| 1. |
- Bergström, Joakim, et al.
(författare)
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Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG : Evidence of Epitope Masking
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBCs) is intact in mice lacking Fc gamma Rs, complement factor 1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG-antigen complexes and/or that IgG "hides" the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extrafollicular antibody-secreting cells, germinal center B-cells, longlived plasma cells, long-term IgG responses, and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type, but not of Fc gamma R-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead, we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP, but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.
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| 2. |
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| 3. |
- Ding, Zhoujie, et al.
(författare)
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IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- IgE, forming an immune complex with small proteins, can enhance the specific antibody and CD4(+) T cell responses in vivo. The effects require the presence of CD23 (Fc epsilon-receptor II)(+) B cells, which capture IgE-complexed antigens (Ag) in the circulation and transport them to splenic B cell follicles. In addition, also CD11c(+) cells, which do not express CD23, are required for IgE-mediated enhancement of T cell responses. This suggests that some type of dendritic cell obtains IgE-Ag complexes from B cells and presents antigenic peptides to T cells. To elucidate the nature of this dendritic cell, mice were immunized with ovalbumin (OVA)-specific IgE and OVA, and different populations of CD11c(+) cells, obtained from the spleens four hours after immunization, were tested for their ability to present OVA. CD8 alpha(-) conventional dendritic cells (cDCs) were much more efficient in inducing specific CD4(+) T cell proliferation ex vivo than were CD8 alpha(+) cDCs or plasmacytoid dendritic cells. Thus, IgE-Ag complexes administered intravenously are rapidly transported to the spleen by recirculating B cells where they are delivered to CD8 alpha(-) cDCs which induce proliferation of CD4(+) T cells.
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| 4. |
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| 5. |
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| 6. |
- Xu, Hui, et al.
(författare)
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Antigen Conjugated to Anti-CD23 Antibodies is Rapidly Transported to Splenic Follicles by Recirculating B Cells
- 2015
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 81:1, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- IgE-antigen complexes, administered intravenously to mice, induce a several 100-fold higher specific antibody response than antigen alone. Additionally, in vivo activation and proliferation of specific CD4(+) T cells is enhanced. The mechanism behind these effects is thought to be that peripheral B cells capture IgE-antigen complexes via their low-affinity receptor for IgE, CD23, and rapidly transport them to splenic B cell follicles where an immune response is initiated. Here, we demonstrate that ovalbumin, covalently coupled to anti-CD23 antibodies and administered intravenously to mice, is also transported to splenic follicles and induces an enhanced primary antibody response. These effects are absent in CD23-deficient mice. No enhanced induction of immunological memory was observed. These findings extend previous observations regarding the in vivo role of CD23 and emphasize that recirculating B cells play an important role in antigen transport to the spleen.
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| 7. |
- Xu, Hui, et al.
(författare)
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IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh) D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fc gamma-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the number of single antibody-forming cells were determined. As a rule, IgG suppressed NP- but not SRBC-specific responses (epitope specific suppression). However, there was one exception: suppression of both IgM anti-SRBC and IgM anti-NP responses occurred when high density SRBC-NP was administered (non-epitope specific suppression). These findings answer a longstanding question in antibody feedback regulation and are compatible with the hypothesis that epitope masking explains IgG-mediated immune suppression.
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| 8. |
- Xu, Hui, et al.
(författare)
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IgG-mediated suppression of antibody responses : Hiding or snatching epitopes?
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : WILEY. - 0300-9475 .- 1365-3083. ; 92:4
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Forskningsöversikt (refereegranskat)abstract
- Antibodies forming a complex with antigen in vivo can dramatically change the antibody response to this antigen. In some situations, the response will be a 100-fold stronger than in animals immunized with antigen alone, and in other situations, the response will be completely suppressed. IgG is known to suppress the antibody response, for example to erythrocytes, and this is used clinically in Rhesus prophylaxis. The mechanism behind IgG-mediated immune suppression is still not understood. Here, we will review studies performed in experimental animal models and discuss the various hypotheses put forward to explain the profound suppressive effect of IgG. We conclude that an exclusive role for negative regulation of B cells through Fc gamma RIIB, increased clearance of erythrocytes from the circulation or complement-mediated lysis is unlikely. Epitope masking, where IgG hides the epitope from B cells, or trogocytosis, where IgG removes the epitope from the erythrocyte, is compatible with many observations. These two mechanisms are not mutually exclusive. Moreover, it cannot be ruled out that clearance, in combination with other mechanisms, plays a role.
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| 9. |
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| 10. |
- Xu, Hui, 1988-
(författare)
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Modulation of B cell access to antigen by passively administered antibodies : an explanation for antibody feedback regulation?
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibody responses can be up- or down-regulated by passive administration of specific antibody together with antigen. Depending on the structure of the antigen and the antibody isotype, responses can be completely suppressed or enhanced up to a 1000-fold of what is seen in animals immunized with antigen alone.IgG suppresses primary antibody responses against erythrocytes. Suppression works well in mice lacking Fc-receptors for IgG, C1q, C3, or complement receptor 1 and 2 (CR1/2). Here, we demonstrate that IgG anti-NP given to mice together with NP-conjugated sheep erythrocytes, suppresses the generation of NP-specific extra-follicular antibody-secreting cells, NP-specific germinal center B cells, induction of memory and long-lived plasma cells. IgG increases antigen clearance but this does not explain the suppressed antibody response. It is demonstrated that IgG-mediated suppression of IgG responses is epitope specific, suggesting that epitope masking is the dominant explanation for IgG-mediated suppression of antibody responses.Both IgE and IgG3 can enhance antibody responses against soluble antigens. IgE-antigen complexes bind to recirculating B cells expressing CD23, an Fc-receptor for IgE. Thirty minutes after intravenous administration, IgE-antigen is found in splenic follicles. Subsequently, germinal center responses, antigen-specific T cell proliferation, and antibody responses are enhanced. We show that also antigen conjugated to anti-CD23 can bind to CD23+ B cells and be transported to splenic follicles. CD11+ spleen cells, rather than CD23+ B cells, present IgE-antigen complexes to T cells. Here, it is demonstrated that CD8α− conventional dendritic cells is the CD11c+ cell population presenting IgE-antigen to T cells.IgG3-mediated enhancement is dependent on CR1/2. We find that IgG3-antigen complexes, administered intravenously to mice, bind to marginal zone B cells via CR1/2. These cells then transport IgG3-antigen into splenic follicles and deposit antigen onto follicular dendritic cells. Mice treated with FTY720, a drug which dislocates marginal zone B cells from the marginal zone, impairs this transport. Studies in bone marrow chimeric mice show that CR1/2 on both B cells and follicular dendritic cells are crucial for IgG3-mediated enhancement.In summary, these observations suggest that antibodies can feedback regulate antibody responses by modulating the access of antigen to the immune system.
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