Study ties specific immune pathway to kidney damage in AAV
Distinct cellular mechanisms may point to kidney prognosis
Written by |
People with ANCA-associated vasculitis (AAV) are more likely to have worse kidney function and related outcomes if their self-targeting antibodies, called ANCAs, activate immune cells via the Fc gamma receptor protein, a study suggested.
“[Fc gamma-driven] ANCA can be a biomarker for poor kidney prognosis in ANCA-associated vasculitis,” the researchers wrote.
The study, “Functional classification of antineutrophil cytoplasmic antibody (ANCA) and its relation with clinical parameters of ANCA-associated vasculitis,” was published in Biochemistry and Biophysics Reports.
AAV is a group of autoimmune conditions marked by inflammation and damage to small blood vessels, which can affect the function of several organs, most often the kidneys and lungs.
In these conditions, the immune system produces ANCAs that typically target one of two proteins, myeloperoxidase (MPO) and proteinase 3 (PR3), on the surface of neutrophils, a type of immune cell. This leads to the overactivation of neutrophils, which release digestive enzymes and reactive oxygen species (ROS), which are highly unstable molecules that can cause cell damage.
Binding to targets
When ANCAs bind to their targets, neutrophils can be activated in two ways: through the ANCA-target bound and/or through Fc gamma, a receptor protein to which another portion of the ANCA binds.
“However, whether the difference in ANCA-mediated neutrophil activation pathways is associated with clinical manifestations of AAV has not been determined,” wrote the researchers, in Japan.
To find out, the team analyzed the effects of antibodies, including ANCAs, isolated from the blood of 112 untreated AAV patients, on neutrophil activation and compared the results with clinical data.
The researchers exposed lab-grown neutrophils from healthy volunteers to AAV patient antibodies and assessed the cells’ activation by measuring ROS levels.
To differentiate the two activation pathways, the team added a molecule (FcX) that blocks the interaction between ANCAs and the Fc gamma receptor. If neutrophil activation was suppressed by at least 50%, it was considered to be driven by Fc gamma binding. If FcX suppressed neutrophil activation by less than 50%, it was defined as driven by MPO or PR3 binding.
Based on test results, patients’ ANCAs were divided into three groups: ANCAs that triggered ROS production via MPO/PR3 binding (66.1%), ANCAs that promoted ROS production via Fc gamma receptor binding (19.6%), or ANCAs that didn’t induce ROS production (14.3%).
When the researchers compared these groups, they found that overall characteristics, such as age, sex, AAV type, overall disease activity (total Birmingham Vasculitis Activity Score, BVAS), and body-wide inflammation levels, were similar.
However, patients whose ANCAs activated neutrophils via the Fc gamma receptor had the highest blood levels of urea nitrogen and creatinine, both markers of reduced kidney function. This difference reached statistical significance when comparing these patients with those with ROS-noninducing ANCAs.
The degree of blood in urine, another marker of kidney damage, and BVAS-based kidney symptom scores were also highest in the Fc gamma receptor group, but the differences did not reach statistical significance, indicating they could be due to chance.
Also, the proportion of patients who didn’t need a liver transplant six months after initiating treatment was significantly lower in the group with ROS-inducing Fc gamma-driven ANCAs than in the ROS-inducing MPO/PR3-driven ANCA group (93.2%) and ROS-noninducing ANCA group (93.8%).
The researchers suggested that neutrophils activated by ANCAs via the Fc gamma receptor may bind more tightly to cells lining the glomeruli, the filtering units of the kidneys, causing more damage through ROS release than neutrophils activated by ANCA-MPO/PR3 binding.
In contrast, BVAS-based body-wide symptom scores were significantly higher among those with ANCAs that didn’t induce ROS production compared with those with ANCAs that triggered ROS production via the Fc gamma receptor.
“Further studies are needed to reveal what factors other than ROS are involved in the general symptoms of AAV,” the researchers wrote.
While there is a need for long-term follow-up, the study results “suggest that ROS-inducing [Fc gamma receptor-driven] ANCA may predict poor kidney prognosis in AAV,” the scientists said.
