Expression of human complement receptor 2 (CR2, CD21)in CR2−/− mice restores humoral immune function

Marchbank, Kevin J.; Watson, Clay C.; Ritsema, David F.; Holers, V. Michael

doi:10.1016/s0162-3109(00)80138-1

Cited by 3 publications

(7 citation statements)

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“…As CR2 dependent BCR signal amplification depends on CD19 7, 8, 20, a potential reason for the lack of response or activation of the B cells in the hCR2 Tg mice in response to Ag is that hCR2 does not associate with, or signal through, mouse CD19. However, we have previously shown using immunoprecipitation, that hCR2 on the mouse A20 B cell line does associate with mouse CD19 17. Furthermore, the fact that stimulation of hCR2 Tg‐derived splenic B cells with anti‐IgM/C3d tetramer conjugates results in substantial Ca 2+ influx (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…In the first Tg approach, we utilized a human P1 phage clone that contained all of the known transcriptional regulatory regions. Although very low levels of hCR2 were found, Tg‐reconstituted Cr2 –/– mice demonstrated a partial restoration of the humoral immune response to SRBC as compared with non‐Tg Cr2 –/– littermate controls 17. The second strain of mice (lambda hCR2) expressed the hCR2 cDNA under the control of a B cell‐specific λ‐promoter/enhancer minigene 16.…”

Section: Introductionmentioning

confidence: 99%

“…The only detectable difference between the two strains of hCR2 Tg mice is the time point during B cell development where hCR2 starts to be expressed 16, 17. In mice where hCR2 is driven by a λ‐promoter/enhancer minigene, premature hCR2 expression on pre/pro‐B cells in the bone marrow appears to change B cell development leading to appearance of functionally altered B cells in the periphery.…”

Section: Introductionmentioning

confidence: 99%

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Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

et al. 2007

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We previously reported that human CR2 (hCR2) prematurely expressed under a murine Vk2 promoter/Vk2-4 enhancer minigene during the CD43 + CD25 -late pro-B cell stage of development results in peripheral B cells with impaired responses to immunization with T-dependent antigens. Herein, we show that hCR2 transgenic (Tg) mice also demonstrate a severe defect in T-independent antigen responses and are substantially protected from clinical arthritis, synovitis and cartilage/bone destruction in a collageninduced arthritis model. This outcome is found despite the apparently normal development of autoreactive T cells with equivalent cytokine and proliferative responses to antigen when compared to non-Tg control mice. These data suggest the presence of an intrinsic B cell defect in the hCR2 Tg mice. We also show that an hCR2-dependent Ca 2+ influx can be generated in both developing and mature Tg B cells, but with different rates of decay as compared to control wild-type (WT) mice. In addition, although analysis of tyrosine-phosphorylated proteins in WT and Tg B cells following B cell receptor (BCR)-induced activation revealed the presence of distinctly different phosphorylation patterns, no differences were identified in several candidate protein targets. Overall, these data suggest that premature hCR2 expression and the consequences thereof during B cell development intrinsically alters the way mature B cells develop and subsequently respond to antigen through the BCR signaling complex.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

et al. 2007

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“…Murine CR1 and CR2 are generated by alternative splicing of the same gene (Cr2) and are both absent in Cr2 ) ⁄ ) animals. Although it has been difficult to ascertain which of the two receptors is required for Ab responses, some reports imply a dominant role for CR2 [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Impaired Antibody Responses but Normal Proliferation of Specific CD4⁺ T Cells in Mice Lacking Complement Receptors 1 and 2

Carlsson¹,

Getahun²,

Rutemark

et al. 2009

Scand J Immunol

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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.

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“…CR2 can form a complex with CD19 and CD81 in the B cell membrane to function as a coreceptor that enhances signals through the BCR (1). CR2 is an important component of the immune system because it is required for the generation of a robust immune response to T-dependent antigens (2)(3)(4). Additionally, CR2 plays a role in the survival of germinal center B cells (5).…”

Section: Introductionmentioning

confidence: 99%

A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation

Makar¹,

Ulgiati²,

Hagman³

et al. 2001

International Immunology

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Expression of human complement receptor type 2 (CR2/CD21) is primarily restricted to mature B cells and follicular dendritic cells. We previously described an intronic transcriptional silencer that controls the appropriate B cell-specific and developmentally restricted expression of human CR2/CD21 in both stably transfected cell lines and transgenic mice. Here we report the identification of a nucleotide sequence within the 2.5 kb CR2 silencer (CRS) that is crucial to its silencer function. This site comprises a binding site for the transcriptional repressor CBF1 (RBP-J or RBP-Jkappa) as well as Sp1 and other as yet uncharacterized proteins. A 2-bp mutation which eliminates the binding of CBF1 and other protein(s) in vitro results in loss of silencer activity in vivo. These results demonstrate the importance of this site in regulating CR2 expression and suggest that CBF1, a component of the developmentally important Notch signaling pathway, may play a role in the control of human CR2 gene expression.

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Expression of human complement receptor 2 (CR2, CD21)in CR2−/− mice restores humoral immune function

Cited by 3 publications

References 0 publications

Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

Impaired Antibody Responses but Normal Proliferation of Specific CD4⁺ T Cells in Mice Lacking Complement Receptors 1 and 2

A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation

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Expression of human complement receptor 2 (CR2, CD21)in CR2−/− mice restores humoral immune function

Cited by 3 publications

References 0 publications

Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

Intrinsic B cell hypo‐responsiveness in mice prematurely expressing human CR2/CD21 during B cell development

Impaired Antibody Responses but Normal Proliferation of Specific CD4+ T Cells in Mice Lacking Complement Receptors 1 and 2

A site in the complement receptor 2 (CR2/CD21) silencer is necessary for lineage specific transcriptional regulation

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Impaired Antibody Responses but Normal Proliferation of Specific CD4⁺ T Cells in Mice Lacking Complement Receptors 1 and 2