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Critical role for mouse marginal zone B cells in PF4/heparin antibody production.

Publication ,  Journal Article
Zheng, Y; Yu, M; Podd, A; Yuan, L; Newman, DK; Wen, R; Arepally, G; Wang, D
Published in: Blood
April 25, 2013

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.

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

April 25, 2013

Volume

121

Issue

17

Start / End Page

3484 / 3492

Location

United States

Related Subject Headings

  • Thrombocytopenia
  • Receptor, Notch2
  • Platelet Factor 4
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Immunology
  • Immunoglobulin G
  • Immunoglobulin Class Switching
  • Immunization
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zheng, Y., Yu, M., Podd, A., Yuan, L., Newman, D. K., Wen, R., … Wang, D. (2013). Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood, 121(17), 3484–3492. https://doi.org/10.1182/blood-2013-01-477091
Zheng, Yongwei, Mei Yu, Andrew Podd, Liudi Yuan, Debra K. Newman, Renren Wen, Gowthami Arepally, and Demin Wang. “Critical role for mouse marginal zone B cells in PF4/heparin antibody production.Blood 121, no. 17 (April 25, 2013): 3484–92. https://doi.org/10.1182/blood-2013-01-477091.
Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, et al. Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood. 2013 Apr 25;121(17):3484–92.
Zheng, Yongwei, et al. “Critical role for mouse marginal zone B cells in PF4/heparin antibody production.Blood, vol. 121, no. 17, Apr. 2013, pp. 3484–92. Pubmed, doi:10.1182/blood-2013-01-477091.
Zheng Y, Yu M, Podd A, Yuan L, Newman DK, Wen R, Arepally G, Wang D. Critical role for mouse marginal zone B cells in PF4/heparin antibody production. Blood. 2013 Apr 25;121(17):3484–3492.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

April 25, 2013

Volume

121

Issue

17

Start / End Page

3484 / 3492

Location

United States

Related Subject Headings

  • Thrombocytopenia
  • Receptor, Notch2
  • Platelet Factor 4
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Immunology
  • Immunoglobulin G
  • Immunoglobulin Class Switching
  • Immunization