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  • 1.
    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)
  • 2.
    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, 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.

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  • 3.
    Lagedal, Rickard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sörman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Huckriede, Joram B
    Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6211 LK Maastricht, The Netherlands..
    Kristensen, Bjarne
    Thermo Fisher Scientific, 3450 Allerod, Denmark..
    Franzén, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Persson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Garcia de Frutos, Pablo
    Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS and CIBERCV, 08036 Barcelona, Spain..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nicolaes, Gerry A F
    Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6211 LK Maastricht, The Netherlands..
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Unit for Integrative Physiology, Department of Medical Cell Biology, Uppsala University, 752 36 Uppsala, Sweden..
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients.2022In: Journal of clinical medicine, ISSN 2077-0383, Vol. 11, no 12, article id 3419Article in journal (Refereed)
    Abstract [en]

    PURPOSE: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival.

    METHODS: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure.

    RESULTS: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively.

    CONCLUSION: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.

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  • 4.
    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.

  • 5.
    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, 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.

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  • 6.
    Sörman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgM and Complement in Regulation of Antibody Responses2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Animals deficient in complement components C1q, C4, C3, and CR1/2 have severely impaired antibody responses. C1q is primarily activated by antibody-antigen complexes. Antigen-specific IgM in complex with an antigen is able to enhance the antibody response against that antigen. This is dependent on the ability of IgM to activate complement. Naïve mice have very low amounts of specific antibodies and therefore it is surprising that classical pathway activation plays a role for primary antibody responses. It was hypothesized that natural IgM, present in naïve mice, would bind an antigen with enough affinity to activate C1q. To test this, a knock-in mouse strain, Cm13, with a point mutation in m heavy chain, making its IgM unable to activate complement was constructed. Surprisingly, the antibody responses in Cm13 were normal. Puzzled by the finding that the ability of IgM to activate complement was required only for some effects, the immunization protocol was changed to mimic an infectious scenario. With this regime, Cm13 mice had an impaired antibody response compared to wildtype (WT) mice. The antibody response in WT mice to these repeated low-dose immunizations was also enhanced. These observations suggest that IgM-mediated enhancement indeed plays a physiological role in initiation of early antibody responses. IgM-mediated enhancement cannot however compensate for the dependecy of T-cell help. Although IgM from WT mice enhanced the antibody response, the T-cell response was not enhanced. The connection between classical pathway activation and CR1/2 is thought to be generation of ligands for CR1/2. In mice, CR1/2 are expressed on B cells and follicular dendritic cells (FDC). Although CR1/2 are crucial for a normal antibody response, the molecular mechanism(s) are not understood. To investigate whether CR1/2 must be expressed on B-cells or FDC to generate a normal antibody response, chimeric mice between WT and CR1/2-deficient mice were constructed. The results show that CR1/2+ FDC were crucial for the generation of antibody responses. In the presence of CR1/2+ FDC, both CR1/2+ and CR1/2- B cells were equally good antibody producers. However, for an optimally enhanced antibody response against IgM-antigen complexes, both B cells and FDC needed to express CR1/2.

    List of papers
    1. Requirement for complement in antibody responses is not explained by the classic pathway activator IgM
    Open this publication in new window or tab >>Requirement for complement in antibody responses is not explained by the classic pathway activator IgM
    Show others...
    2011 (English)In: 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) Published
    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.

    National Category
    Basic Medicine Immunology in the medical area Immunology
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:uu:diva-160601 (URN)10.1073/pnas.1109831108 (DOI)000296378100011 ()21987785 (PubMedID)
    Note
    Author summaryAvailable from: 2011-10-26 Created: 2011-10-26 Last updated: 2018-01-12Bibliographically approved
    2. 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, 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: 2022-01-28Bibliographically approved
    3. Endogenous feedback-regulation by complement-activating IgM
    Open this publication in new window or tab >>Endogenous feedback-regulation by complement-activating IgM
    (English)Manuscript (preprint) (Other academic)
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-263222 (URN)
    Available from: 2015-09-28 Created: 2015-09-28 Last updated: 2018-01-11
    4. Complement receptors 1 and 2 in murine antibody responses to IgM-complexed and uncomplexed sheep erythrocytes
    Open this publication in new window or tab >>Complement receptors 1 and 2 in murine antibody responses to IgM-complexed and uncomplexed sheep erythrocytes
    Show others...
    2012 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 7, p. e41968-Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-183960 (URN)10.1371/journal.pone.0041968 (DOI)000306806600151 ()22848677 (PubMedID)
    Available from: 2012-11-06 Created: 2012-11-06 Last updated: 2022-01-28Bibliographically approved
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  • 7.
    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.
    Enhancement of Antibody Responses by Endogenous IgM2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, no 3, p. 234-234Article in journal (Other academic)
  • 8.
    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.

  • 9.
    Sörman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Hosp, Uppsala, Sweden.
    Knutson, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Hosp, Uppsala, Sweden.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Hosp, Uppsala, Sweden.
    Identification of the novel HLA-B*08:181 allele in a volunteer donor for hematopoietic stem cells2019In: HLA, ISSN 2059-2302, Vol. 93, no 6, p. 485-486Article in journal (Other academic)
    Abstract [en]

    HLA-B*08:181 differs from HLA-B*08:01:01:01 in codon 94, 95, 97 and 99 of exon 3.

    In this report, the HLA‐B*08:181 allele, will be described. The novel allele was found in a potential unrelated donor for hematopoietic stem cells. Currently, there are 5590 alleles described according to the IPD‐IMGT/HLA Database1 for the HLA‐B locus.

    During routine HLA typing of a potential unrelated bone marrow donor, the initial results obtained from Sanger sequencing (SBTengine, GenDX, Utrecht, The Netherlands) of the HLA‐B locus exons 2 to 4, suggested the presence of HLA B*07:227 and B*08:01:01. By testing with polymerase chain reaction ‐ single specific primer (PCR‐SSP) (Olerup, Stockholm, Sweden) this was not confirmed, instead the presence of the common B*07:02:01 together with a B*08:09/08:12 was suggested, thus indicating the possible presence of a novel HLA allele. To verify the finding, the sample was run on the PacBio long‐range platform (PacBio, Menlo Park, California). DNA was extracted from whole blood with the EZ1 DNA Blood kit (Qiagen, Hilden, Germany). The HLA‐B locus was amplified with B locus specific primers from the 5′ to 3′UTR and the end repair and ligation reaction were performed with the SMRTbell Barcoded Adapter Prep Kit (PacBio). Genotyping was performed using PacBio RSII (PacBio) and the resulting data was analyzed using NGSengine (GenDX). The result gave the clear result of B*07:02:01, the same results as previously, but the software gave the suggestion of HLA B*08:129, with three mismatches in exon 3. Consequently, the new allele shared the beginning of exon three with B*07:227, that is also found in B*57 alleles, thus explaining the Sanger sequencing. Comparison of the genomic full‐length sequence of B*08:129 and B*08:181 showed three nucleotide substitutions in codon 97 (A➔G and G➔T, AGG➔GTG) and 99 (C➔T, TAC➔TAT) in exon 3 (Figure 1). The substitution in codon 97 results in an exchange of Arginine to Valine while the nucleotide exchange in codon 99 does not result in any exchange of amino acid (aa). The chemical differences in the aa substitution from an electrically charged aa to a hydrophobic aa in the peptide binding area of the HLA protein would be considered to affect the protein function, that is, residue 97 is facing pockets C and E in the peptide binding groove.2 However, the serological typing of the potential donor showed a clear HLA B7 and B8 phenotype.

    Figure 1

    Sequence alignment of exon 3 of HLA‐B*08:01:01:01, HLA‐B*08:129 and HLA‐B*08:181. Dashes (−) indicate nucleotide identity. Codons are indicated by the numbers at the top

    The extended HLA typing of the donor was A*01:01:01, 03:01:01; B*07:02:01G, 08:181; C*07:02:01, 07:01:01; DRB1*03:01:01, 15:01:01; DRB3*01:01:02; DRB5*01:01:01, DQA1*05:01:01, 01:02:01; DQB1*02:01:01, 06:02:01; DPA1*01:03:01, 02:01:02; DPB1*01:01:01, 04:01:01.

    The genomic sequence of B*08:181 has been submitted to GenBank and the IPD IMGT/HLA Databases (LT707070, HWS10027733).

    The name HLA‐B*08:181 has been officially assigned by the World Health Organization (WHO) Nomenclature Committee in April 2017. This follows the agreed policy that subject to the conditions are identified.3 Lists of such new names will be published in the following WHO Nomenclature Report.

  • 10.
    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)
  • 11.
    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)
  • 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.

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