Further research is, however, required to validate these findings and assess the value of these biomarkers in MS development, scientists say.
The study, “Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients,” was published in the journal EBioMedicine.
Optic neuritis is characterized by inflammatory damage to the optic nerve that sends visual signals to the brain. About 20% of people with MS experience optic neuritis as the first symptom, but not all of those with optic neuritis develop MS.
Thus, biomarkers are important to help identify those with optic neuritis who may or may not develop MS.
Like in MS, the immune system in optic neuritis attacks the fatty coating, called the myelin sheath, on nerve fibers. However, the specific molecular targets (epitopes) of antibodies released by immune cells that lead to myelin damage remain largely unknown.
Here, a gene that carries instructions for the production of a protein of interest is inserted into the gene that encodes a protein displayed on the surface of a phage (a virus that selectively targets bacteria). Instead of displaying whole proteins, MVA technology uses small protein fragments, called peptides, of 12 amino acids in length (amino acids are the building blocks of proteins).
Then, a library containing millions of unique phage-displayed peptides is mixed with a small sample of fluid isolated from patients, typically blood and cerebrospinal fluid — the fluid surrounding the brain and spinal cord.
Displayed peptide amino acid sequences that bind disease-related antibodies are isolated, identified, and compared with proteins in a database to find those targeted by these same antibodies.
In the study, researchers at Protobios, in collaboration with investigators at the University of Helsinki in Finland, applied MVA technology to samples isolated from people with optic neuritis and MS to find molecular targets that can be used as biomarkers to predict optic neuritis progression to MS.
The first phase of the study included a discovery cohort of 24 Finnish patients who were diagnosed with optic neuritis and had never been treated (treatment-naïve). Of these, 15 were subsequently diagnosed with relapsing-remitting MS (RRMS) — the optic neuritis-MS (ON-MS) group — while nine did not develop MS (ON group). Also included were 38 healthy control participants.
A library of 20 million unique peptides was identified, which had defined sets of peptides common to blood and cerebrospinal fluid samples from the same individual and peptides shared between individuals.
The analysis revealed two major groups of closely related epitope peptides with similar amino acid sequences defined as clusters A and B.
In blood samples, cluster A epitopes were most abundant in optic neuritis patients (ON group) and controls, compared to ON-MS patients, whereas a trend of more abundant cluster B epitopes was found in ON-MS and ON patients than controls. In cerebrospinal fluid, clusters A and B were similarly detected in both patient groups compared with controls.
A comparison with database proteins found cluster A matched an epitope on the cytomegalovirus (CMV) — a virus associated with MS. In contrast, peptides of cluster B were close mimics to an epitope found on the Epstein-Barr virus (EBV), also linked to MS risk.
These findings were supported by clinical data showing the highest anti-CMV response was observed in the ON cohort and controls, while all study participants in the discovery cohort were positive for anti-EBV antibodies. Moreover, all individuals who had antibodies against clusters A or B epitopes were positive for CMV and EBV.
The next phase of the study included a validation cohort of 20 treatment-naïve Finnish patients with RRMS, out of which 10 had optic neuritis and 10 exhibited other symptoms. Also included were 448 controls.
All 20 patients had roughly similar responses to cluster A and B epitopes, although those with optic neuritis onset differed slightly from controls.
Combining findings from both groups, clusters A and B epitopes specifically discriminated between these diagnostic cohorts and controls.
The team then conducted a statistical analysis to determine the predictive value of A and B epitopes as blood-based diagnostic biomarkers for the development of MS after optic neuritis onset.
The analysis correctly identified those who developed MS with ON onset with an accuracy of 74.61 at a 75% sensitivity (the likelihood the test will find patients who progress to MS) and 74.22% specificity (the likelihood the test will identify patients who will not progress).
Finally, when compared to an independent external cohort of 192 people with a non-demyelinating disease, the prediction values for A and B epitopes of MS with ON onset were even higher, with an accuracy of 76.62 at 60% sensitivity and 93.23% specificity.
Overall, “in this study, we present an unbiased antibody epitope discovery strategy that resulted in delineation of two epitope biomarkers stratifying subjects with ON and those with MS after ON from healthy controls and patients without any demyelinating disease,” the researchers wrote.
“Specific antibody epitope biomarkers of MS exist in the blood of patients at different stages of disease,” they added. “Further validation of the selected two-epitope biomarker analysis from this initial study are warranted to assess their exact value in MS development.”
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