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Severe unpredictable acute pain and chronic daily pain causes significant morbidity
for individuals with sickle cell disease (SCD). SCD is shown to be a chronic inflammatory
disorder. Regulation of the immune response can potentially modulate the inflammatory
impact on pain in SCD. We sought to determine the balance between patients’ inflammatory
and immune regulatory response and examine whether this balance changes during acute
SCD pain. We conducted a cross sectional analysis involving 3 cohorts: 16 SCD patients
in baseline health, 27 SCD patients during acute pain and 45 healthy African American
controls. Participant plasma was co-cultured with cryopreserved PBMCs from a healthy
donor to induce transcription. We identified transcripts that differentiate SCD patients
from healthy controls and retained ones differentially expressed that exhibit a fold
change >1.4, ANOVA p-value of <0.05 and FDR <10%, thereby defining the disease-specific
plasma-induced signature. Data were subjected to ontological analyses for quantitative
interpretation with Database for Annotation, Visualization and Integrated Discovery
(DAVID) and Ingenuity Pathway Analysis (IPA). For quantitative scoring we created
a composite inflammatory index (I.I.com); average ratio between the mean log intensity
of genes classified as “inflammatory” versus “regulatory”. Student's t-test was used
to compare the mean I.I.com between cohorts. Quantitative scoring of plasma-induced
signatures showed SCD patients had significantly higher mean I.I.com during baseline
health compared to controls (0.713 vs. -1.235-12, p=5.4625-11). SCD patients during
acute pain had significantly higher I.I.com than during baseline health (1.282 vs.
0.713, p=5.2051-8). Our novel assay that assesses inflammatory and immune regulatory
gene expression allowed for determining the balance between these two states. We found
distinct inflammatory signatures in SCD patients compared to controls and in SCD patients
during acute pain as compared to baseline health. This imbalance between inflammation
and immune regulation could contribute to the development of acute and chronic SCD
pain. National Institutes of Health #1R61NS114954-01.
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© 2021 Published by Elsevier Inc.