Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia.
A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism.
Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt Universität, Sauerbruchstrasse, Greifswald, Germany.
Krystin
K
Krauel
Christian
C
Pötschke
Claudia
C
Weber
Wolfram
W
Kessler
Birgitt
B
Fürll
Till
T
Ittermann
Stefan
S
Maier
Sven
S
Hammerschmidt
Barbara M
BM
Bröker
Andreas
A
Greinacher
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001419:Bacteria / Q000276:immunology* / Q000378:metabolism; D001422:Bacterial Adhesion; D003429:Cross Reactions / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism; D005260:Female; D006493:Heparin; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009345:Neisseria meningitidis / Q000276:immunology / Q000378:metabolism; D010978:Platelet Factor 4 / Q000378:metabolism*; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000276:immunology / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D016056:Immunodominant Epitopes; D010978:Platelet Factor 4; D006493:Heparin