CD177 Expression on Neutrophils Predicts Ischemic Stroke Outcome in Humans

BACKGROUND: Neutrophil granulocytes actively contribute to tissue damage after ischemic stroke. The membrane protein CD177 is detectable on variable neutrophil numbers in most individuals (CD177 wild-type [CD177 WT ] genotype), whereas ≈5% of the general population completely lack CD177 (CD177-deficient [CD177 null ] genotype). Despite its known relevance in vasculitis, the role of ischemic stroke remains unknown. METHODS: In 2 prospective cohorts of patients with first-ever ischemic stroke (PROSCIS-B [Prospective Cohort With Incident Stroke Berlin], NOFF-S [Neutrophils: Origin, Fate & Function Stroke]), we assessed the effect of CD177 null and CD177 WT status on stroke severity and outcome (National Institutes of Health Stroke Scale and modified Rankin Scale) over 1 year or 3 months poststroke, respectively. By flow cytometry, we stratified CD177 expression level as CD177 neg , CD177 dim , and CD177 high . The predictive value of the CD177 state was evaluated by multivariable regression and discrimination analyses. RESULTS: In PROSCIS‐B (n=579; mean age, 68.1 years; 38.5% women) and NOFF-S (n=236, 68.4 years, 36.9% women), similar rates of patients were CD177 null (n=26 [4.5%] and n=10 [4.2%], respectively). Patients with CD177 null had a higher probability of unfavorable stroke outcome (modified Rankin Scale score 3–6) than patients with CD177 WT (n=8 of 21 [38.1%] versus 90 of 462 [19.5%] with follow-up, P =0.05, in PROSCIS-B; n=8 of 10 [80.0%] versus n=23 of 142 [16.2%] with follow-up, P <0.0001, in NOFF-S). This association remained when adjusted for age, sex, initial stroke severity defined by National Institutes of Health Stroke Scale score, stroke subtype defined by TOAST (Trial of ORG 10172 in Acute Stroke Treatment), and reperfusion treatment (risk ratio, 3.8 [95% CI, 2.0–7.1]; P <0.001, in NOFF-S). In NOFF-S, the proportion of CD177 dim neutrophils at admission was negatively associated with stroke severity at admission, while that of CD177 high neutrophils predicted a favorable clinical outcome after 3 months. CD177 expression level significantly improved the prediction of stroke outcome in addition to clinical adjustment variables in area under the curve, net reclassification improvement, and integrated discrimination improvement analyses ( P =0.004, P =0.001, and P <0.001, respectively, for CD177 high ). CONCLUSIONS: CD177 expression at admission is an easy-to-measure biomarker for patient stratification. CD177 holds potential as a therapeutic target to modulate immune responses after stroke. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01363856.