Hidden immune activity can occur despite disease remission in AAV
Targeted anti-inflammatory treatments may help reduce future relapse risk
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ANCA-associated vasculitis (AAV), marked by inflammation and damage to small blood vessels in the body, still shows low-level immune activity in the background even when symptoms are absent, a study found.
This is particularly true for its rare type EGPA, fully, eosinophilic granulomatosis with polyangiitis, according to the researchers.
The new study, by a team of scientists in Italy, “provides novel evidence supporting the concept of persistent subclinical immune activation during remission in AAV,” the researchers wrote, referring to a period without disease symptoms.
These findings suggest that regular immune monitoring and targeted anti-inflammatory treatments could help reduce the risk of future relapses, the team noted.
The study, “Immature leukocyte and plasma-induced cell death reveal subclinical immune activation in EGPA patients in remission,” was published in the journal Inflammation Research .
AAV is a group of autoimmune conditions marked by inflammation and damage to small blood vessels. Inflamed blood vessels cannot deliver blood properly to organs, resulting in AAV symptoms.
Most AAV cases are caused by self-reactive antibodies, called ANCAs, that mistakenly target proteins in immune neutrophils, causing their overactivation.
“Although AAV follows a relapsing-remitting course,” in which periods of worsening symptoms are followed by remission, “the immune landscape during remission remains poorly defined,” the researchers wrote.
Disease remission may not mean no immune activity
Patients with AAV may feel well during remission, but the immune system may still be active in ways that are not obvious.
Given this, the research team sought to learn more about what occurs inside the body regardless of whether or not symptoms are present. First, the team looked at changes in leukocytes — a type of immune cells that include neutrophils — in the blood of 62 adults with AAV in remission and 28 age- and sex-matched healthy individuals, who served as controls.
The patients’ median age was 61 and 57% were men. In terms of AAV types, 31 had EGPA, 17 had granulomatosis with polyangiitis (GPA), and 14 had microscopic polyangiitis (MPA).
Data showed that AAV patients, across all three disease types, had significantly more immature neutrophils than healthy individuals, suggesting the immune system was still active even without symptoms. Some neutrophils had unusual shapes, suggesting they may not be developing well, the researchers noted.
Neutrophils vacuolization, which refers to the presence of small empty spaces that often occur in response to damage, was present in 16% of all AAV patients. People with EGPA showed significantly more vacuolated neutrophils than healthy controls.
There were also significantly higher numbers of dead cells in people with GPA and EGPA compared with healthy individuals, “with a trend toward higher rates in MPA,” the researchers wrote.
Also, EPGA patients testing positive for ANCAs had significantly higher levels of cell death compared with those without ANCAs, the data showed.
“Our findings of elevated circulating immature neutrophils support the hypothesis of sustained innate immune activation even after clinical remission has been achieved,” the researchers wrote. “These results align with previous studies reporting the presence of circulating immature neutrophils across all AAV subtypes, likely associated to sustained [immune cell] stimulation driven by ongoing subclinical inflammation.”
Next, the researchers measured blood levels of cytokines and chemokines, which are signaling proteins that regulate inflammation and movement of immune cells. Two proinflammatory cytokines, IL-1beta and IL-18, showed generally higher levels among AAV patients relative to healthy controls.
CCL-23, a cytokine that attracts immune cells through a process called chemotaxis, was found at significantly higher levels in the blood of GPA and MPA patients, but not those with EGPA.
However, EGPA patients with ANCAs showed significantly higher IL-1beta and CCL23 levels than those without ANCAs, and in those with ANCAs, a higher percentage of neutrophils was significantly associated with higher blood levels of IL-1beta and CCL-23.
ANCA status could be used to help guide treatment
To test how these differences affect the immune response, the researchers exposed lab-grown healthy immune cells to plasma from people with EGPA. Plasma is the liquid component of blood; it contains antibodies, including disease-causing ones.
The team found that plasma from ANCA-positive EGPA patients caused more cell death — both programmed, called apoptosis, and uncontrolled, known as necrosis — than plasma from patients without ANCAs and healthy controls.
In addition, immune cells exposed to plasma from ANCA-positive EGPA patients produced significantly more IL-1beta and CCL23 and moved more compared with the other groups, the data showed.
“The distinct immune profiles observed between ANCA-positive and ANCA-negative EGPA are consistent with the notion that these subgroups represent overlapping yet biologically distinct entities, which may inform personalized therapeutic strategies in the future,” the researchers wrote.
Specifically, clinicians could use a person’s ANCA status in determining treatment, according to the team.
“ANCA status could … help guide personalized therapeutic strategies, particularly in patients with persistent immunologic activity despite apparent remission,” the scientists wrote.
