• ScottBrittney N VBNV0000-0003-2743-8267Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, T2N 4N1, Canada. bnscott@ucalgary.ca.Department of Physiology and Pharmacology, Cumming S, Andreas H Kramer, Rita Nguyen, WongConnie H YCHYCalvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Science, Monash University, Craig N Jenne, Stacy Ruddell, Josee Wong, Mandy Tse, Brent W Winston, Andrea Soo, Christopher J Doig, David A Zygun, and Paul Kubes.
• Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, T2N 4N1, Canada. bnscott@ucalgary.ca.
• Neurocrit Care. 2021 Dec 1; 35 (3): 617-630.

BackgroundNeurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury.MethodsWe conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (TH1) and T helper 2 (TH2) cytokines, by multiplex bead-based assay.ResultsInvariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH2/TH1 cytokines early after injury (days 1 - 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH2/TH1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4- iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified.ConclusionsCritically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH2/TH1 cytokine ratios. This work provides further support for a brain-immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system.© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

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