Regulation of Alloantibody Responses

Chong, Anita S.; Sage, Peter T.; Alegre, Maria‐Luisa

doi:10.3389/fcell.2021.706171

Cited by 7 publications

(5 citation statements)

References 87 publications

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“…CD24 appears to be one of the major actors in immune tolerance. It is a cell-surface protein marking B-reg cells, a subset of B cells that suppress immune reactions [38], as was already found in organ transplantation [38,39]. Since gestation can be defined as a semi-allograft, it would be desirable to identify whether B-reg-cell-mediated immune modulation is involved in a successful pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines

Sammar

Apicella

Altevogt

et al. 2022

IJMS

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CD24 is a mucin-like immunosuppressing glycoprotein whose levels increase during pregnancy and decrease in the syncytio- and cytotrophoblasts in early and preterm preeclampsia. We used two modified cell lines that mimic in vitro features of preeclampsia to identify if this phenomenon could be reproduced. Our model was the immortalized placental-derived BeWo and JEG-3 cell lines that overexpress the STOX1 A/B transcription factor gene that was discovered in familial forms of preeclampsia. BeWo and JEG-3 cells stably transduced with the two major isoforms of STOX1-A/B or by an empty vector (control), were propagated, harvested, and analyzed. CD24 mRNA expression was determined by quantitative real-time polymerase nuclear chain reaction (qRT-PCR). CD24 protein levels were determined by Western blots. In STOX1-A/B overexpressing in BeWo cells, CD24 mRNA was downregulated by 91 and 85%, respectively, compared to the control, and by 30% and 74%, respectively in JEG-3 cells. A 67% and 82% decrease in CD24 protein level was determined by immunoblot in BeWo overexpressing STOX1-A/B, respectively, while the reduction in JEG-3 cells was between 47 and 62%. The immortalized BeWo and JEG-3 cell lines overexpressing STOX1-A/B had reduced CD24. Although both cell lines were affected, BeWo appears to be more susceptible to downregulation by STOX-1 than JEG-3, potentially because of their different cell origin and properties. These results strengthen the in vivo results of reduced CD24 levels found in early and preterm preeclampsia. Accordingly, it implies the importance of the reduced immune tolerance in preeclampsia, which was already demonstrated in vivo in the STOX1-A/B model of preeclampsia, and is now implied in the in vitro STOX-1 model, a subject that warrants further investigations.

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Section: Discussionmentioning

confidence: 99%

Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines

Sammar

Apicella

Altevogt

et al. 2022

IJMS

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“…18,36 Multiple studies have found that humoral immunity to foreign MHC involves GC reaction and FO T helper cell formation. 2 Circulating T helper cells have been identified as a marker of ongoing alloimmunity and graft rejection. 2,37,38 Our findings are not incongruent with this work but rather demonstrate that the MZ B cells, not FO B cells, are the major reservoir from which the GC B cells are derived.…”

Section: Discussionmentioning

confidence: 99%

“…2 Circulating T helper cells have been identified as a marker of ongoing alloimmunity and graft rejection. 2,37,38 Our findings are not incongruent with this work but rather demonstrate that the MZ B cells, not FO B cells, are the major reservoir from which the GC B cells are derived. It is not clear whether the selective activation of MZ B cells versus FO B cells is because of differences in the threshold for activation (eg, signaling through inflammatory mediators) or the B cell receptor specificity for allogeneic antigens.…”

Section: Discussionmentioning

confidence: 99%

“…However, the successful impact of transplantation is limited by the formation of anti–major histocompatibility complex (MHC) antibodies, termed allogeneic sensitization. 1,2 For patients awaiting transplantation, allogeneic sensitization can dramatically limit the number of compatible donors, and the formation of anti-donor HLA antibodies after transplantation leads to graft rejection and loss. 3 Further mechanistic insight into the cellular and molecular pathways that lead to allogeneic sensitization could lead to improved risk stratification of patients before transplant and pathway-specific treatments for desensitization and antibody-mediated graft rejection.…”

Section: Introductionmentioning

confidence: 99%

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Marginal Zone B Cells Are Necessary for the Formation of Anti-donor IgG After Allogeneic Sensitization

Kallarakal,

Cohen,

Ibukun

et al. 2024

Transplantation

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Background. The formation of anti–major histocompatibility complex (MHC) antibodies is a significant barrier for many patients awaiting organ transplantation. Patients with preformed anti-MHC antibodies have limited options for suitable donors, and the formation of donor-specific anti-MHC antibodies after transplantation is a harbinger of graft rejection. Despite the recognized importance of anti-MHC antibodies, the mechanisms responsible for the differentiation of B cells after exposure to allogeneic antigens are poorly understood. Methods. To evaluate the differentiation of B cells in response to allogeneic antigen, we used a model of H-2b C57Bl/6 sensitization with H-2d antigen. We used a class I MHC tetramer-based approach to identify allogeneic B cells and flow cytometric crossmatch to identify allogeneic IgM and IgG. Results. We found that although the formation of anti-H-2d IgG was robust, few class-switched B cells and germinal center B cells were formed. Antigen-specific B cells did not express classical memory B-cell markers after sensitization but had an IgM+CD21+ marginal zone B-cell phenotype. The frequency of marginal zone B cells increased after sensitization. Depletion of marginal zone B cells before sensitization or skin grafting resulted in a significant diminution of anti-H-2d IgG and fewer germinal center B cells. Adoptive transfer experiments revealed that marginal zone B cells more efficiently differentiated into germinal center B cells and antidonor IgG-producing cells than follicular B cells. Conclusions. These results demonstrate an important role for marginal zone B cells as a reservoir of alloreactive B cells that are activated by allogeneic antigens.

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“…Tfr inhibit through production of IL-10 and PD1 ( 244 ). Other regulatory cells, such as tTreg, regulatory B cells can inhibit alloantibody production ( 245 ). In a murine model, while Tfh cells are required for production of alloantibody, absence of Tfr worsenes alloantibody production and rejection ( 246 ).…”

Section: Activated/memory Tregmentioning

confidence: 99%

CD4+CD25+ T regulatory cells in renal transplantation

et al. 2022

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The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4+CD25+Foxp3+T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4+T cells and do not markedly increase in tolerant hosts. CD4+CD25+Foxp3+T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4+CD25+Foxp3+T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.

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Regulation of Alloantibody Responses

Cited by 7 publications

References 87 publications

Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines

Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines

Marginal Zone B Cells Are Necessary for the Formation of Anti-donor IgG After Allogeneic Sensitization

CD4+CD25+ T regulatory cells in renal transplantation

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