Characterization of the human neutrophil alloantigen-3a

Greinacher, Andreas; Wesche, Jan; Hammer, Elke; Fürll, Birgitt; Völker, Uwe; Reil, Angelika; Bux, Jürgen

doi:10.1038/nm.2070

Cited by 128 publications

(164 citation statements)

References 19 publications

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“…Third, the approach we developed for the identification of the allospecificity was reported by others during the time of our study (42)(43)(44). Our results are one more example that shows the power of detection, no matter whether it is an alloimmune or an auto- immune disease, for the discovery of Ab specificities.…”

Section: Discussionsupporting

confidence: 53%

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

Foucras

Corbière

Tasca

et al. 2011

The Journal of Immunology

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Fetal/neonatal alloimmune thrombocytopenia is a frequent disease in humans where alloantibodies against platelet Ags lead to platelet destruction and hemorrhage. Although a role in the disease for Abs against MHC has been suspected, this has not been formally demonstrated. Since 2007, a hemorrhagic syndrome due to thrombocytopenia and designated as bovine neonatal pancytopenia (BNP) has been recognized in calves in several European countries. An inactivated antiviral vaccine is strongly suspected to be involved in this syndrome because of its highly frequent use in the dams of affected calves. In this study, we show that BNP is an alloimmune disease, as we reproduced the signs by transferring serum Abs from vaccinated BNP dams into healthy neonatal calves. Ab specificity was strongly associated with the presence of allogeneic MHC class I Abs in the dams. MHC class I staining was also observed on Madin–Darby bovine kidney cells, a cell line related to the one used to produce the vaccine Ag. Our report emphatically demonstrates that alloimmunization against MHC class I is associated with a substantial risk of developing cytopenia-associated syndromes in neonates when a cell line of the same species is used to produce an inactivated vaccine injected into the mother.

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Section: Discussionsupporting

confidence: 53%

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

Foucras

Corbière

Tasca

et al. 2011

The Journal of Immunology

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“…It has been demonstrated previously that direct exposure of resting neutrophils to anti-HNA-3a alone is not sufficient to induce ROS. 12,13 However, ROS was detectable in anti-HNA-3a IgG-primed neutrophils followed by formyl-methionyl-leucyl phenylalanine stimulation. 13 In contrast to this report, we did not observe a significantly augmented respiratory burst reaction neither in resting nor in formyl-methionyl-leucyl phenylalanine-treated neutrophils primed with anti-HNA-3a antibodies using 2 different methods (2′,7′-dichlorofluorescin diacetate and ferricytochromec).…”

Section: Discussionmentioning

confidence: 98%

“…34,42 It is well known that anti-HNA-3a antibodies form strong neutrophil agglutinates in some in vitro assays, such as the GAT assay. Recently, Greinacher et al 12 demonstrated that this mechanism is FcγR independent. The question whether this phenomenon occurs in vivo and participates in the mechanism of TRALI is not clear.…”

Section: Discussionmentioning

confidence: 99%

Anti–Human Neutrophil Antigen-3a Induced Transfusion-Related Acute Lung Injury in Mice by Direct Disturbance of Lung Endothelial Cells

Bayat

Tjahjono

Sydykov

et al. 2013

ATVB

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Objective— Antibodies against human neutrophil antigen-3a (HNA-3a) located on choline transporter-like protein 2 induce severe transfusion-related acute lung injury (TRALI). This study aims to identify the mechanism implicated in anti–HNA-3a-mediated TRALI. Approach and Results— Our analysis shows that anti–HNA-3a recognizes 2 choline transporter-like protein 2 isoforms (P1 and P2) on human microvascular endothelial cells from lung blood vessels but reacts only with the P1 isoform on neutrophils. Direct treatment of HNA-3a–positive endothelial cells with anti–HNA-3a, but not with anti–HNA-3b, leads to reactive oxygen species production, increased albumin influx, and decreased endothelial resistance associated with the formation of actin stress filaments and loosening of junctional vascular endothelium-cadherin. In a novel in vivo mouse model, TRALI was documented by significant increase in lung water content, albumin concentration, and neutrophil numbers in the bronchoalveolar lavage on injection of human anti–HNA-3a in lipopolysaccharides-treated, as well as nontreated mice. Interestingly, although neutrophil depletion alleviated severity of lung injury, it failed to prevent TRALI in this model. Infusion of anti–HNA-3a F(ab′) 2 fragments caused moderate TRALI. Finally, mice lacking nicotinamide adenine dinucleotide phosphate oxidase (NOX2 y/ - ) were protected from anti–HNA-3a-mediated TRALI. Conclusions— These data demonstrate the initiation of endothelial barrier dysfunction in vitro and in vivo by direct binding of anti–HNA-3a on endothelial cells. It seems, however, that the presence of neutrophils aggravates barrier dysfunction. This novel mechanism of TRALI primarily mediated by endothelial cell dysfunction via choline transporter-like protein 2 may help to define new treatment strategies to decrease TRALI-related mortality.

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“…It is generally thought, although unproven, that either receptor cross-linking or direct activation of the receptor may lead to signaling events that cause neutrophil activation and, subsequent, deterioration of the lung vascular integrity. 10,13,32,33 This mechanism is not likely in the case of HLA class II antibodies, because HLA class II antigens are normally not present on neutrophils (see below). Here, we observed, however, that HLA class II antibodies can bind to monocytes that express the cognate antigen and thereby induces the release of potent cytokines and LTB 4 .…”

Section: Discussionmentioning

confidence: 99%

Mechanism of transfusion-related acute lung injury induced by HLA class II antibodies

Sachs

Wasel

Bayat

et al. 2011

Blood

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Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality in the United States and other countries. In most TRALI cases, human leukocyte antigen (HLA) class II antibodies are detected in implicated donors. However, the corresponding antigens are not present on the cellular key players in TRALI: neutrophils and endothelium. In this study, we identify monocytes as a primary target in HLA class II-induced TRALI. Monocytes become activated when incubated with matched HLA class II antibodies and are capable of activating neutrophils, which, in turn, can induce disturbance of an endothelial barrier. In an ex vivo rodent model, HLA class II antibody-dependent monocyte activation leads to severe pulmonary edema in a relevant period of time, whenever neutrophils are present and the endothelium is preactivated. Our data suggest that in most TRALI cases, monocytes are cellular key players, because HLA class II antibodies induce TRALI by a reaction cascade initiated by monocyte activation. Furthermore, our data support the previous assumption that TRALI pathogenesis follows a threshold model. Having identified the biologic mechanism of HLA class II antibodyinduced TRALI, strategies to avoid plasma from immunized donors, such as women with a history of pregnancy, appear to be justified preventive measures. (Blood. 2011;117(2):669-677) IntroductionTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated death in the United States and other countries. 1 It typically presents within 6 hours after transfusion as a clinical syndrome characterized by acute respiratory distress, hypoxemia, and a bilateral pulmonary edema on chest x-ray. 2 The incidence of TRALI has been estimated as 1/5000 for all blood components, and current mortality rates are in the range of 5%-25%. 3 All blood components have been implicated in TRALI, but those containing large amounts of plasma are mainly responsible. [3][4][5] A recently published literature review states that in 80% of all TRALI cases, white blood cell antibodies can be identified in the implicated blood donor, 6 and most implicated donors have been women with a history of pregnancy. Pregnancy results in alloimmunization against paternal white blood cell antigens in 21%-24% of women, 7,8 with 3 main antibody specificities: human leukocyte antigen (HLA) class I, HLA class II, and human neutrophil antigens (HNAs).The capability of antibodies recognizing either HNA 9-11 or HLA class I 12,13 to precipitate TRALI has been proved in different animal models. It is consensus opinion that neutrophil activation is the key mechanism by which antibodies to HNA and to HLA class I mediate TRALI, 4,14 be it by direct binding to the cognate antigen on the surface of the neutrophil [9][10][11]13 or, in the case of HLA class I antibodies, possibly by binding to HLA class I molecules on pulmonary endothelial cells, which leads to neutrophil trapping by the neutrophils' Fc receptors and subsequent neutrophil activation by receptor...

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Characterization of the human neutrophil alloantigen-3a

Cited by 128 publications

References 19 publications

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

Alloantibodies against MHC Class I: A Novel Mechanism of Neonatal Pancytopenia Linked to Vaccination

Anti–Human Neutrophil Antigen-3a Induced Transfusion-Related Acute Lung Injury in Mice by Direct Disturbance of Lung Endothelial Cells

Mechanism of transfusion-related acute lung injury induced by HLA class II antibodies

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