Mice expressing human CR1/CD35 have an enhanced humoral immune response to T-dependent antigens but fail to correct the effect of premature human CR2 expression

Pappworth, Isabel Y.; Hayes, Christine; Dimmick, Jason; Morgan, B. Paul; Holers, V. Michael; Marchbank, Kevin J.

doi:10.1016/j.imbio.2011.06.001

Cited by 8 publications

(10 citation statements)

References 58 publications

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“…hCR1 tg .hCR2 tg . Cr2 −/− mice ( Pappworth et al, 2012 ) and hCR2 tg .C3 −/− mice ( Twohig et al, 2007 ) were routinely confirmed by PCR and immunoblot. All mice used were age and sex matched littermates from colonies maintained at Newcastle University or purchased (B6) from Harlan (UK).…”

Section: Methodsmentioning

confidence: 99%

A novel C3d-containing oligomeric vaccine provides insight into the viability of testing human C3d-based vaccines in mice

Pappworth

Rossbach

et al. 2018

Immunobiology

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The use of C3d, the final degradation product of complement protein C3, as a “natural” adjuvant has been widely examined since the initial documentation of its immunogenicity-enhancing properties as a consequence of binding to complement receptor 2. Subsequently it was demonstrated that these effects are most evident when oligomeric, rather than when monomeric forms of C3d, are linked to various test protein antigens. In this study, we examined the feasibility of enhancing the adjuvant properties of human C3d further by utilizing C4b-binding protein (C4BP) to provide an oligomeric arrayed scaffold fused to the model antigen, tetanus toxin C fragment (TTCF).High molecular weight, C3d-containing oligomeric vaccines were successfully expressed, purified from mammalian cells and used to immunize groups of mice. Surprisingly, anti-TTCF antibody responses measured in these mice were poor. Subsequently we established by in vitro and in vivo analysis that, in the presence of mouse C3, human C3d does not interact with either mouse or even human complement receptor 2.These data confirm the requirement to develop murine versions of C3d based adjuvant compounds to test in mice or that mice would need to be developed that express both human C3 and human CR2 to allow the testing of human C3d based adjuvants in mouse in any capacity.

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Section: Methodsmentioning

confidence: 99%

A novel C3d-containing oligomeric vaccine provides insight into the viability of testing human C3d-based vaccines in mice

Pappworth

Rossbach

et al. 2018

Immunobiology

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“…These studies have not delineated the specific functions of the Cr1 and Cr2 proteins on B cells and FDC, and elevated surface expression of CD19 on Cr1/2KO B cells has been proposed to lead to B cell anergy (17). Additional studies have also utilized Cr1/2 deficient ( Cr1/2KO ) animals to examine the function of human CR1 or CR2 via transgenic expression models of these proteins using immunoglobulin gene promoters (18, 19). In these studies, however, premature expression of the transgenes (compared to native Cr2 ), lack of FDC expression, expression in inappropriate cell types (T cells, etc), and the structural distinctness of human CR1 compared to the mouse Cr1 protein introduces critical variables.…”

Section: Introductionmentioning

confidence: 99%

Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1

Donius

Handy

Weis

et al. 2013

The Journal of Immunology

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Follicular dendritic cells and complement receptors 1 and 2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDC has been shown to provide a secondary signal for B cell activation, to facilitate transport of antigen in immune follicles, and to enhance retention of immune complexes by FDC. We show here that murine B cells predominantly express the Cr2 product from the Cr2 gene while FDC nearly exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we have created an animal that maintains normal cell restricted expression of Cr2 but does not express Cr1. Cr1 deficient (Cr1KO) mice develop normal B1 and B2 immature and mature B cell subsets, and have normal levels of naïve serum antibodies but altered levels of natural antibodies. Immunization of the Cr1KO animal demonstrates deficient antibody responses to T-dependent but not T-independent antigens. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for the animal lacking both Cr1 and Cr2, or C3. Finally, animals lacking only Cr1 respond similar to the WT animal to infections with Streptococcus pneumoniae, a pathogen that animals lacking C3 or both Cr1 and Cr2 are particularly sensitive to. These data, in total, suggest that the production of Cr1 primarily by FDC is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature antibody responses.

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“…A similar goal was advanced recently by the creation of a transgenic Cr1/2KO mouse line expressing human CR1/CD35 (Pappworth et al, 2011). However, in addition to the expression of human CR1 in a non-autochthonous environment these mice possess other disadvantages including premature expression of CR1 during B cell development, a broader cell specific expression pattern than murine Cr1, and the absence of the CD19 co-association exhibited by mouse Cr1.…”

Section: Discussionmentioning

confidence: 99%

Generation of a novel Cr2 gene allele by homologous recombination that abrogates production of Cr2 but is sufficient for expression of Cr1

et al. 2014

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The enhancing effects of the complement system for humoral immunity have primarily focused upon the recognition of complement-bound foreign antigens by a co-receptor complex of the antigen-specific B cell receptor (BCR) and complement receptor 2 (Cr2). In vivo experiments using Cr2 gene deficient mice (which lack the expression of both the Cr1 and Cr2 proteins) do demonstrate depressed humoral responses to immunization but cannot be used to define specific contributions of the singular Cr1 or Cr2 proteins on B cell functions. To study the effect of a Cr2 deficiency in a Cr1 sufficient environment we created a mouse line in which the alternative splice site required for the expression of the Cr2 isoform was removed. This mouse line, Cr2KO, still expressed Cr1 on B cells but was deficient for the full length Cr2 protein. Surprisingly a new alternative splice within the Cr2 gene created a truncated product that encoded a novel protein termed iCr2 that was expressed on the surface of the cells. The Cr2KO mouse thus provides a new model system for the analysis of Cr1 and Cr2 functions in the immune response of the mouse.

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Mice expressing human CR1/CD35 have an enhanced humoral immune response to T-dependent antigens but fail to correct the effect of premature human CR2 expression

Cited by 8 publications

References 58 publications

A novel C3d-containing oligomeric vaccine provides insight into the viability of testing human C3d-based vaccines in mice

A novel C3d-containing oligomeric vaccine provides insight into the viability of testing human C3d-based vaccines in mice

Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1

Generation of a novel Cr2 gene allele by homologous recombination that abrogates production of Cr2 but is sufficient for expression of Cr1

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