It seems that around 25% of MS cases are due to molecular mimicry between EBV EBNA1 and GlialCAM (astrocytes)
Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM
https://www.nature.com/articles/s41586-022-04432-7
Abstract
Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear3.
Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody.
Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients.
Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies
More about EBV: EBNA1 and GlialCam
Some review about the paper
News about it:
https://medicalxpress.com/news/2022-02- ... rosis.html
Scientists have long suspected—but failed to prove—a link between certain viral infections and the development of multiple sclerosis, a crippling autoimmune disease that affects nearly 1 million Americans. Now, a study led by Stanford Medicine researchers has proved that the Epstein-Barr virus, a common type of herpes virus, triggers multiple sclerosis by priming the immune system to attack the body's own nervous system.
The study, published Jan. 24 in Nature, shows that approximately 20 percent to 25 percent of patients with multiple sclerosis have antibodies in their blood that bind tightly to both a protein from the Epstein-Barr virus, called EBNA1, and a protein made in the brain and spinal cord, called the glial cell adhesion molecule, or GlialCAM.
"Part of the EBV protein mimics your own host protein—in this case, GlialCAM, found in the insulating sheath on nerves," said William Robinson, MD, Ph.D., professor of immunology and rheumatology at Stanford. "This means that when the immune system attacks EBV to clear the virus, it also ends up targeting GlialCAM in the myelin."
Myelin forms the protective coating around nerve cells, and when it's damaged, electrical impulses can no longer jump efficiently from one nerve to the next, resulting in the numbness, muscle weakness and severe fatigue of multiple sclerosis.
The lead author of the study is Stanford research scientist Tobias Lanz, MD. The senior author is Robinson, the James. W. Raitt Professor, who credited co-author Lawrence Steinman, MD, professor of neurology at Stanford, with also playing a key role in driving the research.
"This is the first time anyone has shown rather definitively that a virus is the trigger for multiple sclerosis," Steinman said. "And these exciting findings open up some new directions for clinical trials in MS treatment."
MS and viruses: an elusive connection
Previous research has shown that multiple sclerosis patients have increased antibodies to a variety of common viruses, including measles, mumps, varicella-zoster and Epstein-Barr virus. In fact, more than 99 percent of MS patients have EBV antibodies in their blood, indicating a prior infection, compared with 94 percent of healthy individuals. But despite this epidemiologic correlation, scientists have struggled to prove a causal connection.
"Nobody really knows what causes autoimmune diseases, and for many decades, all sorts of different viruses have been hypothesized," Robinson said. "But when people did further mechanistic digging, everything fell apart, and it turned out that getting those other viruses didn't actually cause MS."
To search for this elusive mechanistic link, the researchers started by examining the antibodies produced by immune cells in the blood and spinal fluid of nine MS patients. Unlike in healthy individuals, the immune cells of MS patients traffic to the brain and spinal cord, where they produce large amounts of a few types of antibodies. Patterns of these antibody proteins, called oligoclonal bands, are found during analysis of the spinal fluid and are part of the diagnostic criteria for MS.
"No one knows exactly what those antibodies bind to or where they're from," Robinson said. "So the first thing we did was analyze the antibodies from the oligoclonal bands, and showed that they come from B cells in the spinal fluid."
B cells are a type of white blood cell made in the bone marrow, and the technology to sequence these cells individually was developed by the Robinson lab about eight years ago. "In the past, researchers would take serum and spinal fluid from MS patients and test them on planar arrays or throw them on histology slides to see what sticks," Lanz said. "What we did was a different approach: We took B cells from the spinal fluid, single-cell sorted them and sequenced each one separately. In a single-cell format and at the scale of tens to hundreds of B cells per patient, that had not been done before."
MS antibodies bind viral protein EBNA1
Once the researchers determined that the oligoclonal bands in MS are produced by the sorted B cells in the spinal fluid, they expressed individual antibodies from these cells and tested them for reactivity against hundreds of different antigens.
"We started with human antigens," Robinson said, "but couldn't find clear reactivity. So eventually we tested them against EBV and other herpes viruses, and lo and behold, several of these antibodies, and one in particular, bound to EBV."
Six of the nine MS patients had antibodies that bound to the EBV protein EBNA1, and eight of nine had antibodies to some fragment of EBNA1. The researchers focused on one antibody that binds EBNA1 in a region known to elicit high reactivity in MS patients. They were then able to solve the crystal structure of the antibody-antigen complex, to determine which parts were most important for binding.
Before this discovery, Robinson said he'd been unconvinced that EBV caused MS. "We all thought it was just kind of an artifact; we didn't really think it was causative. But when we found these antibodies that bound EBV in the spinal fluid, produced by the spinal fluid B cells, it made us revisit the potential association that we'd dismissed."
Molecular mimicry provides mechanism for development of MS
Next, the researchers tested the same antibody on a microarray containing more than 16,000 human proteins. When they discovered that the antibody also bound with high affinity to GlialCAM, they knew they'd found a specific mechanism for how EBV infection could trigger multiple sclerosis.
"EBV tricks the immune system into responding not only to the virus, but also to this critical component of the cells that make up the white matter in our brains," Steinman said. "To use a military metaphor, it's like friendly fire: In fighting the virus, we damage our own army."
To find out what percentage of MS might be caused by this so-called "molecular mimicry" between EBNA1 and GlialCAM, the researchers looked at a broader sample of MS patients and found elevated reactivity to the EBNA1 protein and GlialCAM in 20 percent to 25 percent of blood samples in three separate MS cohorts.
"Twenty-five percent is a conservative number," Robinson said, noting that it doesn't include patients who may have previously reacted to GlialCAM following EBV infection but whose immune response has evolved since the initial trigger.
https://medicalxpress.com/news/2022-02- ... rosis.html
Scientists have long suspected—but failed to prove—a link between certain viral infections and the development of multiple sclerosis, a crippling autoimmune disease that affects nearly 1 million Americans. Now, a study led by Stanford Medicine researchers has proved that the Epstein-Barr virus, a common type of herpes virus, triggers multiple sclerosis by priming the immune system to attack the body's own nervous system.
The study, published Jan. 24 in Nature, shows that approximately 20 percent to 25 percent of patients with multiple sclerosis have antibodies in their blood that bind tightly to both a protein from the Epstein-Barr virus, called EBNA1, and a protein made in the brain and spinal cord, called the glial cell adhesion molecule, or GlialCAM.
"Part of the EBV protein mimics your own host protein—in this case, GlialCAM, found in the insulating sheath on nerves," said William Robinson, MD, Ph.D., professor of immunology and rheumatology at Stanford. "This means that when the immune system attacks EBV to clear the virus, it also ends up targeting GlialCAM in the myelin."
Myelin forms the protective coating around nerve cells, and when it's damaged, electrical impulses can no longer jump efficiently from one nerve to the next, resulting in the numbness, muscle weakness and severe fatigue of multiple sclerosis.
The lead author of the study is Stanford research scientist Tobias Lanz, MD. The senior author is Robinson, the James. W. Raitt Professor, who credited co-author Lawrence Steinman, MD, professor of neurology at Stanford, with also playing a key role in driving the research.
"This is the first time anyone has shown rather definitively that a virus is the trigger for multiple sclerosis," Steinman said. "And these exciting findings open up some new directions for clinical trials in MS treatment."
MS and viruses: an elusive connection
Previous research has shown that multiple sclerosis patients have increased antibodies to a variety of common viruses, including measles, mumps, varicella-zoster and Epstein-Barr virus. In fact, more than 99 percent of MS patients have EBV antibodies in their blood, indicating a prior infection, compared with 94 percent of healthy individuals. But despite this epidemiologic correlation, scientists have struggled to prove a causal connection.
"Nobody really knows what causes autoimmune diseases, and for many decades, all sorts of different viruses have been hypothesized," Robinson said. "But when people did further mechanistic digging, everything fell apart, and it turned out that getting those other viruses didn't actually cause MS."
To search for this elusive mechanistic link, the researchers started by examining the antibodies produced by immune cells in the blood and spinal fluid of nine MS patients. Unlike in healthy individuals, the immune cells of MS patients traffic to the brain and spinal cord, where they produce large amounts of a few types of antibodies. Patterns of these antibody proteins, called oligoclonal bands, are found during analysis of the spinal fluid and are part of the diagnostic criteria for MS.
"No one knows exactly what those antibodies bind to or where they're from," Robinson said. "So the first thing we did was analyze the antibodies from the oligoclonal bands, and showed that they come from B cells in the spinal fluid."
B cells are a type of white blood cell made in the bone marrow, and the technology to sequence these cells individually was developed by the Robinson lab about eight years ago. "In the past, researchers would take serum and spinal fluid from MS patients and test them on planar arrays or throw them on histology slides to see what sticks," Lanz said. "What we did was a different approach: We took B cells from the spinal fluid, single-cell sorted them and sequenced each one separately. In a single-cell format and at the scale of tens to hundreds of B cells per patient, that had not been done before."
MS antibodies bind viral protein EBNA1
Once the researchers determined that the oligoclonal bands in MS are produced by the sorted B cells in the spinal fluid, they expressed individual antibodies from these cells and tested them for reactivity against hundreds of different antigens.
"We started with human antigens," Robinson said, "but couldn't find clear reactivity. So eventually we tested them against EBV and other herpes viruses, and lo and behold, several of these antibodies, and one in particular, bound to EBV."
Six of the nine MS patients had antibodies that bound to the EBV protein EBNA1, and eight of nine had antibodies to some fragment of EBNA1. The researchers focused on one antibody that binds EBNA1 in a region known to elicit high reactivity in MS patients. They were then able to solve the crystal structure of the antibody-antigen complex, to determine which parts were most important for binding.
Before this discovery, Robinson said he'd been unconvinced that EBV caused MS. "We all thought it was just kind of an artifact; we didn't really think it was causative. But when we found these antibodies that bound EBV in the spinal fluid, produced by the spinal fluid B cells, it made us revisit the potential association that we'd dismissed."
Molecular mimicry provides mechanism for development of MS
Next, the researchers tested the same antibody on a microarray containing more than 16,000 human proteins. When they discovered that the antibody also bound with high affinity to GlialCAM, they knew they'd found a specific mechanism for how EBV infection could trigger multiple sclerosis.
"EBV tricks the immune system into responding not only to the virus, but also to this critical component of the cells that make up the white matter in our brains," Steinman said. "To use a military metaphor, it's like friendly fire: In fighting the virus, we damage our own army."
To find out what percentage of MS might be caused by this so-called "molecular mimicry" between EBNA1 and GlialCAM, the researchers looked at a broader sample of MS patients and found elevated reactivity to the EBNA1 protein and GlialCAM in 20 percent to 25 percent of blood samples in three separate MS cohorts.
"Twenty-five percent is a conservative number," Robinson said, noting that it doesn't include patients who may have previously reacted to GlialCAM following EBV infection but whose immune response has evolved since the initial trigger.
More reviews
Epstein–Barr virus sparks brain autoimmunity in multiple sclerosis
https://www.nature.com/articles/d41586-022-00382-2
Most people who study multiple sclerosis (MS) propose that the factors underlying initiation of the disease enter the central nervous system (CNS) from outside the brain. The debate about the nature of these factors has split researchers into two main camps. Most see autoimmunity as the driving factor for the illness, but a minority invoke viral culprits.
Writing in Nature, Lanz et al.1 report evidence that might settle this debate through a compromise solution.
Supporters of the autoimmunity thesis point to compatible evidence such as the particular patterns of inflammatory injuries in MS; genetic risk factors involving immune-related genes; and immunotherapy treatments that help to relieve the condition. However, a universally accepted culprit that could be the prompt for an abnormal immune response leading to MS has been missing until now. For the proponents of a viral origin, analysis of human populations using epidemiological evidence from the clinic provides compelling data coupling MS with the Epstein–Barr virus. But this associative connection lacked a causal, disease-triggering link.
Lanz et al. examined antibodies obtained from the cerebrospinal fluid (CSF) of people with MS, and identified antibodies that recognize small regions of protein (antigens) corresponding to proteins of the Epstein–Barr virus. The authors report that such antibodies also recognize the protein GlialCAM, which is a component of glial cells in the brain. This result indicates that GlialCAM can act as a target of these antibodies, providing an ‘autoantigen’ for self-directed autoimmunity; it also suggests that this contributes to the events leading to MS.
Importantly, Lanz and colleagues’ data indicate that these crossreactive antibodies evolve from ones that recognize only the virus, through a process of antibody refinement. In samples of CSF from people with MS, the level of immunoglobulin proteins (which form antibodies) are higher than those in the CSF of healthy people, and this is a diagnostic sign of MS. A technique called electrophoretic separation shows that these immunoglobulins form discrete bands in the electrophoresis analysis, which are produced by individual families (clones) of B cells.
These bands, called CSF-specific oligoclonal bands (OCBs), are absent from blood plasma samples. The nature of the antigens that these immunoglobulins recognize is debated. Previous studies indicated that these OCB antibodies bound to various ubiquitous intracellular proteins, but not to CNS-specific autoantigens, raising doubts about whether such antibodies cause disease4.
Lanz et al. revisited this topic taking a straightforward and powerful approach. They isolated antibody-producing B cells of the immune system called plasmablasts from CSF samples of people with early-stage MS (Fig. 1).
The authors characterized the cells individually and assessed their antigen receptors; the genes encoding these receptors provide an initial blueprint that is modified to form the antibodies that the mature, activated cells produced. The plasmablasts expressed markers on their surface indicating ongoing activation of these cells, possibly indicating antigen recognition — but they did not express proteins required for cell migration, which qualified them as being CNS residents. Key observations of Lanz and colleagues’ study came from the authors’ analysis of the genes encoding immunoglobulin, which shed light on the origin of the cells, and on their target antigens.
[...]
https://www.nature.com/articles/d41586-022-00382-2
Most people who study multiple sclerosis (MS) propose that the factors underlying initiation of the disease enter the central nervous system (CNS) from outside the brain. The debate about the nature of these factors has split researchers into two main camps. Most see autoimmunity as the driving factor for the illness, but a minority invoke viral culprits.
Writing in Nature, Lanz et al.1 report evidence that might settle this debate through a compromise solution.
Supporters of the autoimmunity thesis point to compatible evidence such as the particular patterns of inflammatory injuries in MS; genetic risk factors involving immune-related genes; and immunotherapy treatments that help to relieve the condition. However, a universally accepted culprit that could be the prompt for an abnormal immune response leading to MS has been missing until now. For the proponents of a viral origin, analysis of human populations using epidemiological evidence from the clinic provides compelling data coupling MS with the Epstein–Barr virus. But this associative connection lacked a causal, disease-triggering link.
Lanz et al. examined antibodies obtained from the cerebrospinal fluid (CSF) of people with MS, and identified antibodies that recognize small regions of protein (antigens) corresponding to proteins of the Epstein–Barr virus. The authors report that such antibodies also recognize the protein GlialCAM, which is a component of glial cells in the brain. This result indicates that GlialCAM can act as a target of these antibodies, providing an ‘autoantigen’ for self-directed autoimmunity; it also suggests that this contributes to the events leading to MS.
Importantly, Lanz and colleagues’ data indicate that these crossreactive antibodies evolve from ones that recognize only the virus, through a process of antibody refinement. In samples of CSF from people with MS, the level of immunoglobulin proteins (which form antibodies) are higher than those in the CSF of healthy people, and this is a diagnostic sign of MS. A technique called electrophoretic separation shows that these immunoglobulins form discrete bands in the electrophoresis analysis, which are produced by individual families (clones) of B cells.
These bands, called CSF-specific oligoclonal bands (OCBs), are absent from blood plasma samples. The nature of the antigens that these immunoglobulins recognize is debated. Previous studies indicated that these OCB antibodies bound to various ubiquitous intracellular proteins, but not to CNS-specific autoantigens, raising doubts about whether such antibodies cause disease4.
Lanz et al. revisited this topic taking a straightforward and powerful approach. They isolated antibody-producing B cells of the immune system called plasmablasts from CSF samples of people with early-stage MS (Fig. 1).
The authors characterized the cells individually and assessed their antigen receptors; the genes encoding these receptors provide an initial blueprint that is modified to form the antibodies that the mature, activated cells produced. The plasmablasts expressed markers on their surface indicating ongoing activation of these cells, possibly indicating antigen recognition — but they did not express proteins required for cell migration, which qualified them as being CNS residents. Key observations of Lanz and colleagues’ study came from the authors’ analysis of the genes encoding immunoglobulin, which shed light on the origin of the cells, and on their target antigens.
[...]
Re: More about EBV: EBNA1 and GlialCam
So... [hypothetically] it would be a colossal disaster for Moderna to develop an mRNA vaccine to EBNA1. Any potential anti-EBV antibody will need to be screened for cross reactivity to CNS antigens.
Re: More about EBV: EBNA1 and GlialCam
I didn't think about it, but it looks like a problem for them. Maybe this kind of thing is what makes the procedure so slow.
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