title: Clinical recovery from surgery correlates with single-cell immune signatures.
abstract: Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Brice
authors.initials: B
authors.lastname: Gaudillière
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Gabriela K
authors.initials: GK
authors.lastname: Fragiadakis
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Biomedical Informatics Program, Stanford University, Stanford, CA 94305, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Bruggner
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Mathematics, Stanford University, Stanford, CA 94305, USA. Center for Cancer Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Nicolau
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Finck
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Tingle
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Silva
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ganio
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Yeh
authors.affiliation: Department of Orthopedic Surgery, Stanford University, Redwood City, CA 94063, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Maloney
authors.affiliation: Department of Orthopedic Surgery, Stanford University, Redwood City, CA 94063, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Huddleston
authors.affiliation: Department of Orthopedic Surgery, Stanford University, Redwood City, CA 94063, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Bendall
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Department of Obstetrics and Gynecology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Fantl
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. ang@stanford.edu gnolan@stanford.edu.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Angst
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Stanford University, Stanford, CA 94305, USA. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. ang@stanford.edu gnolan@stanford.edu.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
mesh_terms: D000368:Aged; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D050882:CREB-Binding Protein / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006621:Hip Joint / Q000503:physiopathology / Q000601:surgery*; D006801:Humans; D016130:Immunophenotyping / Q000379:methods*; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000097:blood; D010641:Phenotype; D010766:Phosphorylation; D011183:Postoperative Complications / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D011237:Predictive Value of Tests; D060066:Protein Interaction Maps; D020127:Recovery of Function; D050796:STAT3 Transcription Factor / Q000097:blood; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human