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The Role of IgM and Complement in Antibody Responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An intact complement system including the complement receptors 1 and 2 (CR1/2) is crucial for the generation of a normal antibody response in animals and humans. Moreover, activation of the classical pathway is thought to be important since deficiency in complement components C1q, C2, C4 or C3 lead to impaired antibody responses. The classical pathway is mainly initiated by antibodies bound to their antigen. It is unclear how classical pathway activation can be crucial for primary antibody responses since the levels of specific antibodies are very low in naïve animals. It has been hypothesized that natural IgM, with high enough affinity, can initiate the classical pathway after immunization. To test this, we generated the knock-in mouse strain Cμ13, producing IgM unable to activate complement. Surprisingly, the antibody response against SRBC and KLH in Cµ13 mice was normal. Thus, the importance of classical pathway activation and natural IgM in antibody responses is not dependent on the ability of IgM to activate complement. SIGN-R1, SAP and CRP are other known activators of the classical pathway, but mice lacking these also had normal antibody responses. Complement activation leads to the generation of C3 split products which are ligands for CR1/2. In mice, CR1/2 are expressed on B cells and follicular dendritic cells (FDC), but it is unclear on which cell-type expression of CR1/2 is needed for the generation of a normal antibody response. Some reports argue that increased antigen retention by CR1/2+ FDC would increase the effective antigen concentration, giving more effective B-cell stimulation. In contrast, several mechanisms involving CR1/2 on B cells are suggested. First, marginal zone B cells could transport complement-coated antigen or IC via CR1/2 into the follicle. Second, different ways of co-crosslinking the B-cell receptor with CR1/2, lowering the threshold for B-cell activation, have been proposed. Finally, CR1/2 on B cells are shown in vitro to facilitate endocytosis and thereby presentation of antigen to T cells. We show that abrogated antibody responses in mice lacking CR1/2 are not due to lack of CR1/2-mediated antigen presentation to T cells. Chimeric mice with CR1/2 expression on both B cells and FDC, on neither B cells nor FDC, or on either B cells or FDC, were generated. The antibody response against SRBC was completely dependent of CR1/2-expression on FDC. However, when this requirement was fulfilled, B cells without expression of CR1/2 were equally efficient antibody producers as wildtype B cells. Antigen-specific IgM together with its antigen can enhance the antibody response to that antigen and CR1/2-expression is crucial for the enhancement. We show that the response to IgM in complex with SRBC is dependent on CR1/2 expression on both B cells and FDC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 720
Keyword [en]
Complement, antibody response, mutated IgM, natural IgM, complement receptors, SIGN-R1, SAP, CRP, B cells
National Category
Basic Medicine Immunology in the medical area Immunology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-160610ISBN: 978-91-554-8210-7 (print)OAI: oai:DiVA.org:uu-160610DiVA: diva2:451843
Public defence
2011-12-08, C10:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-11-17 Created: 2011-10-27 Last updated: 2018-01-12Bibliographically approved
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: 2018-01-12Bibliographically approved
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3. Impaired antibody responses but normal proliferation of CD4+ T cells in mice lacking complement receptors 1 and 2
Open this publication in new window or tab >>Impaired antibody responses but normal proliferation of CD4+ T cells in mice lacking complement receptors 1 and 2
2009 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 70, no 2, 77-84 p.Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95525 (URN)10.1111/j.1365-3083.2009.02274.x (DOI)000268061600001 ()19630912 (PubMedID)
Available from: 2007-03-08 Created: 2007-03-08 Last updated: 2017-12-14Bibliographically approved
4. B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells
Open this publication in new window or tab >>B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The complement system, including the complement receptors 1 and 2 (CR1/2), is crucial for the development of antibody responses against a wide range of antigens. Cr2-/- mice are deficient in both CR1 and CR2 and respond poorly upon immunization with antigen alone and with IgM-containing immune complexes. In mice, CR1/2 are expressed exclusively on B cells and follicular dendritic cells (FDC) but it is not clear which of the two cell-types that need to express the receptors for a normal antibody response. Here, bone marrow chimeras were used to distinguish between B cells and FDC. The animals were immunized with SRBC alone or with IgM anti-SRBC and SRBC. For an antibody response to SRBC alone, CR1/2 expression on FDC was crucial. When CR1/2+ FDC were present, B cells from Cr2-/- mice produced equal amounts of antibodies against SRBC as did B cells from WT. However, the response to IgM-SRBC complexes was more efficient in the presence of CR1/2+ B cells although CR1/2+ FDC still played a dominant role. In conclusion, antibody responses to antigen alone required CR1/2+ FDC, whereas CR1/2 expression on B cells was irrelevant. In contrast, in antibody responses to IgM-IC, presence of CR1/2+ B cells led to a higher and more rapid onset of the antibody response.

National Category
Basic Medicine Immunology in the medical area Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-160603 (URN)
Available from: 2011-10-27 Created: 2011-10-26 Last updated: 2018-01-12

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