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Modulation of B cell access to antigen by passively administered antibodies: an explanation for antibody feedback regulation?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Birgitta Heyman)
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 [en]
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: urn:nbn:se:uu:diva-302780ISBN: 978-91-554-9697-5OAI: oai:DiVA.org:uu-302780DiVA: diva2:967648
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
List of papers
1. IgG-mediated suppression of IgG responses to erythrocytes is epitope specific
Open this publication in new window or tab >>IgG-mediated suppression of IgG responses to erythrocytes is epitope specific
(English)Manuscript (preprint) (Other academic)
Keyword
IgG-mediated suppression, antibody, B cell
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-302596 (URN)
External cooperation:
Available from: 2016-09-07 Created: 2016-09-07 Last updated: 2016-09-09
2. Antigen Conjugated to Anti-CD23 Antibodies is Rapidly Transported to Splenic Follicles by Recirculating B Cells
Open this publication in new window or tab >>Antigen Conjugated to Anti-CD23 Antibodies is Rapidly Transported to Splenic Follicles by Recirculating B Cells
2015 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 1, 39-45 p.Article in journal (Refereed) Published
Abstract [en]

IgE-antigen complexes, administered intravenously to mice, induce a several 100-fold higher specific antibody response than antigen alone. Additionally, in vivo activation and proliferation of specific CD4(+) T cells is enhanced. The mechanism behind these effects is thought to be that peripheral B cells capture IgE-antigen complexes via their low-affinity receptor for IgE, CD23, and rapidly transport them to splenic B cell follicles where an immune response is initiated. Here, we demonstrate that ovalbumin, covalently coupled to anti-CD23 antibodies and administered intravenously to mice, is also transported to splenic follicles and induces an enhanced primary antibody response. These effects are absent in CD23-deficient mice. No enhanced induction of immunological memory was observed. These findings extend previous observations regarding the in vivo role of CD23 and emphasize that recirculating B cells play an important role in antigen transport to the spleen.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-242386 (URN)10.1111/sji.12248 (DOI)000346771300006 ()
Available from: 2015-01-26 Created: 2015-01-26 Last updated: 2016-09-09Bibliographically approved
3. IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells
Open this publication in new window or tab >>IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 28290Article in journal (Refereed) Published
Abstract [en]

IgE, forming an immune complex with small proteins, can enhance the specific antibody and CD4(+) T cell responses in vivo. The effects require the presence of CD23 (Fc epsilon-receptor II)(+) B cells, which capture IgE-complexed antigens (Ag) in the circulation and transport them to splenic B cell follicles. In addition, also CD11c(+) cells, which do not express CD23, are required for IgE-mediated enhancement of T cell responses. This suggests that some type of dendritic cell obtains IgE-Ag complexes from B cells and presents antigenic peptides to T cells. To elucidate the nature of this dendritic cell, mice were immunized with ovalbumin (OVA)-specific IgE and OVA, and different populations of CD11c(+) cells, obtained from the spleens four hours after immunization, were tested for their ability to present OVA. CD8 alpha(-) conventional dendritic cells (cDCs) were much more efficient in inducing specific CD4(+) T cell proliferation ex vivo than were CD8 alpha(+) cDCs or plasmacytoid dendritic cells. Thus, IgE-Ag complexes administered intravenously are rapidly transported to the spleen by recirculating B cells where they are delivered to CD8 alpha(-) cDCs which induce proliferation of CD4(+) T cells.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-299721 (URN)10.1038/srep28290 (DOI)000378108400001 ()27306570 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2016-09-09Bibliographically approved
4. 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.

National Category
Immunology in the medical area
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: 2016-09-09Bibliographically approved

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