CD59 Protein Might Protect Against Immune System’s Action in MG

Boosting CD59 at neuromuscular junction has potential as therapeutic strategy

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by Andrea Lobo |

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A cross-section illustration of a muscle.

A protein called CD59 might protect the neuromuscular junction — the place where nerve cells come into contact and communicate with muscle cells — from the harmful action of the body’s immune system in myasthenia gravis (MG) patients, a study in Japan suggests.

“CD59 overexpression might be required for the [neuromuscular junction] reconstruction,” researchers wrote, noting that in this sense, “the induction of CD59 expression at the [neuromuscular junction] would have the potential to be a novel therapeutic strategy in MG.”

The study, “CD59 Expression in Skeletal Muscles and Its Role in Myasthenia Gravis,” was published in the journal Neurology Neuroimmunology & Neuroinflammation.

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MG is an autoimmune disease that affects the communication between nerve and muscle cells at the neuromuscular junction. The disease is caused by self-reactive antibodies that target proteins critical for nerve-muscle communication, most commonly acetylcholine receptors (80%–85% of cases) in muscle cells.

Both acetylcholine receptor antibodies and complement proteins accumulate at neuromuscular junctions in MG. Complement proteins normally induce inflammatory responses to help immune cells fight off infections and eliminate disease-causing microbes. But in the case of MG, these proteins attack neuromuscular junctions, further contributing to MG’s damaging effects and leading to symptoms such as muscle weakness and fatigue.

Complement inhibitors, such as Soliris (eculizumab), are useful therapeutic agents for MG and other complement-mediated disorders. The cluster of differentiation 59 (CD59) is a regulatory protein that can also inhibit the complement cascade and is widely distributed in normal human cells, including in skeletal muscles.

Although complement regulatory proteins like CD59 “could offer protection against complement-mediated damage” in MG, “there is limited information on their expression [levels] at the human [neuromuscular junction],” the researchers wrote.

Muscle samples analyzed from 60 patients and 6 people without myopathy

To learn more, researchers at Kanazawa University in Japan analyzed chest muscle samples from 16 patients diagnosed with MG, as well as leg and arm muscle samples from six patients who had no muscular disorders (non-myopathy controls).

The researchers observed the CD59 protein was strongly localized at the neuromuscular junction in both MG and control patients. Neuromuscular junctions were stained using alpha-bungarotoxin, a neurotoxin that normally binds to acetylcholine receptors.

However, in MG patients, CD59 staining was weaker — reflecting lower levels of the protein — and acetylcholine receptors had an irregular expression pattern. Neuromuscular junctions were also smaller in MG patients compared with non-myopathy controls.

“The destructive condition of [neuromuscular junctions] by complement activation resulted in the decreased expression of both CD59 and [acetylcholine receptors],” the researchers wrote.

When analyzing entire muscle cells, however, the researchers detected an increase in CD59 protein levels in MG patients. By excluding a patient who was experiencing a disease crisis, they found that higher CD59 expression was correlated with lower disease severity and lower disease impact on daily life activities.

The “overexpression of CD59 over the entire muscle cell surface might have consequently made up for the expression at [the neuromuscular junction] and be an essential factor for clinical improvement in MG,” the researchers wrote.

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In addition, the levels of CD59 and acetylcholine receptors messenger RNA (mRNA) in muscle cells were found to be significantly correlated. Of note, mRNA is an intermediate molecule that translates the information contained in genes to produce a protein.

A higher CD59/acetylcholine receptor mRNA ratio was also significantly associated with better clinical parameters, and according to researchers, could be used as “a biomarker of disease severity.”

However, considering the ratio was analyzed using mRNA from muscles, it would be challenging to use it in daily clinical practice.

“To use this index in clinical practice, it would be necessary to identify serum biomarkers that reflect the ratio of CD59/AChR mRNA in the muscles,” the researchers wrote.

Altogether, these findings suggest that the overexpression of CD59 in MG might inhibit complement action and be required for the reconstruction of the neuromuscular junction.