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Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway.

Publication ,  Journal Article
Khandelwal, S; Ravi, J; Rauova, L; Johnson, A; Lee, GM; Gilner, JB; Gunti, S; Notkins, AL; Kuchibhatla, M; Frank, M; Poncz, M; Cines, DB; Arepally, GM
Published in: Blood
December 6, 2018

The mechanisms by which exposure to heparin initiates antibody responses in many, if not most, recipients are poorly understood. We recently demonstrated that antigenic platelet factor 4 (PF4)/heparin complexes activate complement in plasma and bind to B cells. Here, we describe how this process is initiated. We observed wide stable variation in complement activation when PF4/heparin was added to plasma of healthy donors, indicating a responder "phenotype" (high, intermediate, or low). Proteomic analysis of plasma from these healthy donors showed a strong correlation between complement activation and plasma immunoglobulin M (IgM) levels (r = 0.898; P < .005), but not other Ig isotypes. Complement activation response to PF4/heparin in plasma displaying the low donor phenotype was enhanced by adding pooled IgM from healthy donors, but not monoclonal IgM. Depletion of IgM from plasma abrogated C3c generation by PF4/heparin. The complement-activating features of IgM are likely mediated by nonimmune, or natural, IgM, as cord blood and a monoclonal polyreactive IgM generate C3c in the presence of PF4/heparin. IgM facilitates complement and antigen deposition on B cells in vitro and in patients receiving heparin. Anti-C1q antibody prevents IgM-mediated complement activation by PF4/heparin complexes, indicating classical pathway involvement. These studies demonstrate that variability in plasma IgM levels correlates with functional complement responses to PF4/heparin. Polyreactive IgM binds PF4/heparin, triggers activation of the classical complement pathway, and promotes antigen and complement deposition on B cells. These studies provide new insights into the evolution of the heparin-induced thrombocytopenia immune response and may provide a biomarker of risk.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 6, 2018

Volume

132

Issue

23

Start / End Page

2431 / 2440

Location

United States

Related Subject Headings

  • Proteomics
  • Platelet Factor 4
  • Lymphocyte Activation
  • Immunology
  • Immunoglobulin M
  • Humans
  • Heparin
  • Complement Pathway, Classical
  • Complement C3c
  • B-Lymphocytes
 

Citation

APA
Chicago
ICMJE
MLA
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Khandelwal, S., Ravi, J., Rauova, L., Johnson, A., Lee, G. M., Gilner, J. B., … Arepally, G. M. (2018). Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood, 132(23), 2431–2440. https://doi.org/10.1182/blood-2018-03-834598
Khandelwal, Sanjay, Joann Ravi, Lubica Rauova, Alexandra Johnson, Grace M. Lee, Jennifer B. Gilner, Sreenivasulu Gunti, et al. “Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway.Blood 132, no. 23 (December 6, 2018): 2431–40. https://doi.org/10.1182/blood-2018-03-834598.
Khandelwal S, Ravi J, Rauova L, Johnson A, Lee GM, Gilner JB, et al. Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood. 2018 Dec 6;132(23):2431–40.
Khandelwal, Sanjay, et al. “Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway.Blood, vol. 132, no. 23, Dec. 2018, pp. 2431–40. Pubmed, doi:10.1182/blood-2018-03-834598.
Khandelwal S, Ravi J, Rauova L, Johnson A, Lee GM, Gilner JB, Gunti S, Notkins AL, Kuchibhatla M, Frank M, Poncz M, Cines DB, Arepally GM. Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood. 2018 Dec 6;132(23):2431–2440.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 6, 2018

Volume

132

Issue

23

Start / End Page

2431 / 2440

Location

United States

Related Subject Headings

  • Proteomics
  • Platelet Factor 4
  • Lymphocyte Activation
  • Immunology
  • Immunoglobulin M
  • Humans
  • Heparin
  • Complement Pathway, Classical
  • Complement C3c
  • B-Lymphocytes