Higher neutrophil blood levels may be due to endothelial cell changes
Study into what might cause swelling attacks that mark hereditary angioedema
Changes in the properties of endothelial cells that line blood vessels may underlie increases in the numbers of circulating immune neutrophils in people with hereditary angioedema (HAE), according to a recent report.
Although neutrophils are more abundant and activated in the blood of people with HAE types 1 and 2, the consequences of these differences remain unclear, according to its scientists.
The study, “Decreased adhesion to endothelium leads to elevated neutrophil granulocyte count in hereditary angioedema patients,” was published in the journal Scientific Reports.
Higher neutrophil blood levels evident in patients without active HAE
In HAE types 1 and 2, mutations in the SERPING1 gene lead to a lack of functional C1-inhibitor, a protein that normally blocks the activity of kallikrein and coagulation factor 12.
These two proteins stimulate the production of bradykinin, a signaling molecule that regulates inflammation by promoting blood vessel dilation and permeability. An excess of bradykinin is ultimately believed to be responsible for the disease’s sudden swelling attacks.
Still, some aspects of HAE aren’t explained simply by elevated bradykinin levels, with recent evidence suggesting other mechanisms are at play.
In a previous study, the researchers in Hungary found that patients with HAE types 1 and 2 had higher blood levels of neutrophils compared with healthy people, even when they weren’t experiencing active disease symptoms. Neutrophils are immune cells that serve as the body’s first responders to injury or infection.
In this study, the scientists aimed to investigate how an excess of neutrophils, called neutrophilia, arises in HAE.
Specifically, they wanted to know if neutrophilia resulted from too many neutrophils being released from the bone marrow where they are produced (altered maturation), because their properties were altered, or because they were not being eliminated from the bloodstream as they normally should.
Blood samples were collected from 20 patients in that country with HAE types 1 or 2 who were attack free, and 21 healthy people, serving as controls.
Neutrophil numbers tended to be higher in HAE patients than in controls, but the finding did not reach statistical significance.
Markers of neutrophil maturation did not differ between the two groups, indicating that increased neutrophil generation or movement out of the bone marrow was not the cause of the high neutrophil counts in HAE patients.
Likewise, markers of neutrophil clearance or death largely were not different between the groups, again indicating that delayed or impaired elimination wasn’t the source of neutrophilia in HAE patients.
Neutrophils circulate in blood or adhere to endothelial cells in vessel walls
Similarly to their previous studies, researchers found that neutrophils from HAE patients showed signs of being in a significantly higher activation state compared with those from healthy controls.
But whether active neutrophils might stimulate kallikrein-bradykinin signaling in HAE or the reverse is true was not clear.
“The background of this challenging interaction requires extensive further investigations,” the researchers wrote.
Neutrophils from patients in cell cultures showed lower adhesion, an ability to attach, to endothelial cells that line blood vessel walls.
This difference became even more pronounced in response to inflammatory stimuli. The addition of bradykinin did not appear to influence these dynamics.
Neutrophils exist in two different pools: those that are circulating freely in the bloodstream, and those that adhere to endothelial cells in blood vessel walls, called the marginated pool.
High neutrophil numbers in patients’ bloods could be due to the fact that more of these cells are circulating, rather than sticking to blood vessel walls.
“High [neutrophil] counts in these patients may be caused by disturbed adhesion to [endothelial cells] biasing the ratio between marginated and circulating pools,” the researchers wrote.
Ultimately, the scientists believe that alterations in the properties of endothelial cells themselves might be the cause of this adhesion change.
A possible factor underlying this could be soluble E-selectin, a protein involved in endothelial cell adhesion that circulates in the bloodstream after being shed from these cells.
Previous research showed that this protein also is elevated in the bloodstream of HAE patients, especially during attacks.
The mild activation state of circulating neutrophils could be related to elevations in soluble E-selectin or other factors in the bloodstream.
Still, “it is largely unknown if this mild activation of [neutrophils] has positive or negative consequences for [type 1 and 2 HAE] patients, but it is worth further investigation,” the team wrote.