Heterogeneity in neutrophil responses to immune complexes.

Journal Article (Journal Article)

Immune complexes (ICs) can trigger inflammation and thrombosis, in part, by activating neutrophils. Much attention has focused on the serologic characteristics of ICs and Fc receptors associated with cellular activation, but few studies have examined host susceptibility to neutrophil activation by ICs. Here, we use a novel whole blood system to investigate the ability of ICs to cause neutrophil activation and degranulation. Using monoclonal anti-platelet factor 4/heparin (PF4/heparin), anti-protamine/heparin antibodies, patient-derived anti-PF4/heparin antibodies, and heat-aggregated immunoglobulin G as model ICs, we demonstrate that heparin-containing ICs cause robust, heparin-dependent neutrophil activation and degranulation which is mediated by both FcγRIIa and complement. Longitudinal testing over a 1-year period shows that an individual's neutrophil response to ICs represents a fixed phenotype resulting in high, intermediate, or low reactivity. Examination of individuals at the extremes of reactivity (high vs low) shows that phenotypic variation resides in the cellular compartment and is correlated with host white blood cell count and absolute neutrophil count, but not age, sex, race, polymorphisms in neutrophil Fcγ receptors, or CR1, CR3, and Fcγ receptor expression on neutrophils. Together, these studies demonstrate that susceptibility to neutrophil activation by ICs is intrinsic to the host and is likely genetic in origin. These findings may be relevant to the heterogeneous clinical outcomes seen in patients with heparin-induced thrombocytopenia and other IC-mediated disorders and could potentially identify patients at high risk for thrombotic and inflammatory complications.

Full Text

Duke Authors

Cited Authors

  • Duarte, M; Kuchibhatla, M; Khandelwal, S; Arepally, GM; Lee, GM

Published Date

  • October 8, 2019

Published In

  • Blood Adv

Volume / Issue

  • 3 / 19

Start / End Page

  • 2778 - 2789

PubMed ID

  • 31554616

Pubmed Central ID

  • PMC6784526

Electronic International Standard Serial Number (EISSN)

  • 2473-9537

Digital Object Identifier (DOI)

  • 10.1182/bloodadvances.2019000235


  • eng

Conference Location

  • United States