Study identifies inflammatory protein as potential treatment target in AAV
Blocking CD95L-mediated signaling pathway reduced disease severity in mice
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Free-floating CD95L, a protein involved in inflammation and immune responses, is found at significantly higher levels in the blood of people with ANCA-associated vasculitis (AAV) and may be a potential treatment target, according to a study in France.
Through a detailed series of experiments, researchers figured out that CD95L can bind to receptor proteins at the surface of neutrophils, a type of immune cell implicated in AAV. When CD95L binds to these receptors, it triggers neutrophils to produce molecules that trigger tissue damage — which may worsen AAV disease processes.
In addition, blocking this CD95L-mediated signaling pathway reduced disease severity in AAV mouse models, pointing to free-floating, or soluble, CD95L and its associated molecular pathways as a plausible treatment target for AAV.
“This study highlights the pivotal role of sCD95L [soluble CD95L] in the [disease development] of AAV, particularly its impact on neutrophils, and identifies a potent therapeutic strategy that warrants clinical evaluation,” researchers wrote.
An early-access version of the study, “Soluble CD95L triggers Caspase-10-driven reactive oxygen species production in neutrophils and aggravates anti-neutrophil cytoplasmic antibody-vasculitis,” was published in Nature Communications.
Free-floating form of CD95L involved in inflammation
AAV is an autoimmune disease marked by inflammation and damage to small blood vessels. including in the kidneys. Most cases are linked to self-reactive antibodies, called ANCAs, that trigger excessive activation of neutrophils.
These abnormally activated neutrophils release molecules called reactive oxygen species (ROS), which can damage neighboring small blood vessels. However, the molecular mechanisms behind these events “remain incompletely understood,” the researchers wrote.
CD95L is a signaling protein that is normally anchored to the surface of certain cells. Sometimes however, enzymes can cut CD95L off the surface of cells, leaving the protein to float through the bloodstream. This soluble form is involved in inflammation and immune responses.
Protein significantly elevated in people with all three types of AAV
In this study, a team of researchers in France set out to evaluate the role of CD95L signaling in AAV. Their study involved samples from 70 people with AAV and 20 healthy people who served as controls. Regarding AAV types, 39 patients had microscopic polyangiitis (MPA), 19 had granulomatosis with polyangiitis, and 12 had eosinophilic granulomatosis with polyangiitis.
Analyses of kidney samples from two AAV patients and one healthy control showed that the CD95L protein was present at the surface of cells lining the blood vessels of kidneys from patients, but not healthy controls.
To understand whether this protein was being cleaved in AAV, the team analyzed levels of soluble CD95L in the blood of all AAV patients and healthy controls. They found that this protein was significantly elevated in people with all three types of AAV relative to healthy controls.
Importantly, MPA patients with active disease had higher levels of soluble CD95L compared with those with inactive disease, and over time, these levels dropped after effective immunosuppressive treatment.
“This study reveals that the [soluble CD95L] concentration is increased in patients with AAV and is associated with disease severity,” the researchers wrote.
Spurred by this finding, the scientists conducted a comprehensive battery of molecular experiments aimed at understanding how the free-floating CD95L protein may affect neutrophils.
Overall, these findings demonstrated that [sCD95L-mediated signal] exacerbates clinical symptoms in AAV mice and highlight that [suppression] of this signal represents an attractive therapeutic option to prevent kidney failure in patients with AAV.
They found that this version of CD95L can bind to receptor proteins on neutrophils from AAV patients, setting in motion a series of biochemical reactions that ultimately lead the neutrophils to produce more tissue-damaging ROS.
The researchers then tested the effects of DB550, an experimental therapy that blocks the activity of CD95L receptors, in three different mouse models of AAV. The researchers stressed that none of these animal models fully recapitulates human disease, but nonetheless, across all the models there was evidence that DB550 treatment reduced disease severity. In particular, data suggested that DB550 reduced the accumulation of neutrophils in the kidneys, which are often the organs most impacted by AAV.
“Overall, these findings demonstrated that [sCD95L-mediated signal] exacerbates clinical symptoms in AAV mice and highlight that [suppression] of this signal represents an attractive therapeutic option to prevent kidney failure in patients with AAV,” the researchers concluded.
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