What the Immune System Gets So Very Wrong in NMOSD
We explain the rogue immune process that brings on the rare autoimmune disease neuromyelitis optica spectrum disorder.
If you’ve heard of neuromyelitis optica spectrum disorder (NMOSD), it’s probably because you know and love someone who has this super rare condition. Maybe you even have it yourself. It’s often confused with multiple sclerosis (MS), but it’s definitely its own thing. Though both conditions involve a faulty immune response that attacks the central nervous system (CNS), causing similar symptoms—vision, walking, plus bladder and bowel problems—experts say the two disorders are entirely distinct.
Those distinctions all involve the immune system: how it attacks, the severity of those attacks, and the clues an NMOSD attack leave behind.
A Normal Immune Response
First thing to know? NMOSD, like MS, is an autoimmune condition, which means the immune system goes rogue and attacks healthy tissue by mistake.
“Our immune system should know our own brain, but when it doesn’t or if it gets confused, it can cause autoimmunity, where it goes after our own parts,” explains Mary Rensel, M.D., a neurologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research in Cleveland. She’s treated people with NMOSD for more than two decades. “It’s not that the immune system isn’t working at all, but rather that it’s doing too much—and it’s doing it wrong.”
Before diving into what exactly it’s doing wrong, it may help to understand how your immune system is supposed to work. The immune system’s main job is to protect your body from invaders, like viruses, bacteria, and toxins. When these invaders harm the body’s issues, your immune response kicks into gear and causes inflammation at the site of the damage. Inflammation causes swelling, which actually helps your body keep any invader away from other healthy tissue. White blood cells also rise to the occasion and do their best to help fight off the invaders.
In people with NMOSD, though, the immune response is unfortunately not that simple.
Your Immune System on NMOSD
“When we test [NMOSD patients’] blood, we find in 75% of patients, their immune system is producing antibodies directed against aquaporin-4,” says Elias Sotirchos, M.D., director of the NMOSD clinic at Johns Hopkins University in Baltimore. “These antibodies are considered to be the cause of the disease.” What are antibodies, again? They're proteins in your body that are supposed to fight off bacteria, viruses, and toxins.
Aquaporin-4, or AQP4 for short, is none of those things. Instead, it's a protein we all have that helps transport water in and out of certain cells, especially those in the CNS. It’s found on what are known as astrocytes in the CNS, according to the Siegel Rare Neuroimmune Association (SRNA). Astrocytes, Dr. Rensel says, are kind of like a safety net for the body’s nerves—they help protect the blood-brain barrier, among other important tasks—so if they get hurt, nerves get hurt, too.
These AQP4 antibodies, also called NMO-IgG or anti-AQP4, circulate in the blood, he says, and then gain access to the CNS, where they bind onto AQP4 water channels. “We think the antibody binding to its target triggers a cascade of inflammation, leading to damage to the nervous tissue in the area.”
Much like a domino effect, “when these antibodies bind there, they can do other things, such as recruit inflammatory cells,” Dr. Sotirchos explains. Another thing they can do is activate the complement system, which is part of our immune system that, among other things, “can essentially poke holes into cells and cause damage.” Normally, that ability comes in handy when you’re trying to destroy actual bacteria and viruses. Not so much, though, when it’s your own healthy tissue.
NMOSD most commonly targets AQP4 in optic nerves and the spinal cord, followed by a part of the brainstem called the area postrema, says Dr. Sotirchos. Depending on which of these areas is under attack, different symptoms will arise.
The optic nerves. These nerves carry information from the part of your eye called the retina to the brain. So for those with damage and inflammation in the optic nerves (called optic neuritis), vision loss can occur, along with pain in the eye, says Dr. Rensel. One or both eyes may be affected.
The spinal cord. “The spinal cord is an extremely important part of the nervous system because nerves relay information from the brain to the body and vice versa, including the nerves that tell our limbs to move and that control urinary and bowel function, for example,” Dr. Sotirchos explains. When NMOSD affects this area, it leads to what’s called transverse myelitis, or inflammation of the spinal cord. This can lead to symptoms like pain, mild to severe paralysis of the lower limbs, and loss of control over bowel and bladder functions, according to the National Organization for Rare Disorders (NORD).
The brainstem. The area postrema, which is part of the brainstem, only occurs in about 10% of people with NMOSD, Dr. Sotirchos says. “Involvement of this area can lead to a specific syndrome where patients have nausea, vomiting, and hiccups, because this area controls these reflexes in the body.”
Compared with MS attacks, Dr. Rensel says, NMOSD attacks come on “fast and furious” and can be much more severe. “NMOSD relapses are more disabling, and the damage to the nerves is more irreversible,” she says. That means that a single attack can cause permanent vision loss or even blindness, or, if the spinal cord is attacked, paralysis.
What Causes NMOSD Antibodies to Form in the First Place?
Unfortunately, the frustrating answer is that researchers still don’t know. That said, there does appear to be some level of genetic association, and there are certain groups that appear to get NMOSD more than others, Dr. Sotirchos says. “About 90% of patients are women. And there seems to be higher prevalence among people of African descent.”
A significant number of people with NMOSD have other autoimmune conditions, too.
“A number of them will have features consistent with lupus or other autoimmune conditions that are associated with abnormal antibody production, which tells us that there is something abnormal about their B-cells, which are the kind of cells that evolve to produce antibodies in the blood,” Dr. Sotirchos explains. “So it does seem that these patients with NMOSD are prone potentially to develop other autoimmune conditions that involve autoantibodies, suggesting that there is something with their B-cell development that may be dysfunctional and causing the disease.”
How Treatments Target the Immune Response
Scientists may not understand what triggers the immune system in NMOSD, but identifying the target of this haywire response means there are now super-effective treatments available.
There are currently two NMOSD-specific medications approved by the U.S. Federal Drug Administration (FDA), with a third widely believed to be approved in the U.S. soon. And, Dr. Rensel adds, there are a few off-label drugs that doctors already use with some success to help prevent a future NMOSD attack. That’s because the main goal of NMOSD treatments is to help prevent another relapse (which occurs in the vast majority of people with NMOSD, usually within one to three years of the initial attack). “These drugs help lessen relapses and … irreversible damage,” she explains.
Interestingly, many of these treatments work differently on the immune system. “For example, some are trying to block the immune response, some are trying to block the cell that causes the response,” Dr. Rensel says. “All the medications that are being tried work a little differently, which is actually good for the patients because if one doesn’t work, you could actually try a whole different family of medications.”
Treatment has come a long way in the more than 20 years since Dr. Rensel started treating people with NMOSD. “It’s a really exciting day for this disease that used to be a really hard diagnosis with no treatment,” she says. “It’s wonderful that there are treatments now, and trials going on, and treatments work very well. It’s a new day for this disorder, which is wonderful to see.”
- How Your Immune System Works: (2020). National Institutes of Health. “Immune Response.” medlineplus.gov/ency/article/000821.htm
- NMOSD Information From SRNA: Siegel Rare Neuroimmune Association. (2020). “Neuromyelitis Optica Spectrum Disorder.” wearesrna.org/living-with-myelitis/disease-information/neuromyelitis-optica-spectrum-disorder/
- NMOSD Information From NORD: The National Organization for Rare Disorders. (2018). “Neuromyelitis Optica Spectrum Disorder.” rarediseases.org/rare-diseases/neuromyelitis-optica/