title: Critical role for mouse marginal zone B cells in PF4/heparin antibody production.
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.
authors: Blood Research Institute, BloodCenter of Wisconsin, 8727 Watertown Plank Rd, Milwaukee, WI 53226, USA.
authors: Yongwei
authors: Y
authors: Zheng
authors: Mei
authors: M
authors: Yu
authors: Andrew
authors: A
authors: Podd
authors: Liudi
authors: L
authors: Yuan
authors: Debra K
authors: DK
authors: Newman
authors: Renren
authors: R
authors: Wen
authors: Gowthami
authors: G
authors: Arepally
authors: Demin
authors: D
authors: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation; D000925:Anticoagulants / Q000009:adverse effects / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D003029:Coagulants / Q000009:adverse effects / Q000276:immunology; D005434:Flow Cytometry; D006493:Heparin / Q000009:adverse effects / Q000276:immunology*; D007114:Immunization; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010978:Platelet Factor 4 / Q000009:adverse effects / Q000276:immunology*; D051883:Receptor, Notch2 / Q000502:physiology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000175:diagnosis / Q000276:immunology*
chemical_list: D000925:Anticoagulants; D001323:Autoantibodies; D003029:Coagulants; D007074:Immunoglobulin G; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D010978:Platelet Factor 4; D006493:Heparin