Heparin-induced thrombocytopenia (HIT) may be the most common drug-induced immune disease, and can result in devastating or fatal arterial/venous thrombosis and thromboembolism. Patient IgG antibodies that bind to platelet factor 4 (PF4) in a complex with heparin to form lgG/PF4/heparin immune complexes are central to the pathogenesis of HIT. These immune complexes, in turn, bind FcyRlla on the platelet surface and induce platelet activation, leading to thrombocytopenia and contributing to thrombosis. HIT exhibits both features of a T ceW-independent immune response, characterized by the rapid onset and decline of antibodies and no immunological memory, as well as aspects of a secondary T ceW-dependent immune response, characterized by the prevalence of the IgG class of anti-PF4/heparin antibodies and a requirement for T cells. These atypical immunological characteristics of HIT have confounded our understanding ofthe mechanism by which B cells contribute to the immune pathogenesis of the disease. It is known that signals from the B cell receptor (BCR) are required for B cell function. A critical event in BCR signaling is activation of phospholipase Cy2 (PLCy2), which hydrolyzes membrane lipids to generate diacylglycerol (DAG) and inositol 1,4,5- trisphosphate (IP3). DAG leads to activation of a signaling pathway that involves protein kinase C (PKC), a B-cell lymphoma 10 (BcllO)-containing complex, and the protein kinase TAK1. Our previous targeted gene-disruption studies have shown that the PLCy2/Bcl10/TAK1 pathway is essential for BCR-mediated antibody production. Moreover, a mouse model for production of anti-mouse PF4/heparin HIT antibodies has been established, as well as hFcyRlla transgenic mice that can recapitulate HIT. These models make it possible to characterize molecular aspects of the immune response to PF4/heparin complexes that are essential to human HIT development. We propose to use these mouse models, in combination with several other genetically-modified mouse strains, to elucidate how B cells produce the PF4/heparin-specific antibodies that cause HIT, and determine whether manipulation of the PLCy2/Bcl10/TAK1 pathway to control B cell antibody production can prevent HIT. Specifically, we will determine 1) the contribution of marginal zone, B1 and memory B cells to HIT antibody production, 2) whether breakdown of B cell anergy contributes to activation of PF4/heparin-specific B cells, and 3) whether inhibition of the PLCy2/Bcl10/TAK1 pathway can prevent HIT. Identifying the B cell subsets responsible for HIT antibody production, determining how PF4 /heparin-specific B cells are activated, and defining the role of the BCR signaling pathway in HIT antibody production will provide new clues to the pathogenesis of HIT and help to develop novel prevention methods.
This study aims to understand the cause of heparin-induced thrombocytopenia, one of the most common drug-induced life-threatening blood diseases, and is expected to identify specific targets for developing novel and effective ways for the control and prevention of this disease.
|Fahs, Scot A; Hille, Matthew T; Shi, Qizhen et al. (2014) A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123:3706-13|
|Shi, Qizhen; Kuether, Erin L; Chen, Yingyu et al. (2014) Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 123:395-403|
|Kanaji, S; Fahs, S A; Ware, J et al. (2014) Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome. J Thromb Haemost 12:1726-32|
|Zheng, Yongwei; Wang, Alexander W; Yu, Mei et al. (2014) B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood 123:931-4|
|Elbatarny, M; Mollah, S; Grabell, J et al. (2014) Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia 20:831-5|
|Weiler, Hartmut (2014) Inflammation-associated activation of coagulation and immune regulation by the protein C pathway. Thromb Res 133 Suppl 1:S32-4|
|Brott, David A; Katein, Anne; Thomas, Heath et al. (2014) Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury. Toxicol Pathol 42:672-83|
|Zheng, Yongwei; Yu, Mei; Podd, Andrew et al. (2013) Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood 121:3484-92|
|Qi, Xiaopeng; Hong, Jessie; Chaves, Lee et al. (2013) Antagonistic regulation by the transcription factors C/EBP* and MITF specifies basophil and mast cell fates. Immunity 39:97-110|
|Tourdot, Benjamin E; Brenner, Michelle K; Keough, Kathleen C et al. (2013) Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: a case study involving PECAM-1. Biochemistry 52:2597-608|
Showing the most recent 10 out of 176 publications