Overactive Innate Immunity Tied to Higher Stroke Risk

Damian McNamara

June 18, 2019

MILAN — Higher levels of components of innate immunity, such as granulocytes and platelets, and larger ratios of these markers to lymphocytes were associated with greater stroke risk over time in a large prospective cohort study.

Participants were 67% more likely to experience a stroke during a follow-up of 8 years when granulocyte levels doubled over time. Risk increased 32% when platelet levels doubled in this population-based study conducted in the Netherlands.

Higher levels of adaptive immune system lymphocytes emerged as protective, reducing stroke risk by 11%.

"Atherosclerosis is considered an essential pathologic feature of stroke, but recent findings also suggest immune system also contributes to stroke development," Lana Fani, MD, a PhD candidate at Erasmus MC, Rotterdam, the Netherlands, said when presenting the study findings here at the 5th European Stroke Organisation Conference (ESOC) 2019. "But the underlying mechanisms remain unclear."

Unlike the cardiology field, where multiple trials point to the involvement of innate immunity in the inflammatory hypothesis of atherosclerosis, "the role of innate immunity for developing stroke remains unknown," Fani and colleagues note.

For this analysis, the researchers assessed 7734 participants of the Rotterdam study. The median age was 64 years, and 67% were women. Participants had no history of stroke or heart disease at baseline. The investigators measured markers of innate and adaptive immunity in blood samples three times between 2002 and 2015.

After a median follow-up of 8 years, 378 participants experienced an incident stroke. The researchers used Cox models to calculate stroke risk.

Results showed that a doubling of granulocyte counts was associated with greater risk for stroke (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.13 – 2.48).

They also linked a doubling of the platelet count to a greater likelihood of stroke (HR, 1.32; 95% CI, 0.91 – 1.92).

"When we look at innate immunity, both markers lead to an increased risk of stroke," Fani said. "As the markers increase over time, it increased risk...and this represents an overactive immune system."

In contrast, higher lymphocyte counts conferred a decreased risk (HR, 0.89; 95% CI, 0.66 – 1.20). "As expected, adaptive immunity has a more protective effect on stroke risk," Fani said.

Fani and colleagues calculated ratios of granulocytes and platelets to lymphocytes. They found an increased risk with a doubling of the granulocyte-to-lymphocyte ratio (HR, 1.35; 95% CI, 1.03 – 1.75), as well as with a doubling of the platelet-to-granulocyte ratio (HR, 1.21; 95% CI, 0.95 – 1.54).

More inflammation was likewise detrimental. Doubling of the Systemic Immune-Inflammation Index, for example, was associated with an increased stroke risk (HR, 1.20; 95% CI, 0.98 – 1.47).

To examine the role of atherosclerosis, the investigators performed CT scans of the carotid arteries of a subgroup of participants. They found that higher levels of granulocytes were also associated with increased arterial calcification in both the intracranial and extracranial carotid arteries.

"The other markers were less strongly associated," she said.

"I hope I convinced you that the immune system plays a potentially important role in the stroke risk," Fani concluded.

A meeting attendee asked about the effect of patient covariates. "Age is a very important factor to take into consideration, because increasing age also means immunity components increase over time," she replied.

"We saw that in younger individuals, the risk was slightly higher for incident stroke when the innate immunity components increased over time compared to older individuals, but this might reflect different comorbidities between younger and older patients," she said.

Identification of threshold or cutoff values for the immune component levels "might be worth looking at in future studies," Fani said.

Ripe for More Research

"The focus in stroke research needs to go deeper into the immune system. This is a field that needs to be investigated more rigorously," session co-chair Joji B. Kuramatsu, MD, of the Department of Neurology at the Friedrich-Alexander-University of Erlangen-Nurnberg in Germany, told Medscape Medical News when asked to comment.

"We can learn a lot from those studies on the etiology of stroke, as well as potential treatment options during acute stroke," Kuramatsu said.

"We also know that stroke uses immune suppression during the acute phase, so this could potentially lead to some new parameters that could be investigated," he added.

Fani and Kuramatsu have disclosed no relevant financial relationships.

5th European Stroke Organisation Conference (ESOC) 2019: Presented May 24, 2019.

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