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Heparin enhances uptake of platelet factor 4/heparin complexes by monocytes and macrophages
Author(s) -
Joglekar M.,
Khandelwal S.,
Cines D. B.,
Poncz M.,
Rauova L.,
Arepally G. M.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13003
Subject(s) - heparin , platelet factor 4 , pinocytosis , chemistry , internalization , endosome , antigen , endocytic cycle , platelet , protamine sulfate , protamine , platelet activation , cytochalasin b , immune complex , monocyte , immune system , microbiology and biotechnology , endocytosis , immunology , biochemistry , biology , cell
Summary 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 PF 4/heparin, but not to PF 4 bound to other cellular glycosaminoglycans are poorly understood. Objective To investigate differences in cellular responses to cell‐bound PF 4 and PF 4/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 PF 4/heparin complexes ( KKO ), we show that PF 4/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 PF 4/low‐molecular‐weight heparin and complexes composed of heparin and murine PF 4, 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 CD 83 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 PF 4‐containing complexes.

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