Study Indicates Auto-Antibodies Contribute To Destruction Of Nerve Fibers Myelin Sheath, The Hallmark Of Multiple Sclerosis

The study, published in the February issue of Nature Medicine, was conducted by UC San Francisco scientists, in collaboration with investigators at the Albert Einstein College of Medicine in New York City.

The finding suggests that the suspicion of blame, currently resting on the immune systems T cells, which produce such chemical weapons as cytokines, should extend to B cells, which produce antibodies. It also suggests a possible new target for drug therapy for the intermittent, generally progressive neurologic disorder that remains elusive to wholly successful treatment.

The researchers conducted their study on brain tissue taken from patients with multiple sclerosis, as well as animals with a disease model resembling multiple sclerosis, called experimental allergic encephalomyelitis (EAE). And in this investigation they determined that in active lesions an antibody directly contributes to the destruction of myelin, a membranous sheath with highly organized structure that surrounds the communication wires, or axons, between nerve cells in the brain and whose destruction is characteristic of multiple sclerosis.

We determined that these antibodies were bound to their target in myelin as the membrane was in the process of being disintegrated, said the lead author of the study, Claude Genain, MD, an assistant professor of neurology at UCSF. This is direct evidence that the antibody plays an integral role in the formation of the ruptured myelin sheath.

Researchers have long suspected that multiple sclerosis is an auto, or self, immune disease, in which the bodys own immune system turns against specific targets, or antigens, in tissues of the body. (Under normal conditions, the immune system targets foreign antigens, or invaders, such as bacteria or virus, which are usually excluded from the brain compartment.) But teasing out the role and relative contributions of the various, and often intertwined components of the immune system-T cells, B cells and macrophages being the key players--has been daunting.

For the last decade, scientists have focused on the role played by auto-reactive T cells, as studies on EAE have demonstrated that T cells sensitized against myelin protein antigens in the sheath can trigger the immune attack on the brain.

But researchers have not been able to identify the antigen targets of T cell attack in multiple sclerosis itself and the actual molecular mechanisms implicated in myelin damage have remained uncertain.

In recent work, the UCSF/Einstein team has studied an EAE model in which the way myelin is destroyed is identical to the process that occurs in expanding lesions of multiple sclerosis. In this work, they determined that myelin destruction occurred only in the presence of both auto-reactive T cells and auto-reactive B cell antibodies directed against a minor protein of myelin called myelin oligodendrocyte glycoprotein (MOG).

Thus, in the current study, the team was prompted to reconsider the role of B cells and the antibodies they produce, which were generally discounted years ago. A senior author of the study, Cedric Raine, PhD, DSc, professor of neurology, neuroscience and pathology at the Albert Einstein College of Medicine, was a pioneer in investigating the antibody theory during the late 1960s.

Thirty years ago, we suspected antibodies played a role, but we lacked the technology to show it, said Raine. The significance here is that for the first time weve been able to localize antibodies to the myelin sheath and to demonstrate their involvement in myelin breakdown.

The researchers detected MOG antibody, highlighted with a gold-labeled chemical tag for tracing purposes, in brain tissue obtained from patients during active phases of multiple sclerosis, where it appeared to be bound to the MOG antigen on the surface of myelin as the sheath was being destroyed.

These findings directly identified MOG-specific antibodies in actively demyelinating lesions of multiple sclerosis, indicating that these auto-antibodies play an integral part in the formation of vesiculated, disrupted myelin sheaths, said Raine.

Such direct evidence for the role of antibodies in myelin damage has never been shown, said Genain. Weve identified one antibody in EAE. Our study also shows that there are probably others, too.

The finding does not suggest that the role of T-cells should be discounted, said Genain. He suspects that they do initiate and play an integral role in the destruction of the myelin sheath, which acts as electrical insulator, allowing the conduction of nerve impulses along axons. Their principal role, he says, may be their ability to penetrate the blood-brain barrier thereby creating an opening that ushers in a cascade of immune system cells as well as the fluid known as serum, which contains antibodies. Alternatively, the antibodies could be generated within the brain.

What the study does suggest, said Genain, is that T-cells and B-cells may play an integrated role in the destruction of the sheath.

Clearly, he said, the immune system of humans is much more complex than we had been led to believe on the basis of previous work, and much more difficult to manipulate than in rodents. There are many clinical and pathological presentations of multiple sclerosis. We have looked at what can be called hot lesions where there is intense destructive activity and found that these are invariably associated with antibody deposition. However, the respective part played by T and B cell-mediated mechanisms may well differ in individual cases.

One therapeutic answer for the disease surely lies in blocking autoimmune cells before they can attack the myelin sheath, said Genain. For it is in the progressive splitting and swelling of the myelin sheath that the disruption begins, causing inflammation in the surrounding area, destroying nerve-impulse conducting myelin and, ultimately, displacing the axons themselves causing sporadic, then progressive, neurological impairments, including paralysis of the limbs and eyes.

Co-authors of the study include Barbara Cannella, PhD, assistant professor of pathology, at the Albert Einstein College of Medicine, and Stephen L. Hauser, MD, professor and chair of the department of neurology at UCSF.

The study was funded by a grants from the National Institutes of Health, the National Multiple Sclerosis Society and the Nancy Davis Center Without Walls.

Researchers have discovered that the bodys own antibodies, in recent years considered minor, perhaps even inconsequential, culprits in the development of multiple sclerosis, actually play a direct role in the development of the disease.

The study, published in the February issue of Nature Medicine, was conducted by UC San Francisco scientists, in collaboration with investigators at the Albert Einstein College of Medicine in New York City.

The finding suggests that the suspicion of blame, currently resting on the immune systems T cells, which produce such chemical weapons as cytokines, should extend to B cells, which produce antibodies. It also suggests a possible new target for drug therapy for the intermittent, generally progressive neurologic disorder that remains elusive to wholly successful treatment.

The researchers conducted their study on brain tissue taken from patients with multiple sclerosis, as well as animals with a disease model resembling multiple sclerosis, called experimental allergic encephalomyelitis (EAE). And in this investigation they determined that in active lesions an antibody directly contributes to the destruction of myelin, a membranous sheath with highly organized structure that surrounds the communication wires, or axons, between nerve cells in the brain and whose destruction is characteristic of multiple sclerosis.

We determined that these antibodies were bound to their target in myelin as the membrane was in the process of being disintegrated, said the lead author of the study, Claude Genain, MD, an assistant professor of neurology at UCSF. This is direct evidence that the antibody plays an integral role in the formation of the ruptured myelin sheath.

Researchers have long suspected that multiple sclerosis is an auto, or self, immune disease, in which the bodys own immune system turns against specific targets, or antigens, in tissues of the body. (Under normal conditions, the immune system targets foreign antigens, or invaders, such as bacteria or virus, which are usually excluded from the brain compartment.) But teasing out the role and relative contributions of the various, and often intertwined components of the immune system-T cells, B cells and macrophages being the key players--has been daunting.

For the last decade, scientists have focused on the role played by auto-reactive T cells, as studies on EAE have demonstrated that T cells sensitized against myelin protein antigens in the sheath can trigger the immune attack on the brain.

But researchers have not been able to identify the antigen targets of T cell attack in multiple sclerosis itself and the actual molecular mechanisms implicated in myelin damage have remained uncertain.

In recent work, the UCSF/Einstein team has studied an EAE model in which the way myelin is destroyed is identical to the process that occurs in expanding lesions of multiple sclerosis. In this work, they determined that myelin destruction occurred only in the presence of both auto-reactive T cells and auto-reactive B cell antibodies directed against a minor protein of myelin called myelin oligodendrocyte glycoprotein (MOG).

Thus, in the current study, the team was prompted to reconsider the role of B cells and the antibodies they produce, which were generally discounted years ago. A senior author of the study, Cedric Raine, PhD, DSc, professor of neurology, neuroscience and pathology at the Albert Einstein College of Medicine, was a pioneer in investigating the antibody theory during the late 1960s.

Thirty years ago, we suspected antibodies played a role, but we lacked the technology to show it, said Raine. The significance here is that for the first time weve been able to localize antibodies to the myelin sheath and to demonstrate their involvement in myelin breakdown.

The researchers detected MOG antibody, highlighted with a gold-labeled chemical tag for tracing purposes, in brain tissue obtained from patients during active phases of multiple sclerosis, where it appeared to be bound to the MOG antigen on the surface of myelin as the sheath was being destroyed.

These findings directly identified MOG-specific antibodies in actively demyelinating lesions of multiple sclerosis, indicating that these auto-antibodies play an integral part in the formation of vesiculated, disrupted myelin sheaths, said Raine.

Such direct evidence for the role of antibodies in myelin damage has never been shown, said Genain. Weve identified one antibody in EAE. Our study also shows that there are probably others, too.

The finding does not suggest that the role of T-cells should be discounted, said Genain. He suspects that they do initiate and play an integral role in the destruction of the myelin sheath, which acts as electrical insulator, allowing the conduction of nerve impulses along axons. Their principal role, he says, may be their ability to penetrate the blood-brain barrier thereby creating an opening that ushers in a cascade of immune system cells as well as the fluid known as serum, which contains antibodies. Alternatively, the antibodies could be generated within the brain.

What the study does suggest, said Genain, is that T-cells and B-cells may play an integrated role in the destruction of the sheath.

Clearly, he said, the immune system of humans is much more complex than we had been led to believe on the basis of previous work, and much more difficult to manipulate than in rodents. There are many clinical and pathological presentations of multiple sclerosis. We have looked at what can be called hot lesions where there is intense destructive activity and found that these are invariably associated with antibody deposition. However, the respective part played by T and B cell-mediated mechanisms may well differ in individual cases.

One therapeutic answer for the disease surely lies in blocking autoimmune cells before they can attack the myelin sheath, said Genain. For it is in the progressive splitting and swelling of the myelin sheath that the disruption begins, causing inflammation in the surrounding area, destroying nerve-impulse conducting myelin and, ultimately, displacing the axons themselves causing sporadic, then progressive, neurological impairments, including paralysis of the limbs and eyes.

Co-authors of the study include Barbara Cannella, PhD, assistant professor of pathology, at the Albert Einstein College of Medicine, and Stephen L. Hauser, MD, professor and chair of the department of neurology at UCSF.

The study was funded by a grants from the National Institutes of Health, the National Multiple Sclerosis Society and the Nancy Davis Center Without Walls.