Abstract DP170: A High Throughput Analysis Of The Sexually Dimorphic Peripheral Immune Response To Acute Ischemic Stroke

Introduction: Acute ischemic stroke triggers a profound local and systemic immune response that can drive secondary brain injury, post-stroke cognitive decline, susceptibility to infections, and morbidity. The peripheral immune response to stroke may provide both biomarkers for predicting clinical trajectories, and targets for modulation to improve outcomes. While animal studies exist, granular data at the immune subpopulation level from human samples across sex is sparse. We sought to investigate this using high throughput mass cytometry. Methods: We used frozen PBMC samples from male and female patients with acute ischemic stroke (collected 72 hrs from ictus) and age- and sex-matched controls stored in our biobank. Patient MRIs were reviewed to verify the presence of an acute infarct. Patients with prior strokes were excluded. Cells were Fc blocked, barcoded and stained with metal conjugated antibodies for mass cytometry. Data was acquired on a Helios mass cytometer and gated to identify cellular populations. Differences in the immunological profile between controls and stroke patients, stratified by sex and discharge outcome, were analyzed by Wilcoxon tests on R, with p<0.05 as the threshold for statistical significance. Results: We analyzed the peripheral immune response to acute ischemic stroke in 23 stroke patients (12 M, 11 F) and 26 age-matched controls (11 M, 15 F) using mass cytometry. Staining for 42 cellular markers yielded 8 immune cell types and 30 subpopulations. A decrease in the frequencies of most immune cells was noted across sex following acute ischemic stroke compared to controls. There was a trend towards a more innate peripheral immune response in males after stroke with a significant elevation in plasmacytoid dendritic cells. On the other hand, females had a trend towards a more adaptive immune response following stroke with a significantly elevated B memory cell population compared to controls. Further, a significantly lower peripheral blood CD4 and Th17 T cell, and higher CD8 and Th1 T cell response was associated with a favorable mRS at discharge (≼3) in males. Between sexes, males with mRS ≥3 had a CD4 T cell predominant response, compared to a more CD8 response in females. Conclusions: We identified a profound immune suppression in most immune subsets following acute ischemic stroke. However, the adaptive immune response was significantly different between groups and also associated with differential outcomes. Moreover, a B cell predominant response in females may be the driver for worse cognitive outcomes given its association with post-stroke dementia. This response may be targetable and warrants further mechanistic investigation.