Immune Cell Receptor FcyRIV Implicated in Development of EBA
Mouse study suggests blocking this protein may be potential therapeutic target
Blocking the activity of an immune cell receptor protein called FcyRIV prevented the development of epidermolysis bullosa acquisita in mice, a new study reports.
The findings suggest this protein as a potential therapeutic target for this form of epidermolysis bullosa.
The study, “Therapeutic effects of Fc gamma RIV inhibition are mediated by selectively blocking immune complex-induced neutrophil activation in epidermolysis bullosa acquisita,” was published in the journal Frontiers in Immunology.
EBA characterized by blistering in layers of the skin in response to injury
Epidermolysis bullosa acquisita, or EBA, is an autoimmune disease driven by antibodies that bind to a structural protein called collagen VII, giving rise to symptoms like skin blistering. While these collagen-targeting antibodies are needed for EBA to develop, they usually aren’t enough to cause disease on their own, as inflammatory factors are recruited to induce damage.
One type of inflammatory immune cell known to participate in this attack are neutrophils. These cells can detect antibodies using protein receptors on their surface. Here, researchers in Germany conducted a series of tests to examine the role that one of these protein receptors — called FcyRIV, a mouse equivalent of the human FcγRIIIA — plays in EBA.
In an initial series of tests, the researchers showed that blocking the FcyRIV protein prevented the development of EBA in mice that were administered disease-driving antibodies against collagen VII. Whereas mice given a control therapy developed moderate to severe clinical symptoms, those given a FcyRIV-blocking antibody “displayed no clinical signs of EBA during the entire observation period throughout 12 days,” the researchers wrote.
Our findings throw spotlight on the importance of developing targeted therapies aiming to interfere with the physiologic activity of FcγRIV signaling pathway
In further analyses, the researchers found that mice treated with the FcyRIV-blocking antibody had significantly higher numbers of neutrophils in their skin tissue.
“This observation was unexpected since neutrophils are known as the main effector cells of antibody-induced tissue injury in the inflammatory variant of EBA and that function blockade of FcyRIV protected against disease induction,” the researchers wrote.
Neutrophil number at the dermal-epidermal junction — the specific part of skin tissue where autoantibodies target collagen VII in EBA — was also significantly higher with anti-FcyRIV antibodies on day eight of the observation period. But the relative numbers of neutrophils at the junction (percentage) were significantly lower on day three.
Additional tests using neutrophils in dishes revealed that blocking FcyRIV did not affect the cells’ ability to move about. However, blocking this receptor did substantially decrease the inflammatory activation of these cells.
Results support blocking FcyRIV as a potential therapeutic strategy in EBA
These results suggest “that the favorable clinical effect of anti-FcyRIV is exerted by impairment of activation, but not migration, of neutrophils,” the researchers wrote, adding that these results support blocking FcyRIV as a potential therapeutic strategy in EBA.
The team also noted that impaired neutrophil activation might explain why more of these cells accumulated in the skin of treated mice: under normal circumstances, like an infection, neutrophils will enter into tissue, rapidly activate, and then are eliminated. Since the cells aren’t activating normally, this process gets interrupted, so the cells don’t leave the tissue and are therefore detectable at higher levels.
“Our findings throw spotlight on the importance of developing targeted therapies aiming to interfere with the physiologic activity of FcγRIV signaling pathway,” the researchers concluded.
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