Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic’s disease, is a chronic autoimmune disorder primarily characterized by optic neuritis (inflammation of the optic nerve, which connects the eyes to the brain) and myelitis (inflammation of the spinal cord).
Although the exact mechanisms that cause NMOSD are incompletely understood, self-reactive antibodies that target the water channel protein aquaporin-4 (AQP4) are known to play a major role in driving the disease.
What is autoimmunity?
The immune system works to defend the body against foreign invaders, such as viruses and bacteria. Basically, its job is to attack anything that looks like it could cause disease, while leaving the body’s healthy tissue alone.
In autoimmunity, however, the immune system erroneously recognizes the body’s own cells as a foreign threat, and launches an inflammatory attack against those cells. In people with NMOSD, the cells being targeted are in the brain and spinal cord, which is why the condition leads to optic neuritis, myelitis, and other forms of nervous system inflammation.
The biological processes that govern whether or not the immune system recognizes something as a foreign threat are extremely complicated. Scientists are working to understand how these processes are regulated, and what goes wrong when autoimmunity develops.
As is the case with many autoimmune diseases, it’s not clear exactly what causes autoimmunity in NMOSD. It is probable that both genetic and environmental factors play a role. Of note, while only about 3% of NMOSD patients have a family history of the disease, about half have a family history of some kind of autoimmune disorder, supporting a possible role of genetics in the disease’s development.
What are AQP4-IgG?
One way that the immune system fights foreign threats is by producing specialized proteins called antibodies. A given antibody can specifically recognize and bind to a particular molecule seen as a threat (such as a viral protein or part of a bacteria). When an antibody binds to its specific target, it signals to other parts of the immune system that a threat is present, prompting an inflammatory response.
NMOSD is characterized by the presence of autoantibodies — antibodies that erroneously recognize the healthy tissue, leading to autoimmunity. Most NMOSD cases are characterized by antibodies that target a protein called AQP4, which are commonly referred to as AQP4-IgG. Immunoglobulin G, abbreviated IgG, is a type of antibody.
How do AQP4-IgG drive NMOSD?
The AQP4 protein is found on the surface of nervous system cells called astrocytes. These cells do not themselves send electrical signals, but they are critical for supporting the nerve cells (neurons) that do.
When AQP4-IgG binds to AQP4 on the surface of astrocytes, it triggers an immune attack that causes damage to astrocytes through two main mechanisms: antibody dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
In ADCC, the antibody binding prompts cells in the immune system, such as natural killer cells, to kill the targeted cell. In CDC, the antibody triggers the activation of a group of immunological proteins called the complement system, which can kill cells. Both ADCC and CDC are thought to be necessary for the development of NMOSD.
Beyond killing astrocytes, these immunological processes also signal to other parts of the immune system that something is wrong, which can further activate damaging inflammation and immune activity. Ultimately, this damages other cells of the nervous system, particularly oligodendrocytes — the cells responsible for making myelin, the fatty substance that surrounds neurons like a sheath, and is critical for neurons to send electrical signals.
Are other autoantibodies involved?
While AQP4-IgG is the hallmark immunological feature of NMOSD, other autoantibodies may also be involved, at least in some cases.
The blood-brain barrier (BBB), as its name suggests, is a cellular barrier that regulates what substances from the blood are able to pass into the brain and spinal cord. In NMOSD, this barrier can become compromised, which contributes to disease progression. BBB dysfunction has been tied to the presence of autoantibodies that target a protein called GRP-78.
Autoantibodies that target the protein myelin oligodendrocyte glycoprotein (MOG) can cause a disease called MOG antibody disease or MOGAD. While MOGAD has been considered a subtype of NMOSD in the past, current research suggests that the two diseases are distinct from each other.
Last updated: April 15, 2021
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