Involvement of the cysteine-rich domain of glycoprotein IIIa in the expression of the human platelet alloantigen, PlA1: evidence for heterogeneity in the humoral response

Valentin, Nathalie; Visentin, Gian Paolo; Newman, Peter J.

doi:10.1182/blood.v85.11.3028.bloodjournal85113028

Cited by 76 publications

(54 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T cell clones had dissimilar TCR genes [20,21] that could affect their affinity for peptides. Anti-HPA-1a antibodies are known to be heterogeneous for their epitope specificity [80] and functional activity [81], and the large range in anti-HPA-1a concentrations we found (Table 1) may reflect differences in IgG affinity maturation. Importantly, unpredictable fluctuations in circulating HPA-1aspecific T cells occur in both pregnant [18] and nonpregnant FNAIT women (Table 3).…”

Section: Discussionmentioning

confidence: 89%

Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

Jackson

Eastlake

Kumpel

2014

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryFetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs most frequently when human platelet antigen (HPA)-1a-positive fetal platelets are destroyed by maternal HPA-1a immunoglobulin (Ig)G antibodies. Pregnancies at risk are treated by administration of high-dose intravenous Ig (IVIG) to women, but this is expensive and often not well tolerated. Peptide immunotherapy may be effective for ameliorating some allergic and autoimmune diseases. The HPA-1a/1b polymorphism is Leu/Pro33 on β3 integrin (CD61), and the anti-HPA-1a response is restricted to HPA-1b1b and HLA-DRB3*0101-positive pregnant women with an HPA-1a-positive fetus. We investigated whether or not HPA-1a antigen-specific peptides that formed the T cell epitope could reduce IgG anti-HPA-1a responses, using a mouse model we had developed previously. Peripheral blood mononuclear cells (PBMC) in blood donations from HPA-1a-immunized women were injected intraperitoneally (i.p.) into severe combined immunodeficient (SCID) mice with peptides and HPA-1a-positive platelets. Human anti-HPA-1a in murine plasma was quantitated at intervals up to 15 weeks. HPA-1a-specific T cells in PBMC were identified by proliferation assays. Using PBMC of three donors who had little T cell reactivity to HPA-1a peptides in vitro, stimulation of anti-HPA-1a responses by these peptides occurred in vivo. However, with a second donation from one of these women which, uniquely, had high HPA1a-specific T cell proliferation in vitro, marked suppression of the anti-HPA-1a response by HPA-1a peptides occurred in vivo. HPA-1a peptide immunotherapy in this model depended upon reactivation of HPA-1a T cell responses in the donor. For FNAIT, we suggest that administration of antigen-specific peptides to pregnant women might cause either enhancement or reduction of pathogenic antibodies.

show abstract

Section: Discussionmentioning

confidence: 89%

Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

Jackson

Eastlake

Kumpel

2014

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…6 As well, studies have shown that different alloantibodies against HPA-1a recognize different epitopes on GPIIIa. 21 Therefore, it is possible that alloantibodies against some epitopes are inherently more pathogenic and lead to more severe clinical presentation. 22 The syndrome of thrombocytopenia due to passive transfer of PLT antibody is self-limited, and patients with asymptomatic thrombocytopenia do not require treatment.…”

Section: Discussionmentioning

confidence: 99%

Consequences of transfusion of platelet antibody: a case report and literature review

2008

View full text Add to dashboard Cite

BACKGROUND: Passive transfer of platelet (PLT) antibody by blood transfusion can lead to severe thrombocytopenia, bleeding, and an acute transfusion reaction. CASE REPORT: A 49‐year‐old male on warfarin developed thrombocytopenic bleeding within 2 hours of transfusion with a single unit of fresh‐frozen plasma (FFP). The patient's PLT count on admission was 122 × 109 per L. Two hours after transfusion, PLT count has decreased to 5 × 109 per L. The patient's PLT antibody screen by solid‐phase enzyme‐linked immunosorbent assay was negative and his genotype was HPA‐1a/1b. The donor's genotype was HPA‐1b/1b and antibody screen revealed anti‐HPA‐1a. A lookback investigation identified another case of severe thrombocytopenia after FFP infusion 4 years previously. REVIEW OF LITERATURE: A literature review identified 19 cases of passive transfer of PLT antibody that resulted in thrombocytopenia. The PLT nadir of 7 × 109 per L was reached within 6 hours after transfusion with a median time to PLT recovery of 5 days. Transfusion was accompanied by an acute transfusion reaction in 30 percent of recipients. Approximately 75 percent of recipients developed thrombocytopenic bleeding. All cases involved a female donor with a history of pregnancy. High‐plasma‐volume components accounted for the majority of cases while anti‐HPA‐1a was the most frequently implicated antibody. CONCLUSION: Unexplained posttransfusion thrombocytopenia should be investigated to rule out passive transfer of PLT antibodies. Implicated donors should be deferred from subsequent donations. Switching to predominantly male plasma for transfusion may lead to reduction in cases of thrombocytopenia due to passive transfer of PLT antibody. Rational use of blood products may further reduce incidence of this complication.

show abstract

“…The HUVEC model, however, is an artificial model and vascular damage in vivo might occur after more prolonged exposure to antibodies or by a more complex interaction in the presence of accessory factors, provided by granulocytes, monocytes, proinflammatory mediators, platelets and pro-coagulants. Cerebral vascular endothelium may differ from HUVEC, because periventricular vessels have been demonstrated to have a high expression of Fc-IgG receptors [51] and because heterogeneity of HPA-1a expression in different cerebral vessels [4] could not be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…First, the titre, IgG-subclass, or ability to activate complement of HPA-antibodies might be involved [9,10,16] or the co-existence of HLA antibodies, which enhance immune-mediated damage induced by HPA-antibodies [9,[17][18][19]. Secondly, differences in the GPIIIa-domains recognized by anti-HPA-antibodies might influence the manifestation of the disease [4] and thirdly, as the GPIIb/IIIa-complex is expressed on ECs, binding of anti-HPA antibodies to HPAantigen on the endothelial surface might induce vascular tissue damage [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Effect of maternal anti-HPA-1a antibodies and polyclonal IVIG on the activation status of vascular endothelial cells

Radder¹,

Beekhuizen²,

Kanhai³

et al. 2004

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARYMaternal anti-HPA-1a antibodies can cause severe fetal and neonatal alloimmune thrombocytopenia (FNAIT), complicated by intracranial haemorrhage (ICH). Antenatal treatment with maternal intravenous immunoglobulin (IVIG) seems to protect against ICH even when thrombocytopenia persists. The aim of this study was to investigate if anti-HPA-1a antibodies and IVIG potentially affect vascular endothelial cells (ECs) in order to identify susceptibility for ICH. Human umbilical cord endothelial cells (HUVEC) were incubated with anti-HPA-1a antibodies with or without polyclonal IVIG and evaluated for EC activation. Maternal sera with anti-HPA-1a antibodies affected neither the EC expression of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and tissue factor (TF) nor the release of van Willebrand factor (vWF) or interleukin (IL)-8 nor the integrity of ECs. Maternal sera obtained after IVIG treatment and polyclonal IVIG decrease constitutive and cytokine-induced ICAM-1 and VCAM-1 expression on ECs. The results show that maternal anti-HPA1a antibodies cause no activation or damage of ECs in this model. The clinical relevance of the deactivating properties of IVIG on EC activation with respect to ICH deserves further investigation.Keywords fetal or neonatal alloimmune thrombocytopenia intracranial haemorrhage HPA-1a IVIG vascular endothelium

show abstract

Involvement of the cysteine-rich domain of glycoprotein IIIa in the expression of the human platelet alloantigen, PlA1: evidence for heterogeneity in the humoral response

Cited by 76 publications

References 30 publications

Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

Human platelet antigen (HPA)-1a peptides do not reliably suppress anti-HPA-1a responses using a humanized severe combined immunodeficiency (SCID) mouse model

Consequences of transfusion of platelet antibody: a case report and literature review

Effect of maternal anti-HPA-1a antibodies and polyclonal IVIG on the activation status of vascular endothelial cells

Contact Info

Product

Resources

About