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IgM and Complement in Regulation of Antibody Responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Heyman)
2015 (English)Doctoral 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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1140
Keyword [en]
IgG, GC responses, feedback regulation, T-cell responses, antigen presentation, complement receptors 1 and 2
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-263472ISBN: 978-91-554-9357-8 (print)OAI: oai:DiVA.org:uu-263472DiVA: diva2:858038
Public defence
2015-11-19, C4:305, BMC, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-10-28 Created: 2015-09-30 Last updated: 2015-11-10
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
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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, 17589-17590 p.Article 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: 2017-12-08Bibliographically 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
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, e81299- p.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
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: 2015-11-10
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
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, e41968- p.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: 2017-12-07Bibliographically approved

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