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Recapitulation of posttransfusion purpura by cross-strain platelet immunization in mice.

ABSTRACT: Posttransfusion purpura (PTP) is an uncommon but life-threatening condition characterized by profound thrombocytopenia occurring ?1 week after a blood transfusion. The hallmark of PTP is a potent immunoglobulin G antibody specific for a transfused platelet-specific alloantigen, usually located on glycoprotein IIb/IIIa (GPIIb/IIIa; ?IIb/?3 integrin). It is widely thought that this alloantibody somehow causes the thrombocytopenia, despite absence from host platelets of the alloantigen for which it is specific. In studies described here, we found that cross-strain platelet immunization in mice commonly induces GPIIb/IIIa-specific alloantibodies combined with platelet-specific autoantibodies and varying degrees of thrombocytopenia, and we identified 1 strain combination (129S1Svlm/PWKPhJ) in which 95% of immunized mice made both types of antibody and developed severe thrombocytopenia. There was a strong inverse correlation between autoantibody strength and platelet decline (P < .0001) and plasma from mice that produced autoantibodies caused thrombocytopenia when transfused to syngeneic animals, arguing that autoantibodies were the cause of thrombocytopenia. The findings define a model in which a routine alloimmune response to platelets regularly transitions to an autoimmune reaction capable of causing severe thrombocytopenia and support the hypothesis that PTP is an autoimmune disorder.

SUBMITTER: Bougie DW

PROVIDER: S-EPMC6988389 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Recapitulation of posttransfusion purpura by cross-strain platelet immunization in mice.

Bougie Daniel W DW Sutton Jessica J Aster Richard H RH

Blood advances 20200101 2

Posttransfusion purpura (PTP) is an uncommon but life-threatening condition characterized by profound thrombocytopenia occurring ∼1 week after a blood transfusion. The hallmark of PTP is a potent immunoglobulin G antibody specific for a transfused platelet-specific alloantigen, usually located on glycoprotein IIb/IIIa (GPIIb/IIIa; αIIb/β3 integrin). It is widely thought that this alloantibody somehow causes the thrombocytopenia, despite absence from host platelets of the alloantigen for which it ...[more]

PMID: 31968077

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Project description:UnlabelledEquine herpesvirus 1 (EHV-1) is a major pathogen affecting equines worldwide. The virus causes respiratory disease, abortion, and, in some cases, neurological disease. EHV-1 strain KyA is attenuated in the mouse and equine, whereas wild-type strain RacL11 induces severe inflammation of the lung, causing infected mice to succumb at 4 to 6 days postinfection. Our previous results showed that KyA immunization protected CBA mice from pathogenic RacL11 challenge at 2 and 4 weeks postimmunization and that KyA infection elicited protective humoral and cell-mediated immune responses. To investigate the protective mechanisms of innate immune responses to KyA, KyA-immunized mice were challenged with RacL11 at various times postvaccination. KyA immunization protected mice from RacL11 challenge at 1 to 7 days postimmunization. Immunized mice lost less than 10% of their body weight and rapidly regained weight. Virus titers in the lungs of KyA-immunized mice were 1,000-fold lower at 2 days post-RacL11 challenge than virus titers in the lungs of nonimmunized mice, indicating accelerated virus clearance. Affymetrix microarray analysis revealed that gamma interferon (IFN-γ) and 16 antiviral interferon-stimulated genes (ISGs) were upregulated 3.1- to 48.2-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been immunized with KyA. Murine IFN-γ inhibited EHV-1 infection of murine alveolar macrophages and protected mice against lethal EHV-1 challenge, suggesting that IFN-γ expression is important in mediating the protection elicited by KyA immunization. These results suggest that EHV-1 KyA may be used as a live attenuated EHV-1 vaccine as well as a prophylactic agent in horses.ImportanceViral infection of cells initiates a signal cascade of events that ultimately attempts to limit viral replication and prevent infection through the expression of host antiviral proteins. In this study, we show that EHV-1 KyA immunization effectively protected CBA mice from pathogenic RacL11 challenge at 1 to 7 days postvaccination and increased the expression of IFN-γ and 16 antiviral interferon-stimulated genes (ISGs). The administration of IFN-γ blocked EHV-1 replication in murine alveolar macrophages and mouse lungs and protected mice from lethal challenge. To our knowledge, this is the first report of an attenuated EHV-1 vaccine that protects the animal at 1 to 7 days postimmunization by innate immune responses. Our findings suggested that IFN-γ serves as a novel prophylactic agent and may offer new strategies for the development of anti-EHV-1 agents in the equine.

Dataset Information

Recapitulation of posttransfusion purpura by cross-strain platelet immunization in mice.

Publications

Recapitulation of posttransfusion purpura by cross-strain platelet immunization in mice.

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