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Presentation transcript:

APOε4 is associated with enhanced in vivo innate immune responses in human subjects Stephen C. Gale, MD, Li Gao, MD, PhD, Carmen Mikacenic, MD, Susette M. Coyle, RN, Nicholas Rafaels, MS, Tanda Murray Dudenkov, MHS, Jennifer H. Madenspacher, MS, David W. Draper, PhD, William Ge, Jim J. Aloor, PhD, Kathleen M. Azzam, PhD, Lihua Lai, PhD, Perry J. Blackshear, MD, DPhil, Steven E. Calvano, PhD, Kathleen C. Barnes, PhD, Stephen F. Lowry, MD, Siobhan Corbett, MD, PhD, Mark M. Wurfel, Michael B. Fessler, MD Journal of Allergy and Clinical Immunology Volume 134, Issue 1, Pages 127-134.e9 (July 2014) DOI: 10.1016/j.jaci.2014.01.032 Copyright © 2014 Terms and Conditions

Fig 1 Enhanced TNF-α production by APOε3/APOε4 human whole blood in response to TLR ligands. Whole blood from APOε3/APOε3 (n = 7) and APOε3/APOε4 (n = 7) healthy volunteers was left nonstimulated (NS) or exposed to a panel of ligands for TLR2 (1 μg/mL Pam3CKS4 [Pam] and 8 × 107 heat-killed Listeria monocytogenes [HKLM]), TLR4 (1 ng/mL LPS), TLR5 (1 μg/mL flagellin [FLA]), or TLR7/8 (1 μg/mL CL075). After 3 hours, TNF-α protein release into the supernatant was quantified by using ELISA. ND, Not detected. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig 2 Enhanced production of a wide panel of cytokines and chemokines by APOε3/APOε4 human whole blood in response to TLR2 and TLR4 ligands. Whole blood from APOε3/APOε3 (n = 7) and APOε3/APOε4 (n = 7) healthy volunteers was nonstimulated (NS) or stimulated for 3 hours with LPS or Pam3CSK4 (Pam), and then the indicated cytokines (A), chemokines (B and C), and anti-inflammatory mediators (D) were quantified in the supernatant by using a multiplex assay. *P < .05 and **P < .01. G-CSF, Granulocyte colony-stimulating factor; IL-1ra, IL-1 receptor antagonist; IP-10, interferon-inducible protein 10; MCP1, monocyte chemoattractant protein 1; MIP1α, macrophage inflammatory protein 1α. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig 3 APOε3/APOε4 human monocytes display increased lipid rafts. A, RAW 264.7 macrophages were plated in Dulbecco modified Eagle medium with 10% human serum (pooled by APOε genotype) and then left nonstimulated (NS) or exposed to LPS (1 ng/mL for 2 hours). TNF-α was then quantified in the media. Results are representative of 2 independent experiments. ND, Not detected. B-D, Peripheral blood monocytes from APOε3/APOε3 (n = 9) and APOε3/APOε4 (n = 10) human subjects were gated by CD14 (Fig 3, B) and then left unstained or stained with Alexa Fluor 488–cholera toxin B (CtB). CtB was quantified by using flow cytometry, as shown by a representative histogram (Fig 3, C). Mean fluorescence intensity (MFI) for CtB was pooled by APOε genotype for quantification (Fig 3, D). *P < .05 and #P = .11. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig 4 Association of APOE genotype with in vivo LPS responses in human subjects. A, Temperature curve in APOε3/APOε3 (n = 18) and APOε3/APOε4 (n = 7) patients at various time points after intravenous LPS injection. P < .05 for intergenotype difference. B, Plasma TNF-α levels in patients from Fig 4, A. P < .000001 for intergenotype difference. C, Plasma IL-6 levels in patients from Fig 4, A. P = .11. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig 5 Response of APOE3-TR and APOE4-TR mice to systemic LPS. A, Core body temperature of APOE3-TR and APOE4-TR (hereafter called E3 and E4) mice at time points after intraperitoneal saline or LPS (2 mg/kg). B-D, Plasma TNF-α (Fig 5, B), granulocyte colony-stimulating factor (G-CSF; Fig 5, C), and IL-6 (Fig 5, D) levels 1.5 hours after intraperitoneal saline or LPS in E3 and E4 mice. E and F, Plasma alanine aminotransferase (ALT; Fig 5, E) and lactate dehydrogenase (LDH; Fig 5, F) levels 6 hours after intraperitoneal saline or LPS in E3 and E4 mice. G, Apoptosis was quantified in splenic CD4+ T cells, CD8+ T cells, and B cells 6 hours after intraperitoneal LPS with the polycaspase activity reporter FLIVO. *P < .05 and **P < .01 for intergenotype comparison. †P < .05 compared with saline control within genotype. N = 5 per genotype. ND, Not detected. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E1 Total WBC count and percentage compositions of monocytes, neutrophils, and lymphocytes in peripheral blood of APOε3/APOε3 (n = 18) and APOε3/APOε4 (n = 19) patients. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E2 CD14 surface expression of peripheral blood monocytes from APOε3/APOε3 and APOε3/APOε4 (n = 9-10 per genotype) patients. PBMCs were isolated and stained as shown with either isotype control antibody or anti-CD14 antibody. CD14 mean fluorescence intensity (MFI) is shown for both the CD14lo and CD14hi monocyte populations. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E3 APOE genotype distribution among 35 healthy human volunteers who were administered intravenous LPS. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E4 Association of APOE genotype (ε4+ vs ε4−) with in vivo LPS responses in human subjects. A, Temperature curve in APOε4+ (APOε3/APOε4 [n = 7]; APOε2/APOε4 [n = 1]) versus APOε4− (APOε3/APOε3 [n = 18]; APOε2/APOε3 [n = 8]) patients at various time points after intravenous LPS. P = .006 for intergenotype difference (repeated-measures ANOVA). B, Plasma TNF-α levels in patients from Fig E4, A. P < .00001 for intergenotype difference. C, Plasma IL-6 levels in patients from Fig E4, A. P = .064. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E5 Clinical chemistry values in LPS-challenged APOE-targeted replacement mice. Blood urea nitrogen (BUN; n = 5 per genotype) and creatinine kinase (CK; n = 3-5 per genotype) were measured in plasma of APOE3- and APOE4-targeted replacement mice 6 hours after intraperitoneal challenge with 1 mg/kg E coli LPS. Data are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions

Fig E6 APOE genotype distribution by race among patients with severe sepsis from the CELEG cohort. Journal of Allergy and Clinical Immunology 2014 134, 127-134.e9DOI: (10.1016/j.jaci.2014.01.032) Copyright © 2014 Terms and Conditions