For decades, doctors have been puzzled why some patients with entirely different autoimmune disorders share pain from nerve injury (neuropathic pain) in common.
Recently, a clue emerged when researchers found that the immune system in many of these patients makes an autoantibody—an antibody that attacks the body’s own proteins—against CASPR2. CASPR2 is a protein found in the nervous system.
Now, in a new study, scientists show how these autoantibodies can cause pain.
Spanning multiple universities across Europe, the United Kingdom, and the Middle East, a team of researchers led by David Bennett, from the University of Oxford in the UK, finds that human CASPR2 autoantibodies, when injected into mice, decrease the number of potassium channels in neurons (nerve cells), and prevent the channels from getting to the right place along nerve fibers, resulting in pain.
Potassium channels are proteins in the cell membrane that, when functioning properly, quiet the electrical activity of neurons. When the channels function abnormally—when the “brakes” on the neurons are released—this electrical activity goes up, contributing to pain.
“This finding is helpful for patients with CASPR2 autoantibodies because these individuals can suffer very badly from pain and do not respond to normal treatments,” says Andreas Goebel from the University of Liverpool in the UK. Goebel was not involved in the study.
The study may also have relevance for patients with other types of pain.
The new work appeared online February 8, 2018 in the journal Neuron.
On the attack
One of the jobs of the immune system is to make antibodies that attack unwelcome invaders like bacteria and viruses. But in patients with autoimmune disorders, the immune system mistakenly produces antibodies against the body’s own proteins.
These “self-antibodies”, or autoantibodies, can cause a range of symptoms depending on the protein they attack. Patients with autoantibodies to the CASPR2 protein can develop a range of disorders that each feature their own unique set of symptoms—but a common thread is neuropathic pain. This is something that one of Bennett’s co-authors, Angela Vincent, saw in her patients.
“She told me that of her patients with CASPR2 autoantibodies, many seemed to experience pain,” says Bennett.
Fortunately, the researchers already knew that the CASPR2 protein is necessary so that potassium channels get to the right spot along nerve fibers. So they wondered if the CASPR2 autoantibodies, by attacking the CASPR2 protein, were preventing the proper placement of the potassium channels, resulting in increased electrical excitability of neurons and pain.
From humans to mice
The team first wanted to confirm that the CASPR2 autoantibodies themselves could actually cause pain.
To do so, the researchers isolated CASPR2 autoantibodies from two patients with autoimmune disease who also had neuropathic pain. The researchers then treated normal mice each day with these human autoantibodies for two to three weeks, keeping an eye on whether this led to pain in the animals.
And indeed that’s just what they saw: Within 11-15 days the mice became hypersensitive when the researchers poked their paws with a thin filament (a common experimental technique used to study pain in animals). This is called mechanical hypersensitivity.
After ruling out other potential causes of pain, the scientists saw fewer potassium channels in the animals’ nerve cells. So they concluded that the autoantibodies contributed to pain through effects on these channels.
Releasing the brakes makes neurons hyperexcitable
Since the CASPR2 autoantibodies are thought to inhibit the normal function of the CASPR2 protein, the team believed that animals without that protein would also show mechanical hypersensitivity.
To test this idea, the researchers genetically engineered mice so they would lack fully functioning CASPR2 protein. Similar to the normal mice treated with CASPR2 autoantibodies, these animals also had mechanical hypersensitivity to pokes of the paw.
Next, the team took a look at pain neurons from these mice and found that the cells had fewer potassium channels and were also hyperexcitable. They also saw that the channels were redistributed along nerve fibers away from their normal location.
Similarly, in other experiments, the team saw that the CASPR2 autoantibodies decreased the number of potassium channels, and increased cell excitability, when they were applied to neurons from normal mice.
With this evidence, the group concluded that the CASPR2 autoantibodies released the brakes that the channels normally apply to nerve cells, causing increased electrical excitability of neurons, with subsequent pain.
What about other types of pain?
Not much is likely to change for patients with high levels of CASPR2 autoantibodies. This is because these patients already receive immune therapy to decrease levels of the autoantibodies, in order to treat their other symptoms.
“Clinically, treatment for these patients may not yet change much,” says Goebel. “More studies are needed to determine whether [immune therapy] will work for patients with lower levels of CASPR2 autoantibodies.”
For the wider population of people with pain who don’t have CASPR2 autoantibodies but may still have hyperexcitable neurons, the study casts the CASPR2 protein itself in an interesting light: Perhaps increasing the amount of CASPR2 protein could decrease the excitability of neurons and in doing so reduce pain.
At the least, Bennett hopes the findings encourage researchers to pay more attention to the impact that antibodies have on pain.
“We should be considering antibodies in the generation of neuropathic pain much more,” he says.
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.