BTK Signaling Molecules Show Altered Levels in NMOSD Patients
Key players in B-cell signaling pathways and related inflammatory molecules were elevated in the blood of people with neuromyelitis optica spectrum disorder (NMOSD) compared with healthy people, a study found.
The findings suggest that targeting this signaling pathway could show therapeutic promise in NMOSD, the researchers noted.
The study, “Changes in the BTK/NF-κB signaling pathway and related cytokines in different stages of neuromyelitis optica spectrum disorders,” was published in the European Journal of Medical Research.Â
NMOSD is an autoimmune disorder that leads to inflammation that primarily affects the spinal cord and optic nerve, which sends and receives signals from the eye.
While the exact disease mechanisms are not known, about 70% of patients have antibodies against the aquaporin-4 (AQP4) protein. These antibodies lead to the destruction of astrocytes, the nervous system support cells on which AQP4 resides.
Anti-AQP4 antibodies are produced by B-cells, an immune cell population, in the blood. B-cells are activated by a complex signaling cascade beginning with activation of the bruton tyrosine kinase (BTK) enzyme. It helps B-cells proliferate, or grow, and produce antibodies and inflammatory molecules that mediate autoimmunity.
In models of other autoimmune disorders, such as multiple sclerosis, inhibiting this signaling cascade with BTK inhibitors can lower inflammation and thwart disease progression. But the mechanisms about how these signaling molecules may interact to contribute to NMOSD are less clear.
The researchers examined blood levels of several of these signaling molecules and associated inflammatory molecules in NMOSD patients and healthy volunteers to identify whether they might play a role in these underlying disease mechanisms.
Participants were recruited from the Second Hospital of Hebei Medical University, China and included 32 healthy people, 24 people with acute NMOSD — meaning they were actively experiencing symptoms and had worsening disability — and eight people with NMOSD who were in remission and not experiencing symptoms.
Of the 32 total NMOSD patients, 26 had anti-AQP4 antibodies.
The scientists measured the activity levels of the genes for several molecules involved in B-cell signaling, including BTK, inhibitor of nuclear factor kappa B Kinase (IKK), and phosphatidylinositol 3-kinase (PI3K), as well as nuclear factor kappa B (NF-kB).
Gene activity of all measured molecules was significantly increased among patients with acute NMOSD relative to healthy controls. Except for PI3K, all were also significantly elevated in acute NMOSD relative to patients in remission. PI3K was significantly increased in patients in remission compared with controls.
That PI3K remained altered in patients even in remission suggests these patients “are still in an abnormal immune state,” the researchers wrote.
Gene and protein levels of CXCL2 and CXCL12, two inflammatory molecules related to the B-cell signaling pathways, were also measured. Gene activity of both was elevated in acute patients and protein levels were elevated in both acute and remission groups relative to the control group.
The data support the idea that the BTK signaling pathway in B-cells may be impaired in NMOSD, perhaps contributing to disease mechanisms. Similarly to multiple sclerosis and other autoimmune disorders, “BTK inhibitors may be also a potential therapeutic target for NMOSDs,” the researchers wrote, noting “the effect of different BTK inhibitors in NMOSDs will be further studied in our following experiments.”
About the Author
