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Heyman, Birgitta
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Publications (10 of 56) Show all publications
Bergström, J., Xu, H. & Heyman, B. (2017). Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking. Frontiers in Immunology, 8, Article ID 238.
Open this publication in new window or tab >>Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking
2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 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.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-317472 (URN)10.3389/fimmu.2017.00238 (DOI)000395546800001 ()28321225 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-03-15 Created: 2017-03-15 Last updated: 2018-01-13Bibliographically approved
Zhang, L., Ding, Z. & Heyman, B. (2017). IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C3. Scientific Reports, 7, Article ID 5400.
Open this publication in new window or tab >>IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C3
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5400Article in journal (Refereed) Published
Abstract [en]

IgG3, passively administered together with small proteins, induces enhanced primary humoral responses against these proteins. We previously found that, within 2 h of immunization, marginal zone (MZ) B cells capture IgG3-antigen complexes and transport them into splenic follicles and that this requires the presence of complement receptors 1 and 2. We have here investigated the localization of IgG3 anti-2, 4, 6-trinitrophenyl (TNP)/biotin-ovalbumin-TNP immune complexes in the follicles and the involvement of classical versus total complement activation in this process. The majority (50-90%) of antigen inside the follicles of mice immunized with IgG3-antigen complexes co-localized with the follicular dendritic cell (FDC) network. Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3, and lack of either C1q or C3 also impaired the ability of IgG3 to enhance antibody responses. Finally, IgG3 efficiently primed for a memory response against small proteins as well as against the large protein keyhole limpet hemocyanine.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-333611 (URN)10.1038/s41598-017-05704-3 (DOI)000405464200037 ()28710441 (PubMedID)
Funder
Swedish Research CouncilKing Gustaf V Jubilee Fund
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2017-11-16Bibliographically approved
Sörman, A., Westin, A. & Heyman, B. (2017). IgM is Unable to Enhance Antibody Responses in Mice Lacking C1q or C3 [Letter to the editor]. Scandinavian Journal of Immunology, 85(5), 381-382
Open this publication in new window or tab >>IgM is Unable to Enhance Antibody Responses in Mice Lacking C1q or C3
2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 85, no 5, p. 381-382Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-328827 (URN)10.1111/sji.12540 (DOI)000400011500008 ()28218951 (PubMedID)
Available from: 2017-11-01 Created: 2017-11-01 Last updated: 2018-01-13Bibliographically approved
Bergström, J. J. E. & Heyman, B. (2017). Mice Immunized With IgG Anti-Sheep Red Blood Cells (SRBC) Together With SRBC Have a Suppressed Anti-SRBC Antibody Response but Generate Germinal Centers and Anti-IgG Antibodies in Response to the Passively Administered IgG. Frontiers in Immunology, 8, Article ID 911.
Open this publication in new window or tab >>Mice Immunized With IgG Anti-Sheep Red Blood Cells (SRBC) Together With SRBC Have a Suppressed Anti-SRBC Antibody Response but Generate Germinal Centers and Anti-IgG Antibodies in Response to the Passively Administered IgG
2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 911Article in journal (Refereed) Published
Abstract [en]

Antigen-specific IgG antibodies, passively administered together with large particulate antigens such as erythrocytes, can completely suppress the antigen-specific antibody response. The mechanism behind has been elusive. Herein, we made the surprising observation that mice immunized with IgG anti-sheep red blood cells (SRBC) and SRBC, in spite of a severely suppressed anti-SRBC response, have a strong germinal center (GC) response. This occurred regardless of whether the passively administered IgG was of the same allotype as that of the recipient or not. Six days after immunization, the GC size and the number of GC B cells were higher in mice immunized with SRBC alone than in mice immunized with IgG and SRBC, but at the other time points these parameters were similar. GCs in the IgG-groups had a slight shift toward dark zone B cells 6 days after immunization and toward light zone B cells 10 days after immunization. The proportions of T follicular helper cells (TFH) and T follicular regulatory cells (TFR) were similar in the two groups. Interestingly, mice immunized with allogeneic IgG anti-SRBC together with SRBC mounted a vigorous antibody response against the passively administered suppressive IgG. Thus, although their anti-SRBC response was almost completely suppressed, an antibody response against allogeneic, and probably also syngeneic, IgG developed. This most likely explains the development of GCs in the absence of an anti-SRBC antibody response.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2017
Keywords
sheep erythrocytes, IgG-mediated immune suppression, rhesus prophylaxis, germinal center, rheumatoid factor
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-334052 (URN)10.3389/fimmu.2017.00911 (DOI)000406886900001 ()28824636 (PubMedID)
Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2017-11-29Bibliographically approved
Sörman, A. & Heyman, B. (2017). Specific IgM and Regulation of Antibody Responses. In: Hiromi Kubagawa, Peter D. Burrows (Ed.), IgM and Its Receptors and Binding Proteins: (pp. 67-87). Springer Berlin/Heidelberg
Open this publication in new window or tab >>Specific IgM and Regulation of Antibody Responses
2017 (English)In: IgM and Its Receptors and Binding Proteins / [ed] Hiromi Kubagawa, Peter D. Burrows, Springer Berlin/Heidelberg, 2017, p. 67-87Chapter in book (Refereed)
Abstract [en]

Specific IgM, administered together with the antigen it recognizes, enhances primary antibody responses, formation of germinal centers, and priming for secondary antibody responses. The response to all epitopes on the antigen to which IgM binds is usually enhanced. IgM preferentially enhances responses to large antigens such as erythrocytes, malaria parasites, and keyhole limpet hemocyanine. In order for an effect to be seen, antigens must be administered in suboptimal concentrations and in close temporal relationship to the IgM. Enhancement is dependent on the ability of IgM to activate complement, but the lytic pathway is not required. Enhancement does not take place in mice lacking complement receptors 1 and 2 (CR1/2) suggesting that the role of IgM is to generate C3 split products, i.e., the ligands for CR1/2. In mice, these receptors are expressed on follicular dendritic cells (FDCs) and B cells. Optimal IgM-mediated enhancement requires that both cell types express CR1/2, but intermediate enhancement is seen when only FDCs express the receptors and low enhancement when only B cells express them. These observations imply that IgM-mediated enhancement works through several, non-mutually exclusive, pathways. Marginal zone B cells can transport IgM-antigen-complement complexes, bound to CR1/2, from the marginal zone and deposit them onto FDCs. In addition, co-crosslinking of the BCR and the CR2/CD19/CD81 co-receptor complex may enhance signaling to specific B cells, a mechanism likely to be involved in induction of early extrafollicular antibody responses.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2017
Series
Current Topics in Microbiology and Immunology, ISSN 0070-217X ; 408
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-346587 (URN)10.1007/82_2017_24 (DOI)000413935700005 ()28643202 (PubMedID)978-3-319-64526-1 (ISBN)978-3-319-64524-7 (ISBN)
Available from: 2018-03-21 Created: 2018-03-21 Last updated: 2018-03-21Bibliographically approved
Ding, Z., Dahlin, J. S., Xu, H. & Heyman, B. (2016). IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells. Scientific Reports, 6, Article ID 28290.
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, article id 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: 2018-01-10Bibliographically approved
Xu, H., van Mechelen, L., Henningsson, F. & Heyman, B. (2015). Antigen Conjugated to Anti-CD23 Antibodies is Rapidly Transported to Splenic Follicles by Recirculating B Cells. Scandinavian Journal of Immunology, 81(1), 39-45
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, p. 39-45Article 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: 2018-01-11Bibliographically approved
Sörman, A. R., Rutemark, C. & Heyman, B. (2015). Enhancement of antibody responses by endogenous (complement activating) IgM. Paper presented at 15th European Meeting on Complement in Human Disease (EMCHD), JUN 27-30, 2015, Uppsala, SWEDEN. Molecular Immunology, 67(1), 185-186
Open this publication in new window or tab >>Enhancement of antibody responses by endogenous (complement activating) IgM
2015 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 185-186Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-261053 (URN)000357144100204 ()
Conference
15th European Meeting on Complement in Human Disease (EMCHD), JUN 27-30, 2015, Uppsala, SWEDEN
Available from: 2015-09-01 Created: 2015-08-28 Last updated: 2018-01-11Bibliographically approved
Bergström, J. J. & Heyman, B. (2015). IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors.. PLoS ONE, 10(11)
Open this publication in new window or tab >>IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors.
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11Article in journal (Refereed) Published
Abstract [en]

Antigen-specific IgG antibodies, passively administered to mice or humans together with large particulate antigens like erythrocytes, can completely suppress the antibody response against the antigen. This is used clinically in Rhesus prophylaxis, where administration of IgG anti-RhD prevents RhD-negative women from becoming immunized against RhD-positive fetal erythrocytes aquired transplacentally. The mechanisms by which IgG suppresses antibody responses are poorly understood. We have here addressed whether complement or Fc-receptors for IgG (FcγRs) are required for IgG-mediated suppression. IgG, specific for sheep red blood cells (SRBC), was administered to mice together with SRBC and the antibody responses analyzed. IgG was able to suppress early IgM- as well as longterm IgG-responses in wildtype mice equally well as in mice lacking FcγRIIB (FcγRIIB knockout mice) or FcγRI, III, and IV (FcRγ knockout mice). Moreover, IgG was able to suppress early IgM responses equally well in mice lacking C1q (C1qA knockout mice), C3 (C3 knockout mice), or complement receptors 1 and 2 (Cr2 knockout mice) as in wildtype mice. Owing to the previously described severely impaired IgG responses in the complement deficient mice, it was difficult to assess whether passively administered IgG further decreased their IgG response. In conclusion, Fc-receptor binding or complement-activation by IgG does not seem to be required for its ability to suppress antibody responses to xenogeneic erythrocytes.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-270784 (URN)10.1371/journal.pone.0143841 (DOI)000365889800078 ()26619292 (PubMedID)
Funder
Swedish Research Council, K2012-57X-07492-25-6
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2018-01-10Bibliographically approved
Heyman, B. (2014). Antibodies as Natural Adjuvants. In: FC RECEPTORS: (pp. 201-219).
Open this publication in new window or tab >>Antibodies as Natural Adjuvants
2014 (English)In: FC RECEPTORS, 2014, p. 201-219Chapter in book (Refereed)
Abstract [en]

Antibodies in complex with specific antigen can dramatically change the antibody response to this antigen. Depending on antibody class and type of antigen, >99 % suppression or >100-fold enhancement of the response can take place. IgM and IgG3 are efficient enhancers and operate via the complement system. In contrast, IgG1, IgG2a, and IgG2b enhance antibody and CD4(+) T cell responses to protein antigens via activating Fc gamma-receptors. IgE also enhances antibody and CD4(+) T cell responses to small proteins but uses the low-affinity receptor for IgE, CD23. Most likely, IgM and IgG3 work by increasing the effective concentration of antigen on follicular dendritic cells in splenic follicles. IgG1, IgG2a, IgG2b, and IgE probably enhance antibody responses by increasing antigen presentation by dendritic cells to T helper cells. IgG antibodies of all subclasses have a dual effect, and suppress antibody responses to particulate antigens such as erythrocytes. This capacity is used in the clinic to prevent immunization of Rhesus-negative women to Rhesus-positive fetal erythrocytes acquired via transplacental hemorrage. IgG-mediated suppression in mouse models can take place in the absence of Fc gamma-receptors and complement and to date no knock-out mouse strain has been found where suppression is abrogated.

Series
Current Topics in Microbiology and Immunology, ISSN 0070-217X ; 382
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-247741 (URN)10.1007/978-3-319-07911-0_9 (DOI)000348980000010 ()25116101 (PubMedID)978-3-319-07911-0 (ISBN)978-3-319-07910-3 (ISBN)
Available from: 2015-03-23 Created: 2015-03-23 Last updated: 2018-01-11Bibliographically approved
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