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  • 1. Arvola, M
    et al.
    Gustafsson, E
    Svensson, L
    Jansson, L
    Holmdahl, R
    Heyman, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Okabe, M
    Mattsson, R
    Immunoglobulin-secreting cells of maternal origin can be detected in Bcell-deficient mice.2000In: Biol. Reprod., Vol. 63, p. 1817-Article in journal (Refereed)
  • 2.
    Bergman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antigen-Specific IgM Causes Deposition of C3 on Sheep Red Blood Cells Within Seconds After Immunization2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 442-442Article in journal (Other academic)
  • 3.
    Bergström, Joakim J E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11Article in journal (Refereed)
    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.

  • 4.
    Bergström, Joakim J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    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 IgG2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 911Article in journal (Refereed)
    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.

  • 5.
    Bergström, Joakim J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Westin, Annika Grahn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG-Mediated Suppression of Primary IgG Anti-SRBC Responses is not Dependent on Fc gamma R or Complement2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 443-443Article in journal (Other academic)
  • 6.
    Bergström, Joakim J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG-mediated Immune Suppression: Discrepancy between Suppression of Antibody and Germinal Center Responses?2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 210-210Article in journal (Other academic)
  • 7.
    Bergström, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 238Article in journal (Refereed)
    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.

  • 8.
    Carlsson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Getahun, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rutemark, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Impaired antibody responses but normal proliferation of CD4+ T cells in mice lacking complement receptors 1 and 22009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 70, no 2, p. 77-84Article in journal (Refereed)
    Abstract [en]

    Severely impaired Ab responses are seen in animals lacking C   (complement) factors C2, C3 or C4 as well as CR1/2 (C receptors 1 and   2). The molecular mechanism behind this phenomenon is not understood.   One possibility is that C-containing immune complexes are endocytosed   via CR2 on B cells and presented to specific CD4(+) T cells, which   would then proliferate and provide efficient help to specific B cells.   In vitro, B cells can endocytose immune complexes via CR1/2 and present   the Ag to T cells. Whether absence of this Ag presenting function in   Cr2(-/-) mice (mice lacking CR1/2) explains their low Ab response is   unclear. To address this question, Cr2(-/-) and wild type mice were   transferred with OVA-specific T cells, obtained from the DO11.10 strain   which has a transgenic TCR recognizing an OVA peptide. The animals were   subsequently immunized with sheep red blood cells (SRBC) conjugated to   OVA. Interestingly, proliferation of the OVA-specific T cells was   normal in Cr2(-/-) mice, although their Ab response to both SRBC and   OVA was severely impaired. These observations suggest that the impaired   Ab response in Cr2(-/-) mice cannot be explained by a lack of  appropriate induction of T cell help.

  • 9.
    Carlsson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hjelm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Conrad, Daniel H.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    IgE enhances specific antibody and T cell responses in mice overexpressing CD232007In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 66, no 2-3, p. 261-270Article in journal (Refereed)
    Abstract [en]

    IgE administered with its specific antigen in vivo induces enhanced proliferation of specific T cells as well as enhanced production of specific antibodies. Both effects are dependent on the low-affinity receptor for IgE (CD23) and the underlying mechanism is thought to be increased antigen presentation following uptake of IgE/antigen complexes via CD23+ B cells. By contrast, CD23 negatively regulates antibody responses to antigens administered with alum, i.e. without IgE. This effect has been observed as low IgG1 and IgE responses in transgenic mice overexpressing CD23 (CD23Tg). The present study was designed to test whether IgE could enhance antibody and T-cell responses in CD23Tg animals or whether CD23's downregulatory effect precludes IgE-mediated enhancement. IgE-anti-TNP administered with OVA-TNP enhances the OVA-specific antibody responses in wild-type (wt) and CD23Tg mice equally well. Interestingly, the total magnitude of antibody responses to IgE + OVA-TNP and to uncomplexed OVA-TNP, as well as to sheep erythrocytes and keyhole limpet haemocyanine, were lower in the CD23Tg mice. IgE induced proliferation of OVA-specific CD4+ T cells to the same degree in wt and CD23Tg mice. The effect on T cells was dependent on CD23+ B cells as demonstrated in in vitro proliferation assays. In conclusion, CD23 does indeed have dual immunoregulatory effects in the same animal. The receptor mediates enhancement of antibody and T-cell responses to IgE-complexed antigen, most likely via increased presentation of complexed antigen, while it negatively regulates the total antibody response to a variety of antigens.

  • 10.
    Dahlin, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Prospective Isolation of Committed Mast Cell Progenitors from Mouse Blood2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 436-436Article in journal (Other academic)
  • 11.
    Dahlin, Joakim S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Feinstein, Ricardo
    Statens veterinärmedicinska anstalt.
    Cui, Yue
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    CD11c(+) Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung2012In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 189, no 8, p. 3869-3877Article in journal (Refereed)
    Abstract [en]

    Patients with allergic asthma have more lung mast cells, which likely worsens the symptoms. In experimental asthma, CD11c(+) cells have to be present during the challenge phase for several features of allergic inflammation to occur. Whether CD11c(+) cells play a role for Ag-induced increases of lung mast cells is unknown. In this study, we used diphtheria toxin treatment of sensitized CD11c-diphtheria toxin receptor transgenic mice to deplete CD11c(+) cells. We demonstrate that recruitment of mast cell progenitors to the lung is substantially reduced when CD11c(+) cells are depleted during the challenge phase. This correlated with an impaired induction of endothelial VCAM-1 and led to a significantly reduced number of mature mast cells 1 wk after challenge. Collectively, these data suggest that Ag challenge stimulates CD11c(+) cells to produce cytokines and/or chemokines required for VCAM-1 upregulation on the lung endothelium, which in turn is crucial for the Ag-induced mast cell progenitor recruitment and the increase in mast cell numbers.

  • 12.
    Dahlin, Joakim S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Committed mast cell progenitors in mouse blood differ in maturity between Th1 and Th2 strains2013In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no 10, p. 1333-1337Article in journal (Refereed)
    Abstract [en]

    Mast cell progenitors (MCp) leave the bone marrow and migrate to peripheral tissues where they mature. Although the existence of committed MCp in adult mouse and human blood has been postulated, they have never been found. We have isolated a rare population of cells in adult mouse blood, committed to the mast cell lineage. These were identified as lineage c-kithi ST2+ integrin β7hi CD16/32hi cells. Moreover, a major difference in maturity of these cells based on FcεRI expression was observed between the Th2-prone BALB/c strain and the Th1-prone C57BL/6 strain (66% vs 25% FcεRI+, respectively). Therefore, the choice of mouse strain is critical when studying disease models such as experimental asthma where mast cells and their progenitors are involved.

  • 13.
    Dahlin, Joakim S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny Martinsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of committed mast cell progenitors in mouse blood2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, no S1, p. 175-176Article in journal (Other academic)
  • 14.
    Dahlin, Joakim S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ivarsson, Martin A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgE Immune Complexes Stimulate an Increase in Lung Mast Cell Progenitors in a Mouse Model of Allergic Airway Inflammation2011In: PLoS One, ISSN 1932-6203, Vol. 6, no 5, p. e20261-Article in journal (Refereed)
    Abstract [en]

    Mast cell numbers and allergen specific IgE are increased in the lungs of patients with allergic asthma and this can be reproduced in mouse models. The increased number of mast cells is likely due to recruitment of mast cell progenitors that mature in situ. We hypothesized that formation of IgE immune complexes in the lungs of sensitized mice increase the migration of mast cell progenitors to this organ. To study this, a model of allergic airway inflammation where mice were immunized with ovalbumin (OVA) in alum twice followed by three daily intranasal challenges of either OVA coupled to trinitrophenyl (TNP) alone or as immune complexes with IgE-anti-TNP, was used. Mast cell progenitors were quantified by a limiting dilution assay. IgE immune complex challenge of sensitized mice elicited three times more mast cell progenitors per lung than challenge with the same dose of antigen alone. This dose of antigen challenge alone did not increase the levels of mast cell progenitors compared to unchallenged mice. IgE immune complex challenge of sensitized mice also enhanced the frequency of mast cell progenitors per 10 6 mononuclear cells by 2.1-fold. The enhancement of lung mast cell progenitors by IgE immune complex challenge was lost in FcR gamma deficient mice but not in CD23 deficient mice. Our data show that IgE immune complex challenge enhances the number of mast cell progenitors in the lung through activation of an Fc receptor associated with the FcR gamma chain. This most likely takes place via activation of Fc epsilon RI, although activation via Fc gamma RIV or a combination of the two receptors cannot be excluded. IgE immune complex-mediated enhancement of lung MCp numbers is a new reason to target IgE in therapies against allergic asthma.

  • 15.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rutemark, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgM-mediated enhancement of immune responses2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1177-1178Article in journal (Other academic)
  • 16.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rutemark, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ouchida, Rika
    Ohno, Hiroshi
    Wang, Ji-Yang
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Complement-Activating IgM Enhances the Humoral but Not the T Cell Immune Response in Mice2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e81299-Article in journal (Refereed)
    Abstract [en]

    IgM antibodies specific for a certain antigen can enhance antibody responses when administered together with this antigen, a process believed to require complement activation by IgM. However, recent data show that a knock-in mouse strain, C mu 13, which only produces IgM unable to activate complement, has normal antibody responses. Moreover, the recently discovered murine IgM Fc receptor (Fc mu R or TOSO/FAIM3) was shown to affect antibody responses. This prompted the re-investigation of whether complement activation by specific IgM is indeed required for enhancement of antibody responses and whether the mutation in C mu 13 IgM also caused impaired binding to Fc mu R. The results show that IgM from C mu 13 and wildtype mice bound equally well to the murine Fc mu R. In spite of this, specific C mu 13 IgM administered together with sheep red blood cells or keyhole limpet hemocyanine was a very poor enhancer of the antibody and germinal center responses as compared with wildtype IgM. Within seconds after immunization, wildtype IgM induced deposition of C3 on sheep red blood cells in the blood. IgM which efficiently enhanced the T-dependent humoral immune response had no effect on activation of specific CD4+ T cells as measured by cell numbers, cell division, blast transformation, or expression of the activation markers LFA-1 and CD44 in vivo. These observations confirm the importance of complement for the ability of specific IgM to enhance antibody responses and suggest that there is a divergence between the regulation of T-and B-cell responses by IgM.

  • 17.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rutemark, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ouchida, Rika
    Ohno, Hiroshi
    Wang, Ji-Yang
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Divergent Regulation of B and T Cell Responses by Complement-Activating IgM2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 442-442Article in journal (Other academic)
  • 18.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dahlin, Joakim S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 28290Article in journal (Refereed)
    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.

  • 19.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Role of CD23 Expression on Follicular Dendritic Cells in IgE-mediated Enhancement2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 215-215Article in journal (Other academic)
  • 20.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Lu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG3-mediated enhancement of antibody responses is dependent on expression of complement receptors 1 and 22014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 277-278Article in journal (Other academic)
  • 21. Getahun, A
    et al.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Studies on the mechanism by which antigen-specific IgG suppresses primary antibody responses: evidence for epitope masking and decreased localization of antigen in the spleen2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 70, no 3, p. 277-287Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (IgG) has the ability to suppress the Ab response against the Ag to which it binds. Although the mechanism remains unclear, this phenomenon has physiological relevance and is used clinically in Rh prophylaxis. As suppression works well in mice lacking the inhibitory FcgammaRIIB, the two most likely explanations are that IgG masks epitopes and/or that IgG increases the clearance of Ag. In the present study, mice were immunized with sheep red blood cells (SRBC) to which the hapten 5-iodo-4-hydroxyl-3-nitrophenacetyl (NIP) was conjugated at high or low density and the ability of IgG anti-NIP to suppress the Ab response to NIP and SRBC was assayed. Only the NIP-specific response was suppressed when mice were immunized with SRBC-NIP(low), whereas both NIP- and SRBC-specific responses were suppressed when SRBC-NIP(high) was used. This is best explained by epitope masking; at high epitope density, IgG also blocks neighbouring epitopes from recognition by B cells. We also examined the effects of IgG-mediated suppression on T-cell responses directly in vivo. While IgG anti-SRBC administered with sheep red blood cells ovalbumin (SRBC-OVA) almost completely suppressed the anti-SRBC and anti-OVA Ab responses, the OVA-specific T-cell response was still 50% of that observed in control mice. This is probably the result of decreased Ag exposure as IgG-bound SRBC were cleared faster from the bloodstream and were found at lower concentration in the spleen than unbound SRBC. These results suggest that both Ag clearance and epitope masking occurs during IgG-mediated suppression, but that under physiological circumstances epitope masking is the predominant mechanism.

  • 22.
    Getahun, Andrew
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahlström, Jörgen
    Wernersson, Sara
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG2a-mediated enhancement of antibody and T cell responses and its relation to inhibitory and activating Fcγ receptors2004In: Journal of Immunology, Vol. 172, p. 5269-5276Article in journal (Refereed)
  • 23.
    Getahun, Andrew
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Heyman, Birgitta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    How antibodies act as natural adjuvants.2005In: Immunol Lett, ISSN 0165-2478Article in journal (Other scientific)
  • 24. Getahun, Andrew
    et al.
    Hjelm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heyman, Birgitta
    IgE enhances antibody and T cell responses in vivo via CD23+ B cells2005In: Journal of Immunology, Vol. 175, no 3, p. 1473-1482Article in journal (Refereed)
  • 25.
    Getahun, Andrew
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Hjelm, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Heyman, Birgitta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    IgE enhances antibody and T cell responses in vivo via CD23+ B cells.2005In: J Immunol, ISSN 0022-1767, Vol. 175, no 3, p. 1473-82Article in journal (Refereed)
  • 26.
    Getahun, Andrew
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hjelm, Fredrik
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgE enhances antibody responses and T cell activation in vivo: A central role for B cellsManuscript (Other academic)
  • 27.
    Gustafsson, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Calounova, Gabriela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hjelm, Fredrik
    Kriz, Vitezslav
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grönvik, Kjell-Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mostoslavsky, Gustavo
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells2011In: BMC Immunology, ISSN 1471-2172, E-ISSN 1471-2172, Vol. 12, p. 3-Article in journal (Refereed)
    Abstract [en]

    Background: Shb, a ubiquitously expressed Src homology 2 domain-containing adaptor protein has previously been implicated in the signaling of various tyrosine kinase receptors including the TCR. Shb associates with SLP76, LAT and Vav, all important components in the signaling cascade governing T cell function and develeopment. A Shb knockout mouse was recently generated and the aim of the current study was to address the importance of Shb deficiency on T cell development and function.

    Results: Shb knockout mice did not display any major changes in thymocyte development despite an aberrant TCR signaling pattern, including increased basal activation and reduced stimulation-induced phosphorylation. The loss of Shb expression did however affect peripheral CD4+ TH cells resulting in an increased proliferative response to TCR stimulation and an elevated IL-4 production level of naïve TH cells. This suggests a TH2 skewing of the Shb knockout immune system, seemingly caused by an altered TCR signaling pattern.

    Conclusion: Our results indicate that Shb appears to play an important modulating role on TCR signaling, thus regulating the peripheral CD4+ TH2 cell response.

  • 28. Hashimoto, Motomu
    et al.
    Hirota, Keiji
    Yoshitomi, Hiroyuki
    Maeda, Shinji
    Teradaira, Shin
    Akizuki, Shuji
    Prieto-Martin, Paz
    Nomura, Takashi
    Sakaguchi, Noriko
    Koehl, Joerg
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Takahashi, Minoru
    Fujita, Teizo
    Mimori, Tsuneyo
    Sakaguchi, Shimon
    Complement drives Th17 cell differentiation and triggers autoimmune arthritis2010In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, ISSN 20457757, Vol. 207, no 6, p. 1135-1143Article in journal (Refereed)
    Abstract [en]

    Activation of serum complement triggers Th17 cell-dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or beta-glucan, both of which activate serum complement, evoked Th17 cell-mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or beta-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)(-/-) mice but not in C5aR-deficient RAG(-/-) recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.

  • 29.
    Henningsson, F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    B Cell-mediated Antigen Transport to Splenic Follicles2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 1, p. 73-74Article in journal (Refereed)
  • 30.
    Henningsson, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dahlin, Joakim S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Linkevicius, Marius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Grönvik, Kjell-Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgE-Mediated Enhancement of CD4(+) T Cell Responses in Mice Requires Antigen Presentation by CD11c(+) Cells and Not by B Cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e21760-Article in journal (Refereed)
    Abstract [en]

    IgE antibodies, administered to mice together with their specific antigen, enhance antibody and CD4(+) T cell responses to this antigen. The effect is dependent on the low affinity receptor for IgE, CD23, and the receptor must be expressed on B cells. In vitro, IgE-antigen complexes are endocytosed via CD23 on B cells, which subsequently present the antigen to CD4(+) T cells. This mechanism has been suggested to explain also IgE-mediated enhancement of immune responses in vivo. We recently found that CD23(+) B cells capture IgE-antigen complexes in peripheral blood and rapidly transport them to B cell follicles in the spleen. This provides an alternative explanation for the requirement for CD23(+) B cells. The aim of the present study was to determine whether B-cell mediated antigen presentation of IgE-antigen complexes explains the enhancing effect of IgE on immune responses in vivo. The ability of spleen cells, taken from mice 1-4 h after immunization with IgE-antigen, to present antigen to specific CD4(+) T cells was analyzed. Antigen presentation was intact when spleens were depleted of CD19(+) cells (i.e., primarily B cells) but was severely impaired after depletion of CD11c(+) cells (i.e., primarily dendritic cells). In agreement with this, the ability of IgE to enhance proliferation of CD4(+) T cells was abolished in CD11c-DTR mice conditionally depleted of CD11c(+) cells. Finally, the lack of IgE-mediated enhancemen of CD4(+) T cell responses in CD23(-/-) mice could be rescued by transfer of MHC-II-compatible as well as by MHC-II-incompatible CD23(+) B cells. These findings argue against the idea that IgE-mediated enhancement of specific CD4(+) T cell responses in vivo is caused by increased antigen presentation by B cells. A model where CD23(+) B cells act as antigen transporting cells, delivering antigen to CD11c(+) cells for presentation to T cells is consistent with available experimental data.

  • 31.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antibodies as Natural Adjuvants2014In: 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.

  • 32.
    Heyman, Birgitta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Antibody feedback inhibition - a biological principle of immune regulation2005In: Transfusionmedicine and hematology, Vol. 32, p. 348-354Article in journal (Other scientific)
  • 33.
    Hjelm, F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Getahun, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heyman, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Antibody-mediated regulation of the immune response2006In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 64, no 3, p. 177-184Article in journal (Refereed)
    Abstract [en]

    Antibodies administered in vivo together with the antigen they are specific for can regulate the immune response to that antigen. This phenomenon is called antibody-mediated feedback regulation and has been known for over 100 years. Both passively administered and actively produced antibodies exert immunoregulatory functions. Feedback regulation can be either positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. Usually, the response to the entire antigen is up- or downregulated, regardless of which epitope the regulating antibody recognizes. IgG of all isotypes can suppress responses to large particulate antigens like erythrocytes, a phenomenon used clinically in Rhesus prophylaxis. IgG suppression works in mice lacking the known Fc-gamma receptors (FcgammaR) and a likely mechanism of action is epitope masking. IgG1, IgG2a and IgG2b administered together with soluble protein antigens will enhance antibody and CD4+ T-cell responses via activating FcgammaR, probably via increased antigen presentation by dendritic cells. IgG3 as well as IgM also enhance antibody responses but their effects are dependent on their ability to activate complement. A possible mechanism is increased B-cell activation caused by immune complexes co-crosslinking the B-cell receptor with the complement-receptor 2/CD19 receptor complex, known to lower the threshold for B-cell activation. IgE-antibodies enhance antibody and CD4+ T-cell responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, the mechanism probably being increased antigen presentation by CD23+ B cells.

  • 34.
    Hjelm, F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Verbeek, S
    Heyman, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 62, no 5, p. 453-461Article in journal (Refereed)
    Abstract [en]

    Antibodies, administered together with their specific antigen, can feedback-regulate antibody responses to this antigen. IgG1, IgG2a and IgG2b enhance antibody responses to soluble protein antigens. This effect is primarily mediated by FcRs as enhancement is impaired in FcR gamma-/- mice, reported to lack Fc gammaRI and Fc gammaRIII because of deletion of the common FcR gamma chain. Also IgG3 can enhance antibody responses. However, this effect is unperturbed in FcR gamma-/- mice but severely impaired in complement-depleted animals and in animals lacking complement receptor 1 and 2. Although this argues against involvement of Fc gammaRs, FcR gamma-/- mice may express one-fifth of the normal levels of Fc gammaRI and, in addition, Fc gammaRI has been suggested to bind IgG3. We re-investigated the dependence of IgG3-mediated enhancement on Fc gammaRs using a mouse strain selectively lacking Fc gammaRI and found that IgG3-mediated enhancement is completely normal. Unlike IgE and IgG2a, which are both thought to enhance T-cell proliferation via FcR-mediated antigen presentation, IgG3 was a poor enhancer of T-cell proliferation both in vivo and in vitro. These findings argue against a significant involvement of Fc gammaRs in IgG3-mediated enhancement of antibody responses and support our previous conclusion that complement plays a major role.

  • 35.
    Hjelm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, Fredrik
    Verbeek, Sjef
    Heyman, Birgitta
    IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice2005In: Scandinavian Journal of Immunology, Vol. 62, no 5, p. 453-461Article in journal (Refereed)
  • 36. Hjelm, Fredrik
    et al.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Verbeek, Sjef
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgG3-Mediated Enhancement of the Antibody Response is Normal in FcγRI-Deficient Mice2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, Vol. 62, no 5, p. 453-461Article in journal (Refereed)
  • 37.
    Hjelm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Karlsson, Mikael C. I.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A novel B cell-mediated transport of IgE-immune complexes to the follicle of the spleen.2008In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 180, no 10, p. 6604-6610Article in journal (Refereed)
    Abstract [en]

    Ag administered i.v. to mice along with specific IgE or IgG2a induces higher Ab- and CD4(+) T cell responses than Ag administered alone. The IgE effect is completely dependent on the low-affinity receptor for IgE, CD23, whereas the IgG2a effect depends on activating FcgammaRs. In vitro studies suggest that IgE/Ag is presented more efficiently than Ag alone to CD4(+) T cells by CD23(+) B cells and that IgG2a/Ag is presented by FcgammaR(+) dendritic cells (DCs). In this study, we investigate in vivo the early events leading to IgE- and IgG2a-mediated enhancement of immune responses. OVA administered i.v. in PBS in combination with specific IgE binds circulating B cells after 5 min and is found in B cell follicles bound to follicular B cells (CD23(high)) after 30 min. This novel B cell-dependent route of entry is specific for IgE because IgG2a-Ag complexes were trapped in the marginal zone. OVA-specific CD4(+) T cells were found at the T-B border in the T cell zones 12 h after immunization both with IgE/OVA or IgG2a/OVA and proliferated vigorously after 3 days. The findings suggest that IgE- and IgG2a-immune complexes are efficient stimulators of early CD4(+) T cell responses and that Ag bound to IgE has a specific route for transportation into follicles.

  • 38.
    Hjelm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Karlsson, Mikael
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Follicular B cells capture IgE-immune complexes and mediate activation of naïve T cellsManuscript (Other academic)
  • 39. Karlsson, Mikael C.I.
    et al.
    Getahun, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    FcγRIIB in IgG-mediated suppression of antibody responses: Different impact in vivo and in vitro2001In: Journal of Immunology, Vol. 167, p. 5558-5564Article in journal (Refereed)
  • 40.
    Kleinau, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Martinsson, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gustavsson, Susanne
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Importance of CD23 for collagen-induced arthritis: delayed onset and reduced severity in CD23-deficient mice1999In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 162, no 7, p. 4266-4270Article in journal (Refereed)
    Abstract [en]

    Increased expression of the low affinity receptor for IgE, FcepsilonRII/CD23 has been observed in rheumatoid arthritis. In view of this, we have investigated the expression and influence of CD23 in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. CD23+ cells were analyzed in lymph nodes of DBA/1 mice immunized with bovine collagen type II (BCII) in CFA or with CFA only. The percentage of CD23+ lymph node cells was increased in both BCII/CFA- and CFA-immunized mice at 1, 3, and 7 wk after immunization compared with unimmunized mice, indicating a role for the adjuvant to trigger general inflammation and CD23 expression. To investigate the functional role of CD23 in CIA, CD23-deficient mice on the DBA/1 genetic background were studied. After immunization with BCII/CFA, these mice developed CIA with delayed onset and reduced severity compared with wild-type mice. These findings suggest that an increased number of CD23+ cells is part of an inflammatory response and that CD23 expression is of pathogenic importance in the arthritic process.

  • 41. Martin, Rebecca
    et al.
    Brooks, Keith
    Henningson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Brigitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Conrad, Daniel
    IgE enhances B cell-derived exosomal induced T cell proliferation2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, p. P5013-Article in journal (Other academic)
  • 42. Martin, Rebecca K.
    et al.
    Brooks, Keith B.
    Henningsson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Conrad, Daniel H.
    Antigen Transfer from Exosomes to Dendritic Cells as an Explanation for the Immune Enhancement Seen by IgE Immune Complexes2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110609-Article in journal (Refereed)
    Abstract [en]

    IgE antigen complexes induce increased specific T cell proliferation and increased specific IgG production. Immediately after immunization, CD23(+) B cells capture IgE antigen complexes, transport them to the spleen where, via unknown mechanisms, dendritic cells capture the antigen and present it to T cells. CD23, the low affinity IgE receptor, binds IgE antigen complexes and internalizes them. In this study, we show that these complexes are processed onto B-cell derived exosomes (bexosomes) in a CD23 dependent manner. The bexosomes carry CD23, IgE and MHC II and stimulate antigen specific T-cell proliferation in vitro. When IgE antigen complex stimulated bexosomes are incubated with dendritic cells, dendritic cells induce specific T-cell proliferation in vivo, similar to IgE antigen complexes. This suggests that bexosomes can provide the essential transfer mechanism for IgE antigen complexes from B cells to dendritic cells.

  • 43.
    Rutemark, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alicot, Elisabeth
    Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, USA.
    Bergman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ma, Minghe
    Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, USA.
    Getahun, Andrew
    Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, USA.
    Ellmerich, Stephan
    Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
    Carroll, Michael
    Immune Disease Institute and Program in Cellular and Molecular Medicine, Children’s Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, USA.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Requirement for complement in antibody responses is not explained by the classic pathway activator IgM2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 43, p. 17589-17590Article in journal (Refereed)
    Abstract [en]

    Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen-Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

  • 44.
    Rutemark, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Getahun, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henningsson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Complement receptors 1 and 2 in murine antibody responses to IgM-complexed and uncomplexed sheep erythrocytes2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41968-Article in journal (Refereed)
    Abstract [en]

    Early complement components are important for normal antibody responses. In this process, complement receptors 1 and 2 (CR1/2), expressed on B cells and follicular dendritic cells (FDCs) in mice, play a central role. Complement-activating IgM administered with the antigen it is specific for, enhances the antibody response to this antigen. Here, bone marrow chimeras between Cr2(-/-) and wildtype mice were used to analyze whether FDCs or B cells must express CR1/2 for antibody responses to sheep erythrocytes (SRBC), either administered alone or together with specific IgM. For robust IgG anti-SRBC responses, CR1/2 must be expressed on FDCs. Occasionally, weak antibody responses were seen when only B cells expressed CR1/2, probably reflecting extrafollicular antibody production enabled by co-crosslinking of CR2/CD19/CD81 and the BCR. When SRBC alone was administered to mice with CR1/2(+) FDCs, B cells from wildtype and Cr2(-/-) mice produced equal amounts of antibodies. Most likely antigen is then deposited on FDCs in a way that optimizes engagement of the B cell receptor, making CR2-facilitated signaling to the B cell superfluous. SRBC bound to IgM will have more C3 fragments, the ligands for CR1/2, on their surface than SRBC administered alone. Specific IgM, forming a complex with SRBC, enhances antibody responses in two ways when FDCs express CR1/2. One is dependent on CR1/2(+) B cells and probably acts via increased transport of IgM-SRBC-complement complexes bound to CR1/2 on marginal zone B cells. The other is independent on CR1/2(+) B cells and the likely mechanism is that IgM-SRBC-complement complexes bind better to FDCs than SRBC administered alone. These observations suggest that the immune system uses three different CR1/2-mediated effector functions to generate optimal antibody responses: capture by FDCs (playing a dominant role), transport by marginal zone B cells and enhanced B cell signaling.

  • 45.
    Sörman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Specific IgM and Regulation of Antibody Responses2017In: 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.

  • 46.
    Sörman, Anna Rolfsdotter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rutemark, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Enhancement of antibody responses by endogenous (complement activating) IgM2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 185-186Article in journal (Other academic)
  • 47.
    Sörman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Westin, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgM is Unable to Enhance Antibody Responses in Mice Lacking C1q or C32017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 85, no 5, p. 381-382Article in journal (Refereed)
  • 48.
    Sörman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Lu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    How antibodies use complement to regulate antibody responses2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 79-88Article, review/survey (Refereed)
    Abstract [en]

    Antibodies, forming immune complexes with their specific antigen, can cause complete suppression or several 100-fold enhancement of the antibody response. Immune complexes containing IgG and IgM may activate complement and in such situations also complement components will be part of the immune complex. Here, we review experimental data on how antibodies via the complement system upregulate specific antibody responses. Current data suggest that murine IgG1, IgG2a, and IgG2b upregulate antibody responses primarily via Fc-receptors and not via complement. In contrast, IgM and IgG3 act via complement and require the presence of complement receptors 1 and 2 (CR1/2) expressed on both B cells and follicular dendritic cells. Complement plays a crucial role for antibody responses not only to antigen complexed to antibodies, but also to antigen administered alone. Lack of C1q, but not of Factor B or MBL, severely impairs antibody responses suggesting involvement of the classical pathway. In spite of this, normal antibody responses are found in mice lacking several activators of the classical pathway (complement activating natural IgM, serum amyloid P component (SAP), specific intracellular adhesion molecule-grabbing non-integrin R1 (SIGN-R1) or C-reactive protein. Possible explanations to these observations will be discussed.

  • 49.
    Xu, Hui
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechelen, Lenny
    Henningsson, Frida
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anti-CD23-Antigen Conjugates Localize Antigen to Splenic Follicles and Enhance Specific Ab Response2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 443-443Article in journal (Other academic)
  • 50.
    Xu, Hui
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechelen, Lennyvan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henningsson, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anti-CD23-antigen Conjugates Localize Antigen to Splenic Follicles and Enhance Specific Ab Response2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 238-238Article in journal (Other academic)
12 1 - 50 of 56
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