Semaphorin 3<scp>A</scp> alters endothelial cell immunogenicity by regulating <scp>C</scp>lass <scp>II</scp> transactivator activity circuits

Schlahsa, Laura; Zhang, HaiJiao; Battermann, Anja; Verboom, Murielle; Immenschuh, Stephan; Stripecke, Renata; Engelmann, Katrin; Blasczyk, Rainer; Figueiredo, Constança

doi:10.1111/trf.12631

Cited by 4 publications

(3 citation statements)

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“…Knockdown of HLA-DR was performed as previously described 57 . In brief, confluent HUVECs in passage 3 were transduced with enhanced green fluorescent protein (GFP) containing lentiviral vectors encoding for sequences targeting HLA-DR (shDR) or CIITA (shCIITA) or a non-specific short hairpin RNA (shNS) as a control, for 24 h. After treatment with IFN-γ for 3 days, cells were examined for HLA-DR expression and antibody-mediated cytotoxicity by flow cytometry in the GFP-positive cell population, representing successfully transduced ECs.…”

Section: Methodsmentioning

confidence: 99%

HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway

et al. 2019

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Antibody-mediated rejection (AMR) is the major cause of allograft loss after solid organ transplantation. Circulating donor-specific antibodies against human leukocyte antigen (HLA), in particular HLA class II antibodies are critical for the pathogenesis of AMR via interactions with endothelial cells (ECs). To investigate the effects of HLA class II antibody ligation to the graft endothelium, a model of HLA-DR antibody-dependent stimulation was utilized in primary human ECs. Antibody ligation of HLA class II molecules in interferon-γ-treated ECs caused necrotic cell death without complement via a pathway that was independent of apoptosis and necroptosis. HLA-DR-mediated cell death was blocked by specific neutralization of antibody ligation with recombinant HLA class II protein and by lentiviral knockdown of HLA-DR in ECs. Importantly, HLA class II-mediated cytotoxicity was also induced by relevant native allele-specific antibodies from human allosera. Necrosis of ECs in response to HLA-DR ligation was mediated via hyperactivation of lysosomes, lysosomal membrane permeabilization (LMP), and release of cathepsins. Notably, LMP was caused by reorganization of the actin cytoskeleton. This was indicated by the finding that LMP and actin stress fiber formation by HLA-DR antibodies were both downregulated by the actin polymerization inhibitor cytochalasin D and inhibition of Rho GTPases, respectively. Finally, HLA-DR-dependent actin stress fiber formation and LMP led to mitochondrial stress, which was revealed by decreased mitochondrial membrane potential and generation of reactive oxygen species in ECs. Taken together, ligation of HLA class II antibodies to ECs induces necrotic cell death independent of apoptosis and necroptosis via a LMP-mediated pathway. These findings may enable novel therapeutic approaches for the treatment of AMR in solid organ transplantation.

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Section: Methodsmentioning

confidence: 99%

HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway

et al. 2019

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“…It's also amusing to find three relevant articles from European researchers in the August issue of the American Association of Blood Banks (AABB) Journal Transfusion [4,5,6], and five American groups (and only one European) reporting their findings in this December issue of T RANSFUSION MEDICINE AND HEMOTHERAPY , the official publication of the German Society for Blood Transfusion and Immunohematology (DGTI) [8-12]. May the prophets receive appropriate recognition in their own countries!…”

mentioning

confidence: 99%

Responder Individuality in Red Blood Cell Alloimmunization

Gassner

2014

Transfus Med Hemother

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“…The human CIITA expression is tightly regulated at the transcriptional [160][161][162][163][164][165] and post-transcriptional levels 35,166 in a cell type-specific manner. In order to avoid cisacting elements present in the 3' UTR of CIITA mRNA that mediate the transcript degradation 71,72 and guarantee protein expression regardless of cell-specific regulatory mechanisms, the CIITA cDNA lacking the 5` and 3` UTRs was obtained through reverse translation of the human CIITA amino acid sequence ( Figure 5).…”

Section: Ciita Sequence Design and Optimization For Expression In Hummentioning

confidence: 99%

Avaliação do fator CIITA como potencial adjuvante molecular para vacinas e imunoterapias

Palma¹

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degradation. This modulation is achieved by controlling the levels of Promyelocytic Leukemia (PML) proteins attached to Small Ubiquitin-like Modifier (SUMO) proteins, a post-translational modification required for the PML-CIITA interaction, which impairs the proteasomal degradation. This new mechanism described here contributes to the developing understanding of the CIITA post-translational regulation in non-immune cells, and might have important implications in the use of this transcription factor as a molecular adjuvant for immunotherapies. Descriptors: CIITA protein, human; MHC class II transactivator protein; proteasome; PML protein, human; small ubiquitin-related modifier proteins.

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Semaphorin 3A alters endothelial cell immunogenicity by regulating Class II transactivator activity circuits

Abstract: This study links Sema3A signaling in ECs with increased CIITA levels and higher HLA-DR expression, resulting in CD4+ T-cell activation, which might have important implications for tissue and organ transplantation.

Cited by 4 publications

References 38 publications

HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway

HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway

Responder Individuality in Red Blood Cell Alloimmunization

Avaliação do fator CIITA como potencial adjuvante molecular para vacinas e imunoterapias

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