Maternal Anti-αIIb Antibodies Target Fetal Hematopoietic Stem Cells and May Lead to Pancytopenia and Miscarriage in Fnait
Notice bibliographique
Résumé
Abstract Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a devastating disorder characterized by an aberrant maternal immune response against paternally inherited polymorphisms on fetal platelet antigens. Affected fetuses can experience severe bleeding (e.g. intracranial hemorrhage; ICH), neurological sequelae and death. The targeted platelet antigens are located predominantly on platelet surface receptor αIIbβ3 integrin. It is estimated that 0.5-1.5/1000 live neonates are born with FNAIT although this incidence may largely underestimate the prevalence of the disease due to miscarriage. We have previously demonstrated that anti-β3 alloantibodies can target not only fetal platelets but also the β3 subunit on endothelial cells leading to ICH and placental vascular pathologies (J Clin Invest. 2015; Nat Commun. 2017). Although the number of polymorphisms in the αIIb subunit is similar to the β3 subunit, reported incidences of anti-β3 mediated FNAIT are far greater. It is currently unknown whether this due to miscarriage in anti-αIIb mediated FNAIT. αIIb was previously considered to be exclusively expressed on platelets, however hematopoietic stem cells (HSCs) and their early progenitors can express αIIbβ3 during embryonic development and αIIb is one of the earliest markers of hematopoietic commitment. Throughout gestation, HSCs migrate from yolk sac to the aorta-gonadal-mesonephros, placenta, fetal liver and finally bone marrow. We hypothesize that miscarriage is prevalent in anti-αIIb mediated FNAIT and that maternal anti-αIIb antibodies may target HSCs resulting in decreased blood cell counts, increased bleeding and fetal death. Methods: We established an animal model of anti-αIIb mediated FNAIT by immunizing αIIb-/- mice with 108 wild-type (WT, αIIb+/+) platelets. Immunized αIIb-/- mice were then bred with WT males. We used non-immunized (naive) αIIb-/- x WT breeding pairs as a control. Sera of immunized and naive mice were collected prior to breeding and ultrasound was used to detect fetal death. Mice were sacrificed at E14.5 and fetuses, placentas and fetal livers were weighed. Cell suspensions were prepared from these tissues as well as fetal blood and analyzed with flow cytometry. Fluorescent markers were used to identify HSCs (CD34+/CD117+/Lin- or CD34+/CD45+) and blood cell counts for T cells (CD3+,CD4+,CD8+), B cells (CD19+), myeloid lineage cells (CD11b+) and megakaryocytes (GPIbα+). Results: Sera of immunized mice showed a significant anti-αIIb immune response. Pups of immunized mice had low platelet counts, reduced body weight and bleeding diathesis. Ultrasound revealed miscarriage occurred mainly at E14.5 of immunized αIIb+/- fetuses. The miscarriage rate in our anti-αIIb mediated FNAIT model appeared significantly higher than the anti-β3 model. At E14.5, our results showed live fetuses of immunized mice had significantly lower body and liver weight although no significant difference in placental weight was observed. We found fetal liver HSCs have increased maternal antibody binding when incubated with sera from immunized αIIb-/- mice versus naive αIIb-/- mice in vitro, suggesting that maternal anti-αIIb antibodies target fetal HSCs in vivo . Preliminary data also demonstrated that fetuses in the immunized group had reduced overall HSCs as well as αIIb+ HSC subsets in the placenta, liver and yolk sac. Fetal blood analysis showed reduced hematopoietic lineage cells in the immunized group, particularly T cells (CD3+), B cells and megakaryocytes. Conclusions: We established an anti-αIIb mouse model of FNAIT and revealed a high rate of miscarriage, which may explain the paucity of reported human cases. Our results indicate maternal anti-αIIbantibodies may bind and target fetal HSCs during embryonic development, which contributes significantly to impaired placental and fetal liver development, and fetal death. Destruction of early αIIb+ HSC progenitors may explain the decrease in HSCs (both αIIb+ and αIIb-) and account for the pancytopenia in FNAIT fetuses. Further experiments are in progress to elucidate the mechanism by which destruction of αIIb+ HSCs contributes to fetal pathology. *J.S. and B.E.O contributed equally to this work Disclosures No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».