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B cells lacking complement receptors 1 and 2 are equally efficient producers of IgG in vivo as wildtype B cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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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: urn:nbn:se:uu:diva-160603OAI: oai:DiVA.org:uu-160603DiVA: diva2:451774
Available from: 2011-10-27 Created: 2011-10-26 Last updated: 2011-11-23
In thesis
1. The Role of IgM and Complement in Antibody Responses
Open this publication in new window or tab >>The Role of IgM and Complement in Antibody Responses
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
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:nbn:se:uu:diva-160610 (URN)978-91-554-8210-7 (ISBN)
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: 2011-11-23Bibliographically approved

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