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Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood 2013 Apr 25;121(17):3484-92

Date

03/06/2013

Pubmed ID

23460609

Pubmed Central ID

PMC3637017

DOI

10.1182/blood-2013-01-477091

Scopus ID

2-s2.0-84879407772   27 Citations

Abstract

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of platelet factor 4 (PF4), heparin, and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, the B-cell origin of HIT antibody production is not known. Here, we show that anti-PF4/heparin antibodies are readily generated in wild-type mice on challenge with PF4/heparin complexes, and that antibody production is severely impaired in B-cell-specific Notch2-deficient mice that lack marginal zone (MZ) B cells. As expected, Notch2-deficient mice responded normally to challenge with T-cell-dependent antigen nitrophenyl-chicken γ globulin but not to the T-cell-independent antigen trinitrophenyl-Ficoll. In addition, wild-type, but not Notch2-deficient, B cells plus B-cell-depleted wild-type splenocytes adoptively transferred into B-cell-deficient μMT mice responded to PF4/heparin complex challenge. PF4/heparin-specific antibodies produced by wild-type mice were IgG2b and IgG3 isotypes. An in vitro class-switching assay showed that MZ B cells were capable of producing antibodies of IgG2b and IgG3 isotypes. Lastly, MZ, but not follicular, B cells adoptively transferred into B-cell-deficient μMT mice responded to PF4/heparin complex challenge by producing PF4/heparin-specific antibodies of IgG2b and IgG3 isotypes. Taken together, these data demonstrate that MZ B cells are critical for PF4/heparin-specific antibody production.

Author List

Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, Arepally G, Wang D

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Renren Wen PhD Associate Investigator in the Blood Research Institute department at BloodCenter of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
Antibody Formation
Anticoagulants
Antigen-Presenting Cells
Autoantibodies
B-Lymphocytes
Coagulants
Flow Cytometry
Heparin
Immunization
Immunoglobulin Class Switching
Immunoglobulin G
Mice
Mice, Inbred C57BL
Mice, Knockout
Platelet Factor 4
Receptor, Notch2
Thrombocytopenia
jenkins-FCD Prod-469 c3fc8ab87196149f9b23743c01b947d47e7319e5