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  • 1.
    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)
  • 2.
    Dahlin, Joakim S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden..
    Ding, Zhoujie
    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.
    Distinguishing Mast Cell Progenitors from Mature Mast Cells in Mice2015In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 14, p. 1703-1711Article in journal (Refereed)
    Abstract [en]

    Mast cells originate from the bone marrow and develop into c-kit(+) FcRI(+) cells. Both mast cell progenitors (MCp) and mature mast cells express these cell surface markers, and ways validated to distinguish between the two maturation forms with flow cytometry have been lacking. Here, we show that primary peritoneal MCp from naive mice expressed high levels of integrin 7 and had a low side scatter (SSC) light profile; whereas mature mast cells expressed lower levels of integrin 7 and had a high SSC light profile. The maturation statuses of the cells were confirmed using three main strategies: (1) MCp, but not mature mast cells, were shown to be depleted by sublethal whole-body -irradiation. (2) The MCp were small and immature in terms of granule formation, whereas the mature mast cells were larger and had fully developed metachromatic granules. (3) The MCp had fewer transcripts of mast cell-specific proteases and the enzyme responsible for sulfation of heparin than mature mast cells. Moreover, isolated peritoneal MCp gave rise to mast cells when cultured in vitro. To summarize, we have defined MCp and mature mast cells in naive mice by flow cytometry. Using this strategy, mast cell maturation can be studied in vivo.

  • 3.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibodies can enhance or suppress the immune responses against their specific antigens. This phenomenon is known as antibody-mediated feedback regulation. We have studied the mechanisms underlying IgE-, IgM-, and IgG3-mediated enhancement of immune responses in mouse models using intravenous immunization. We attempted to answer the following questions: 1) Which cell type presents IgE-complexed antigens to CD4+ T cells? 2) Is complement activation required for specific IgM to enhance antibody responses? 3) Does IgM enhance CD4+ T-cell responses? 4) How are IgG3-antigen complexes transported into B-cell follicles?

    We found that CD23+ B cells transporting IgE-antigen complexes into B-cell follicles were not required to prime the antigen-specific CD4+ T cells in vivo, whereas CD11c+ cells were indispensable. After examining the three most common subpopulations of CD11c+ cells in the spleen, we determined that it was CD8α- conventional dendritic cells migrating into the T-cell zone following immunization that presented IgE-complexed antigens to CD4+ T cells.

    Next, we showed that specific IgM from Cµ13 mice, which is unable to activate complement, failed to enhance either antibody or germinal center responses whereas wild-type IgM enhanced both responses. Therefore, specific IgM must activate complement to enhance humoral responses. In addition, wild-type IgM did not up-regulate CD4+ T-cell responses.

    Finally, we showed that IgG3-antigen complexes were transported by marginal zone B cells into B-cell follicles via binding to complement receptors 1 and 2 (CR1/2) on those cells. The immune complexes were captured by follicular dendritic cells as early as 2 h after immunization. Germinal center responses were also enhanced by IgG3. Using bone marrow chimeric mice, we found that CR1/2 expression was required on both marginal zone B cells and follicular dendritic cells to provide an optimal enhancement of antibody responses.

    List of papers
    1. IgE-Mediated Enhancement of CD4(+) T Cell Responses in Mice Requires Antigen Presentation by CD11c(+) Cells and Not by B Cells
    Open this publication in new window or tab >>IgE-Mediated Enhancement of CD4(+) T Cell Responses in Mice Requires Antigen Presentation by CD11c(+) Cells and Not by B Cells
    Show others...
    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e21760-Article in journal (Refereed) Published
    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.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-156628 (URN)10.1371/journal.pone.0021760 (DOI)000292632000024 ()21765910 (PubMedID)
    Available from: 2011-08-04 Created: 2011-08-04 Last updated: 2018-01-12Bibliographically approved
    2. CD8αconventional dendritic cells are the dominant cells presenting IgE-complexed Ag to CD4+ T cells
    Open this publication in new window or tab >>CD8αconventional dendritic cells are the dominant cells presenting IgE-complexed Ag to CD4+ T cells
    (English)Manuscript (preprint) (Other academic)
    Keywords
    IgE, dendritic cells, antigen presentation, T cells
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-237336 (URN)
    Available from: 2014-12-01 Created: 2014-12-01 Last updated: 2018-01-11
    3. Complement-Activating IgM Enhances the Humoral but Not the T Cell Immune Response in Mice
    Open this publication in new window or tab >>Complement-Activating IgM Enhances the Humoral but Not the T Cell Immune Response in Mice
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e81299-Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-213930 (URN)10.1371/journal.pone.0081299 (DOI)000327216200119 ()
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2017-12-06Bibliographically approved
    4. Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles
    Open this publication in new window or tab >>Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles
    2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 4, p. 1681-1689Article in journal (Refereed) Published
    Abstract [en]

    Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2(+) MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23.

    Keywords
    antigen transport, marginal zone B cells, complement receptors 1 and 2
    National Category
    Immunology in the medical area
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-233024 (URN)10.4049/jimmunol.1400331 (DOI)000341139300019 ()
    Available from: 2014-10-06 Created: 2014-09-29 Last updated: 2018-01-11
  • 4.
    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)
  • 5.
    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.

  • 6.
    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)
  • 7.
    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.

  • 8.
    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)
  • 9.
    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)
  • 10.
    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)
  • 11.
    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.

  • 12.
    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.

  • 13. Thyagarajan, Radha
    et al.
    Banday, Viqar
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lejon, Kristina
    Contribution of autoallergy to the pathogenesis in the NOD mice2015In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 48, no 5, p. 298-304Article in journal (Refereed)
    Abstract [en]

    The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

  • 14.
    Zhang, Lu
    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.
    IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C32017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5400Article in journal (Refereed)
    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.

  • 15.
    Zhang, Lu
    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.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henningsson, Frida
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    MZ B Cells Transport IgG3-Ag to Splenic Follicles and Induce Germinal Centres2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 442-443Article in journal (Other academic)
  • 16.
    Zhang, Lu
    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.
    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.
    Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 4, p. 1681-1689Article in journal (Refereed)
    Abstract [en]

    Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2(+) MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23.

  • 17.
    Zhang, Lu
    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.
    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.
    Marginal-zone B cells transport IgG3-antigen immune complexes into splenic B cell follicles2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 278-278Article in journal (Other academic)
  • 18.
    Zhang, Lu
    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.
    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.
    MZ B Cells Transport IgG3-Ag to Splenic Follicles and Induce Germinal Centers2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 239-239Article in journal (Other academic)
1 - 18 of 18
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