Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life—a case study

Abstract

BackgroundThe perinatal period carries the highest risk for stroke in childhood; however, the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. A new pathophysiological model describes the development of neonatal arterial ischemic stroke (NAIS) as the combined result of prenatal inflammation and hypoxic–ischemic insult. Neuroinflammation and a systemic inflammatory response are also important features of NAIS. Identifying key players of the inflammatory system is in the limelight of current research.Case presentationWe present four NAIS cases, in whom detailed analysis of intracellular and plasma cytokine levels are available from the first month of life. All neonates were admitted with the initial diagnosis of hypoxic ischemic encephalopathy (HIE); however, early MRI examination revealed NAIS. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Peripheral blood mononuclear cells were assessed with flow cytometry and plasma cytokine levels were measured. Pooled data from the cohort of four NAIS patients were compared to infants with HIE.At 6 and 72 h of age, the prevalence of IL10+ CD8+ lymphocytes remained lower in NAIS. At 6 h, CD8+ lymphocytes in NAIS produced more IL-17. At 72 h, CD8+ cells produced more IL-6 in severe HIE than in NAIS, but IL-6 production remained elevated in CD8 cells at 1 month in NAIS, while it decreased in HIE. At 1 week, the prevalence of TGF-β + lymphocytes prone to enter the CNS was elevated in NAIS. On the other hand, by 1 month of age, the prevalence of TGF-β + CD4+ lymphocytes decreased in NAIS compared to HIE. At 72 h, we found elevated plasma levels of IL-5, MCP-1, and IL-17 in NAIS. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE.ConclusionsDifferences in the cytokine network are present between NAIS and HIE. CD8 lymphocytes appear to shift towards the pro-inflammatory direction in NAIS. The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month.

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

“…A characteristic cytokine gene expression kinetics follows cardiac arrest in adults, as well as in neonates after HIE. 30,31 At 6 days after the injury, placebo animals demonstrated a persistent proinflammatory state reflected by higher IL-6 levels. In humans, high IL-6 levels correlate with early neurological deterioration, cerebral perfusion deficits, infarct volume, and poor long-term outcomes.…”

The role of lymphocytes in neonatal encephalopathy

“…IL-6, IL-4, IL-12, and IL-17 are elevated in neonates with NE and neonatal arterial ischemic stroke (NAIS). These cytokines are still increased in NE neonates after one month ( Bajnok et al., 2018 ).…”

INFLAMMATORY CYTOKINES (IL-6, TNF-α) AS a PROGNOSTIC FACTOR IN THE SEVERITY OF BRAIN DAMAGE IN NEWBORNS

“…Конкретні нейронні системи і популяції клітин вражаються вибірково, механізми ушкодження включають окислювальний стрес, ексайтотоксичність, запалення і активацію кількох різних шляхів клітинної загибелі. Деякий прогрес в цій області намітився в останні роки, коли стало зрозумілим, що надмірний запальний процес лежить в основі виникнення тканинних уражень при багатьох патологічних станах, а чисельні медіатори запалення і, зокрема, прозапальні цитокіни, здатні прямо чи опосередковано ініціювати програмовану чи некротичну смерть клітин [4,5,6].…”