Scientists ID potential biomarkers to help in MG diagnosis
Set of inflammatory molecules also could prove useful for classifying MG
A set of inflammatory molecules could be useful as biomarkers for identifying and classifying myasthenia gravis (MG), potentially aiding in the diagnosis of the rare neuromuscular disease, according to a new study led by researchers in Sweden.
Proteins and regulatory molecules associated with inflammatory processes could serve as disease biomarkers, helping to differentiate between healthy individuals and those with MG.
They also might help to specifically characterize subgroups of the autoimmune disease, such as early-onset (EOMG) and late-onset (LOMG) myasthenia gravis, the scientists noted.
The results of the study, “Serum protein biomarker profile distinguishes acetylcholine receptor antibody seropositive myasthenia gravis patients from healthy controls,” were published in the journal Science.
“These findings expand our knowledge of the immunological pathways associated with [myasthenia gravis],” the team wrote.
Diagnosis, classification of MG often is complicated
MG is an autoimmune disease in which the body produces antibodies that target and inhibit the function of molecules necessary for muscle contraction, causing symptoms of muscle weakness and fatigue in patients.
Nerve cells signal muscles to contract by the release of a neurotransmitter called acetylcholine. Acetylcholine binds to the acetylcholine receptor (AChR) on the surface of muscle cells, translating it into muscle contraction. If the binding between AChR and acetylcholine is compromised by antibodies targeting the AChR, the muscle cannot contract.
Most autoantibodies found in people with MG are directed against AChR, classifying these patients as acetylcholine receptor antibody-positive. In these patients, MG is considered EOMG if it appears before age 50, or LOMG if it starts at age 50 or older.
Classifying MG can be complicated, however. Patients can belong to different subgroups depending on age, symptoms, and type of autoantibodies, impacting treatment and disease progression.
“Developing objective and reliable MG biomarkers in disease diagnosis, follow-up, and predicting disease activity is needed for clinical follow-up and clinical trials and is considered one of the top priority areas in MG research,” the researchers wrote.
Knowing that there is a link between inflammatory proteins and autoimmune diseases, the team analyzed the protein profile in samples from 98 MG patients in Sweden and Latvia. All patients were AChR-positive, and were matched by age and sex with 77 healthy individuals, who served as controls. The median age for patients was 61, and for controls, 55. Around 40% of both patients and controls were men.
From a panel of 92 inflammatory proteins analyzed, 23 showed significant differences between MG AChR-positive patients and healthy controls. A total of 16 proteins were elevated, and seven were decreased in the patient group. The five biomarkers with the best potential to distinguish between healthy controls and MG AChR-positive patients were CCL28, TNFSF14, 4E-BP1, TGF-alpha, and ST1A1.
Developing objective and reliable MG biomarkers in disease diagnosis, follow-up, and predicting disease activity is needed for clinical follow-up and clinical trials and is considered one of the top priority areas in MG research.
These proteins, due to their immune system functions, could help reveal mechanisms related to MG development. For example, CCL28, elevated by around 75% in MG patients compared with controls, is a protein that directs B-cells — which are responsible for producing antibodies — to specific body areas.
TNFSF14 promotes inflammation and induces functional changes in cells during inflammatory processes. Although its levels are higher in other autoimmune diseases, TNFSF14 was decreased in MG AChR-positive patients, especially in those who were not on immunosuppressive treatment.
“Recognizing specific inflammatory protein biomarkers relating to distinct immune pathways confers additional insights into the underlying pathophysiology” of MG, the researchers wrote.
Investigating microRNA as potential biomarkers
MicroRNAs, small molecules that can control protein production in cells, have shown potential as biomarkers in MG AChR-positive patients in previous studies. Now, researchers found that TNFSF14 and ST1A1 levels had an inverse correlation with three key microRNAs — miR-150-5p, miR-30e-5p, and miR-21-5p — potentially indicating an indirect regulation of the two proteins by these microRNAs.
To identify biomarkers that could potentially distinguish between MG subgroups, the team then analyzed data from 46 EOMG and 52 LOMG patients. Of these, 70 were receiving immunosuppressive treatment, while 28 were not.
TGF-beta-1, a regulatory protein, was present at higher levels in EOMG patients, while the protein OPG was higher in the LOMG group. “Age had a moderate positive correlation with OPG,” the researchers wrote.
Regarding immunosuppressive treatment and the degree of disease severity, correlations were also found between these parameters and specific proteins. However, more robust studies are required to confirm the findings, the researchers noted.
Study limitations, according to the team, include immunosuppressive treatment in most patients, potentially influencing inflammatory protein levels.
Overall, the data “present a distinct serum profile of inflammatory protein biomarkers that can separate AChR [positive] MG patients from [healthy controls] and is representative of a broad activation of the immune system,” the team concluded.
The researchers emphasized, however, that the potential serum biomarkers identified need to be validated in further studies, to establish molecular signatures for patient subgroup stratification and monitoring of treatment response.
About the Author
