Study Finds New Molecules Targeted by the Immune System

Researchers have identified four new brain proteins that are targeted by inflammatory T-cells in multiple sclerosis (MS), which could aid in the development of more specific and safer treatments for people with the condition.

The study, “Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis,” was published in Science Advances.

T-cells are a type of immune cell equipped with a specialized receptor that can recognize one specific target, called an antigen, (a piece of a bacteria, for example), with very high specificity. When a T-cell’s receptor binds to its antigen, it triggers the cell to launch an inflammatory attack.

MS is an autoimmune disorder in which the body’s immune system mistakenly attacks healthy parts of the nervous system. Part of this attack is thought to be driven by T-cells responding to “autoantigens” — healthy parts of the body that the cell mistakes for an infectious threat.

Knowing which molecules are targeted by the immune system to initiate the inflammatory attack in MS could lead to treatment approaches that instruct the immune system to “tolerate” such molecules. These potentially could be safer than current therapies that more broadly modulate the immune system.

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“Existing MS treatments are quite indiscriminate in their effect on the immune system, which risks eventually causing complications, such as infections,” Mattias Bronge, PhD, a student at the Karolinska Institutet, in Sweden, said in a press release. “Guiding future treatments more accurately towards the immune cells driving the disease can therefore lead to greater efficacy and fewer side effects.”

While a number of candidates have been reported in MS, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), therapies promoting tolerance to such autoantigens have been “of modest efficacy at best,” the researchers wrote.

“One explanation for the lack of efficacy is that effective tolerization therapy requires targeting of a greater number of autoantigens and preferably personalized according to each individual’s disease-driving autoantigens,” they added.

“Once a patient’s individual autoantigen profile is identified, a treatment can be adapted accordingly. Most autoimmune diseases are driven by T cells and, if we can find a way to target them in diseases like MS, we can pave the way for more precise treatments with fewer side effects for other autoimmune diseases,” said Hans Grönlund, PhD, a principal researcher at Karolinska and co-author of the study.

The team led by scientists at Karolinska Institutet set out to identify novel autoantigens involved in MS.

The scientists screened for T-cell reactivity to 63 different brain proteins. In an initial screen, the team used samples from 16 MS patients who had been treated with Tysabri (natalizumab), alongside nine samples from healthy controls.

Results were validated in two additional groups. One group included 61 Tysabri-treated MS patients and 28 sex-matched healthy controls. The other included 31 untreated MS patients, in addition to 20 samples from healthy controls and 19 samples from people with neurological diseases other than MS.

In addition to established autoantigens such as MOG, the results unveiled four likely autoantigens that never before have been implicated in MS: fatty acid–binding protein 7 (FABP7), prokineticin-2 (PROK2), reticulon-3 (RTN3), and synaptosomal-associated protein 91 (SNAP91).

“In this study, we performed a broad screening of T cell reactivity against CNS proteins and identified FABP7, PROK2, RTN3, and SNAP91 as T cell–targeted autoantigens in MS,” the researchers concluded.

“This is, to our knowledge, the first time that these four proteins have been identified as T cell targets in MS,” they added.

In subsequent experiments, the researchers immunized the mice with each of the proteins — that is, the proteins were injected alongside other molecules to stimulate an immune response against the protein. While the mice did not develop MS-like symptoms, analysis of the mice’s brains showed that immunization with all four proteins resulted in increased inflammation in the nervous system.

“These novel autoantigens could pave the way for rapid and effective diagnostic tests and provide targets for future antigen-specific tolerization immunotherapies,” the scientists wrote.

The researchers found no differences in autoantigen response based on variations in the HLA-DRB1 gene, an immune-related gene known to affect MS risk. They noted that autoantigen responses tended to be stronger in males than females, but stressed that there was considerable variability, making it difficult to draw firm conclusions from this relatively small study.