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http://purl.uniprot.org/citations/25960020http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25960020http://www.w3.org/2000/01/rdf-schema#comment"

Background

Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies to a self-antigen, platelet factor (4) and heparin. The reasons why antibodies form to PF4/heparin, but not to PF4 bound to other cellular glycosaminoglycans are poorly understood.

Objective

To investigate differences in cellular responses to cell-bound PF4 and PF4/heparin complexes, we studied the internalization of each by peripheral blood-derived monocytes, dendritic cells and neutrophils.

Methods and results

Using unlabeled and fluorescently-labeled antigen and/or labeled monoclonal antibody to PF4/heparin complexes (KKO), we show that PF4/heparin complexes are taken up by monocytes in a heparin-dependent manner and are internalized by human monocytes and dendritic cells, but not by neutrophils. Complexes of PF4/low-molecular-weight heparin and complexes composed of heparin and murine PF4, protamine or lysozyme are internalized similarly, suggesting a common endocytic pathway. Uptake of complexes is mediated by macropinocytosis, as shown by inhibition using cytochalasin D and amiloride. Internalized complexes are transported intact to late endosomes, as indicated by co-staining of vesicles with KKO and lysosomal associated membrane protein-2 (LAMP-2). Lastly, we show that cellular uptake is accompanied by expression of MHCII and CD83 co-stimulatory molecules.

Conclusions

Taken together, these studies establish a distinct role for heparin in enhancing antigen uptake and activation of the initial steps in the cellular immune response to PF4-containing complexes."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.org/dc/terms/identifier"doi:10.1111/jth.13003"xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Cines D.B."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Poncz M."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Arepally G.M."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Rauova L."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Khandelwal S."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/author"Joglekar M."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/name"J Thromb Haemost"xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/pages"1416-1427"xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/title"Heparin enhances uptake of platelet factor 4/heparin complexes by monocytes and macrophages."xsd:string
http://purl.uniprot.org/citations/25960020http://purl.uniprot.org/core/volume"13"xsd:string
http://purl.uniprot.org/citations/25960020http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/25960020
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http://purl.uniprot.org/uniprot/P02776http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/25960020
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