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Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking
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.
2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, 238Article in journal (Refereed) Published
Abstract [en]

Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBCs) is intact in mice lacking Fc gamma Rs, complement factor 1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG-antigen complexes and/or that IgG "hides" the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extrafollicular antibody-secreting cells, germinal center B-cells, longlived plasma cells, long-term IgG responses, and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type, but not of Fc gamma R-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead, we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP, but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.

Place, publisher, year, edition, pages
2017. Vol. 8, 238
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-317472DOI: 10.3389/fimmu.2017.00238ISI: 000395546800001PubMedID: 28321225OAI: oai:DiVA.org:uu-317472DiVA: diva2:1081849
Funder
Swedish Research Council
Available from: 2017-03-15 Created: 2017-03-15 Last updated: 2017-11-29Bibliographically approved
In thesis
1. A Search for the Masked Mechanism Behind IgG-Mediated Suppression of Antibody Responses
Open this publication in new window or tab >>A Search for the Masked Mechanism Behind IgG-Mediated Suppression of Antibody Responses
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibodies passively administered together with their specific antigen can enhance or suppress the specific antibody response. This phenomenon is known as antibody feedback regulation. Whether this modulation causes up- or downregulation of the antibody response depends both on the antibody isotype and the antigen used. IgG antibodies passively administered together with particulate antigens, e.g. erythrocytes, can completely prevent the induction of an antibody response to the antigen. The suppressive capacity of IgG has been routinely used in the clinic since the 1960’s in RhD-prophylaxis to prevent hemolytic disease of the fetus and newborn. Although studied for decades, the underlying mechanism of IgG-suppression has remained elusive. The main focus of this thesis has been to elucidate the mechanism behind IgG-suppression of antibody responses in vivo in mouse models using intravenous immunization with specific IgG together with native or haptenated sheep red blood cells, SRBC. We show that IgG-suppression of IgM and long-term serum IgG-responses operates independently of activating FcγRI, III, IV, or the inhibitory FcγRIIB, thus confirming and extending previous findings. Moreover, we demonstrate for the first time that C1q, C3 and CR1/2 are dispensable for IgG-suppression of antibody responses. These findings strongly argue against the involvement of Fc-dependent mechanisms as the explanation for IgG-suppression. Interestingly, GC formation occurs in IgG-suppressed mice although the antibody response to surface SRBC epitopes are completely suppressed. The data suggests that these GCs develop in response to intracellular SRBC epitopes as well as to the passively administered suppressive IgG. Moreover, we demonstrate that passively administered IgG suppresses several parameters of an antibody/B cell response including antigen specific GC and non-GC B cells, extra-follicular antibody secreting cells, long-lived plasma cells and induction of immunological memory. Before the onset of the present study, two mechanisms appeared compatible with the majority of experimental findings: IgG-mediated antigen clearance and epitope masking. Herein we show that the contribution of IgG-mediated antigen clearance is negligible and that suppression of IgG-responses is strictly epitope specific. This provides compelling evidence that a very important mechanism underlying IgG-suppression is epitope masking.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1315
Keyword
FcγR, complement, sheep erythrocytes, IgG-mediated immune suppression, rhesus prophylaxis, rhesus D antigen, germinal center
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-317480 (URN)978-91-554-9853-5 (ISBN)
Public defence
2017-05-11, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2017-04-13 Created: 2017-03-16 Last updated: 2017-04-21

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Bergström, JoakimXu, HuiHeyman, Birgitta

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