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APO?4 is associated with enhanced in vivo innate immune responses in human subjects.

ABSTRACT: BACKGROUND:The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (?3) and disease-associated (?2 and ?4) alleles, but its connection to human innate immunity is undefined. OBJECTIVE:We sought to define the relationship of APO?4 to the human innate immune response. METHODS:We evaluated APO?4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APO?4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. RESULTS:Whole blood from healthy APO?3/APO?4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APO?3/APO?3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APO?3/APO?4 monocytes. By contrast, APO?3/APO?3 and APO?3/APO?4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APO?3/APO?4 patients had higher hyperthermia and plasma TNF-? levels and earlier plasma IL-6 than APO?3/APO?3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APO?4 was associated with increased coagulation system failure among European American patients. CONCLUSIONS:APO?4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.

SUBMITTER: Gale SC

PROVIDER: S-EPMC4125509 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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APOε4 is associated with enhanced in vivo innate immune responses in human subjects.

Gale Stephen C SC Gao Li L Mikacenic Carmen C Coyle Susette M SM Rafaels Nicholas N Murray Dudenkov Tanda T Madenspacher Jennifer H JH Draper David W DW Ge William W Aloor Jim J JJ Azzam Kathleen M KM Lai Lihua L Blackshear Perry J PJ Calvano Steven E SE Barnes Kathleen C KC Lowry Stephen F SF Corbett Siobhan S Wurfel Mark M MM Fessler Michael B MB

The Journal of allergy and clinical immunology 20140318 1

<h4>Background</h4>The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined.<h4>Objective</h4>We sought to define the relationship of APOε4 to the human innate immune response.<h4>Methods</h4>We evaluated APOε4 in several functional models of the human innate ...[more]

PMID: 24655576

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Project description:BackgroundBrucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5-40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis.Methodology/principal findingsBlood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-?, and IFN-? in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-?; and HKBM or Rev1-induced secretion of IL-1?, IL-2, GM-CSF, IFN-?, and TNF-?. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1?, IL-2, and TNF-? secretion in response to LPS and HKBM, and IFN-? secretion in response to HKBM.Conclusions/significanceThis work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may allow for better follow-up care of brucellosis patients through improved identification of patients at risk for relapse.

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APO?4 is associated with enhanced in vivo innate immune responses in human subjects.

Publications

APOε4 is associated with enhanced in vivo innate immune responses in human subjects.

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