title: A population of atypical CD56(-)CD16(+) natural killer cells is expanded in PTSD and is associated with symptom severity.
abstract: BACKGROUND
  Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity.
  
  
  METHODS
  We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI.
  
  
  RESULTS
  PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074).
  
  
  CONCLUSIONS
  This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Bersani
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA. Electronic address: Owen.Wolkowitz@ucsf.edu.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Wolkowitz
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Lorrie
authors.initials: L
authors.lastname: Eppling
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Aschbacher
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA; Department of Clinical Sciences, Section for Psychiatry, Lund University, Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindqvist
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, New York, NY, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, New York, NY, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: Flory
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, New York, NY, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bierer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, New York, NY, USA.
authors.forename: Iouri
authors.initials: I
authors.lastname: Matokine
authors.affiliation: Department of Psychiatry, New York University, New York, NY, USA; Steven and Alexandra Cohen Center for Posttraumatic Stress and TBI, New York, NY, USA.
authors.forename: Duna
authors.initials: D
authors.lastname: Abu-Amara
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Coy
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hough
authors.affiliation: Department of Psychiatry, New York University, New York, NY, USA; Steven and Alexandra Cohen Center for Posttraumatic Stress and TBI, New York, NY, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Marmar
authors.affiliation: Department of OB/GYN and Reproductive Science, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Synthia H
authors.initials: SH
authors.lastname: Mellon
mesh_terms: D000328:Adult; D019002:CD56 Antigen; D003130:Combat Disorders / Q000276:immunology* / Q000503:physiopathology*; D058851:GPI-Linked Proteins; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D017452:Receptors, IgG; D012720:Severity of Illness Index; D013313:Stress Disorders, Post-Traumatic / Q000276:immunology* / Q000503:physiopathology*; D014728:Veterans
chemical_list: D019002:CD56 Antigen; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C522918:NCAM1 protein, human; D017452:Receptors, IgG
keywords: Innate immune system; Natural killer cells; Posttraumatic stress disorder; Psychoimmunology