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Impaired antibody responses but normal proliferation of CD4+ T cells in mice lacking complement receptors 1 and 2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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.
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.

Place, publisher, year, edition, pages
2009. Vol. 70, no 2, 77-84 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95525DOI: 10.1111/j.1365-3083.2009.02274.xISI: 000268061600001PubMedID: 19630912OAI: oai:DiVA.org:uu-95525DiVA: diva2:169778
Available from: 2007-03-08 Created: 2007-03-08 Last updated: 2011-11-23Bibliographically approved
In thesis
1. Antibody Feedback Regulation and T Cells
Open this publication in new window or tab >>Antibody Feedback Regulation and T Cells
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibodies, passively administered or actively produced, regulate immune responses to the antigen they recognize. This phenomenon is called antibody-mediated feedback regulation. Feedback regulation can be positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. The outcome depends on size, structure, dose, and route of administration of the antigen as well as on class and subclass of the regulating antibody. This thesis investigates the role of T cells in antibody-mediated feedback enhancement, using both in vivo and in vitro approaches. IgE-antibodies enhance antibody responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, and most likely depends on increased antigen presentation by CD23+ B cells. Strengthening this hypothesis, we show that IgE-mediated CD4+ T cell proliferation in vitro required the presence of CD19+ CD43- CD23+ B cells. CD23 has also been shown to negatively regulate immune responses. Transgenic mice overexpressing CD23 are known to have impaired responses to antigens in alum. We here demonstrate that they are normal regarding IgE-mediated enhancement. IgG3 enhances antibody responses, and previous data suggested involvement of complement. We found that IgG3-mediated enhancement works well in mice lacking the only Fc-receptor known to bind IgG3, CD64. Although IgG3 could enhance antibody responses it had no major effect on T cell responses. Complement-receptors 1/2 (CR1/2) are required for the initiation of normal antibody responses. Although mice lacking CR1/2 had impaired antibody responses after immunization with sheep erythrocytes, their specific T cell responses were unaffected. The presented data do not support the idea that increased complement-mediated antigen presentation is a major mechanism behind the involvement of complement in antibody responses. They support the hypothesis that antigens forming complement-containing immune complexes may activate specific B cells by co-crosslinking BCR and CR1/2.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 233
Keyword
Fc receptors, B cell, T cell, antigen presentation, complement receptors, complement, IgE, IgG3, CD23, antibody
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-7631 (URN)978-91-554-6814-9 (ISBN)
Public defence
2007-03-30, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-03-08 Created: 2007-03-08Bibliographically approved
2. 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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