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)
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1255
IgG, IgG3, IgE, suppression, enhancement, epitope masking, antigen transport, antigen presentation, follicular B cells, marginal zone B cells
Immunology Immunology in the medical area
Research subject Immunology
IdentifiersURN: urn:nbn:se:uu:diva-302780ISBN: 978-91-554-9697-5OAI: oai:DiVA.org:uu-302780DiVA: diva2:967648
2016-12-01, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Harris, Helena, Professor
Heyman, Birgitta, Professor
List of papers