New research from Austrian scientists may reveal a link between Epstein-Barr virus (EBV) and multiple sclerosis (MS), and explain why only some people are infected with EBV (previously found to increase the risk of MS by 32 times) Go on to develop neurodegenerative diseases.
The researchers say that unique regulatory mechanisms in the body that normally prevent the immune system from attacking EBV also lead to attacks on healthy brain cells.
However, certain genetic variations in humans, as well as variation between different EBV strains and other viral infections, appear to make these quality control mechanisms less effective. The findings may help researchers better understand why some people infected with EBV may develop MS while others do not.
Thomas Berger, MD, professor at the Medical University of Vienna, discussed the findings at a joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) held last year in Italy.
The title of his speech was “Ineffective immune control of autoreactive responses to Epstein-Barr virus is an important cause of multiple sclerosis“.
Genetic variation may underlie link between MS and EBV
In multiple sclerosis, the immune system attacks healthy cells in the brain and spinal cord. Exactly what triggers this self-targeted immune attack is not fully understood, but EBV infection has been identified as one of the strongest risk factors for MS.
Previous research has shown that an EBV protein called EBNA1 has a similar structure to a human brain protein called GlialCAM. It is thought that when the immune system targets viral proteins to fight infection, it may also accidentally attack similarly shaped proteins in the nervous system, setting the stage for multiple sclerosis.
EBV is best known as the virus that causes infectious mononucleosis, commonly known as mononucleosis. It also often causes non-specific illness in childhood—in fact, the vast majority of people are infected with Epstein-Barr virus as adults.
Because EBV is common but multiple sclerosis is not, this begs the question of why only some people infected with EBV go on to develop the autoimmune disease.
“If MS occurs in only a small proportion of EBV-infected patients, then there must be something else involved – either to prevent an autoimmune response, on the one hand, or to trigger MS on the other,” said Dr. Jay said.
The researchers are now trying to better understand what determines whether a person develops an EBNA1-specific autoimmune response to GlialCAM and goes on to develop multiple sclerosis.
If MS occurs only in a small proportion of patients infected with EBV, then there must be some other factor that either prevents an autoimmune response, on the one hand, or triggers MS, on the other.
To do this, the team analyzed data from 270 multiple sclerosis patients who had blood samples dating back to their first EBV infection. The infection occurred an average of 8.2 years before patients were diagnosed with MS. 270 matched samples from healthy individuals were also analyzed.
The results show that following EBV infection, immune cells often unexpectedly target the brain protein GlialCAM as well as the viral protein EBNA1. In fact, the initial immune response to EBNA1 and GlialCAM was “completely similar” regardless of whether one had multiple sclerosis or not, Berger said.
Statistical model finds some patients have 260 times higher risk
However, the researchers found significant differences in the activity of other immune cells that help regulate the immune system. Specifically, people who later developed MS had much lower levels of certain types of natural killer (NK) cells and cytotoxic CD8 T cells than healthy controls.
As their name suggests, these types of immune cells are capable of killing other cells—the researchers believe that these regulatory cells typically eliminate immune cells that target GlialCAM before they cause the autoimmune problems that lead to multiple sclerosis.
The scientists identified several factors associated with reduced activity of these regulatory cells.For one, patients who carry certain immunomodulatory gene variants have lower regulatory cell activity, e.g. KLRC2 and NKG2D.
Regulating cellular activity is also affected by specific strains of EBV virus. In particular, certain strains of Epstein-Barr cause human cells to produce more of an immunomodulatory protein called HLA-E, and people infected with these strains tend to have fewer activated regulatory cells.
Mutations in genes that provide instructions for making HLA-E are also associated with differences in the activity of regulatory immune cells, as is previous infection with another common virus that can modulate HLA-E activity (called cytomegalovirus, or CMV).
Taking the findings together, Berger said, “there are very clear differences between immune responses in healthy controls compared with MS patients.”
“Both specific viruses, as well as host susceptibility, can lead to ineffective control of EBV-mediated autoimmune responses,” he added.
In statistical models, the scientists calculated that patients with genetic risk factors who were infected with an EBV strain that upregulated HLA-E were up to 260 times more likely to develop MS than patients without these genetic factors who were infected with other EBVs. strains.
The findings may help better explain the link between EBV and MS, and why the virus only causes the disease in some people. If future work validates the results, the findings could pave the way for better monitoring of people at high risk for MS and lead to new treatments designed to halt the progression of the disease.
NOTE: The MS News Today team is providing in-depth coverage of the disease The 9th ECTRIMS-ACTRIMS Joint Meeting, October 11-13.go here Check out the latest stories from the conference.