Last updated: 2016-11-16
3. 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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Zhang, LuDing, ZhoujieXu, HuiHeyman, Birgitta

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