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Allen saved the defenceman's initial shot, but Montreal captain Shea Weber inadvertently put the puck in the net when his clearing attempt deflected off teammate Phillip Danault. Barrie made it when he ripped a shot past Allen from the blue line with the Oilers on a power play at of the third period.
Edmonton was coming off a win at Ottawa on Tuesday in which superstar forwards McDavid and Leon Draisaitl were held off the scoresheet for the first time in 11 games. McDavid was held scoreless again, while Draisaitl picked up an assist on Barrie's goal.
There was a scary moment in the second period when Montreal forward Paul Byron was hit in the head by a slapshot from Habs defenceman Joel Edmundson. Byron went to the Canadiens dressing room but returned to the game shortly after. You do what you have to do, follow the protocols and go about your business. The Oilers lead the league with 13 goals from defencemen. The last time McDavid was held pointless in back-to-back games was Dec.
The Canadian Press Note to readers: This s a corrected story. A previous version had the incorrect records for the teams. Fabbro scored with Ryan Ellis and Matt Duchene also scored and Pekka Rinne made 24 saves for Nashville, which snapped a three-game losing streak. With the Predators on a power play, Filip Forsberg had the puck in the right circle and slid a cross-ice pass to Ellis in the left circle, where he fired a one-timer into the virtually open net behind Greiss.
Forsberg and Predators captain Roman Josi each had a pair of assists. Obviously, I want to show it on the ice and play well and get wins for this team. Duchene gave Nashville another brief lead at , but Staal answered right back at to tie it again. He is sidelined with a lower-body injury. The teams have also met in the playoffs on three occasions, all in Western Conference quarterfinal series.
Detroit won the first two matchups in and , with Nashville taking the series in They are 0 for 20 during the current drought and have just four power-play goals in 15 games this season. We have to keep it simple. We have to get it set up. Jim Diamond, The Associated Press. So far, so good. Cam Atkinson collected his franchise-record 15th career short-handed goal and three assists, and Roslovic also scored in the second. The year-old Stenlund has two goals and three assists in four games this year.
But he is in line for more playing time after Koivu decided to retire during his 16th NHL season. Pius Suter also scored for the Blackhawks. Chicago led after Kane sent a wrist shot past a screened Joonas Korpisalo for a power-play goal 29 seconds into the third.
But Columbus responded with two goals in 80 seconds. First, Jenner slammed home a rebound from right in front for his fourth. Then Roslovic got his second of the game when he beat Kevin Lankinen from the bottom of the right circle into the period. Atkinson banged a shot off the cross bar and Del Zotto knocked it in for the tying goal with to go.
Then Stenlund put Columbus ahead to stay with his eighth goal in 40 career regular-season games. Atkinson poked the puck away from Beaudin near the blue line, got it back and beat Lankinen from the high slot for a lead. It was Atkinson's third short-handed goal of the season and No. He also scored a short-handed goal on a penalty shot during Monday night's victory over Carolina.
Murphy could be sidelined for two weeks with a right hip injury, and Shaw was placed on injured reserve after entering the concussion protocol. Merzlikins, 26, had been sidelined by an upper-body injury since he got hurt during practice on Feb. Columbus also recalled defenceman Andrew Peeke from its taxi squad. Peeke, who turns 23 on March 17, recorded an assist while playing in his first game of the season, replacing Dean Kukan in the lineup. Niederreiter went in on a breakaway off a long pass from Dougie Hamilton and got goaltender Anton Khudobin leaning to the right before scoring to his left.
Warren Foegele added a goal in the final minute. Jordan Staal and Sebastian Aho both had a goal and an assist for the Hurricanes. Joe Pavelski scored his eighth of the year for Dallas, which has only one win its last seven games since sweeping a four-game homestand to open the season. The Stars lost on back-to-back days at the end of January in Carolina, including a shootout. James Reimer made 34 saves for the Hurricanes and has won all three against Dallas.
Khudobin stopped 27 shots while playing for the first time in three games. He was disciplined and didn't dress Sunday, a day after being late for practice. Rookie goalie Jake Oettinger made consecutive starts for the first time in his NHL career, stopping a total of 60 shots in back-to-back overtime losses at home to the Chicago Blackhawks. Dallas scored three times in the second period, including Pavelski's one-timer on a 5-on-3 power play, but also had a goal taken off the board when Carolina challenged and replays showed the Stars were clearly offside.
The Hurricanes tied the game at 3 with 27 seconds left in the second period when Brock McGinn extended his goal streak to four games by scoring on a long rebound. Staal was falling down when he swiped Andrei Svechnikov's pass into the net for a lead earlier in the period, and had both elbows on the ice when pumping his arms to celebrate his goal. That was only 30 seconds after the Stars tied the game on Mark Pysyk's first goal. Pysyk followed his own shot and poked home the rebound.
That was the goal that was challenged, but it was only 23 seconds later when Hintz scored on a hard charge and a pass from Denis Gurianov. Staal assisted on Aho's power-play goal in the first period with a nifty backhand pass. Staal had his back to the net when delivered a no-look pass to Aho in the right circle. Hintz had a shot just over two minutes into the game that skimmed over the top of Reimer's glove and ricocheted off and over the crossbar. He missed his third game in a row because of a lower-body injury.
The reduced-capacity attendance was 3,, the smallest crowd in the Stars' seven home games. The usual hockey capacity is 18, at the American Airlines Center, where twice attendance has topped out at 4, this season. Hellebuyck stopped 41 shots -- 18 in a scoreless first period -- to anchor Winnipeg's victory over Ottawa on Thursday night.
The Jets improved to against the Senators with the two teams set to square off again Saturday. Josh Norris scored the lone goal for Ottawa, which outshot Winnipeg The Senators said prior to the contest Zub's inconclusive test result came back Thursday after testing negative Wednesday. Josh Brown dressed in Zub's place. Zub, a year-old rookie, has played six games with Ottawa, recording two assists. Following the game Senators head coach D. The NHL has postponed 35 games this season, but the seven Canadian teams in the North Division have yet to see their schedule interrupted.
Ottawa controlled a scoreless first, outshooting Winnipeg The Jets went ahead just eight seconds into the second when Stastny registered his third of the season. Our goaltender was outstanding in the first period and we weren't and then we got better. DeMelo was originally credited with the goal before an official scoring change. DeMelo, a former Senator, said there was a simple explanation for Winnipeg's improved play in the second. We've got a lot of speed and a lot of guys who can make good plays but it starts with moving your feet and when you move your feet things start to open up.
Their record maybe doesn't speak for how they play and how hard they play. We're in for a tough one again Saturday. But as the period ended Murray appeared to be shaken up and wasn't on the bench to start the third as backup Marcus Hogberg went in goal. Norris scored Ottawa's goal at , his third, before Pionk countered with his first of the season at Many axons within the brain and spinal cord are myelinated.
The myelin sheath provides a high-resistance, low-capacitance insulator that increases the reliability and speed of action potentials conducted along axon fibers. Myelin is what makes the white matter of brain white. It is a multilayered sheath formed by the oligodendroglial cells, or oligodendrocytes, that insulate axons Figure 2.
The internodal axon is normally surrounded by myelin sheaths whose thicknesses are related to the caliber of the ensheathed axon. The processes of a given oligodendrocyte wrap themselves around portions of the surrounding axons. As each process wraps itself around, it forms layers of myelin. Each process thus becomes a segment of the axon's myelin sheath. Saltatory conduction is a rapid process, with the impulse taking only 20 one-thousandths of a second to jump from one node of Ranvier to the next; as a result, myelinated fibers conduct impulses with a high velocity.
Significantly, voltage-dependent sodium channels are clustered at the nodes of Ranvier but are relatively more scarce in the internodal axonal membrane. In contrast, potassium channels, which exist in low density at nodes, are more abundant in the internodal and paranodal axonal membrane, under the myelin sheath. Following damage to the myelin, conduction velocity is reduced, and conduction slows along the demyelinated axon Figure 2.
Studies using evoked potentials to examine human subjects with MS have demonstrated that this slowing of conduction does not, in itself, necessarily produce clinical deficits. When conduction failure occurs, the axon potential is not propagated from one end of the fiber to the other, and information is lost. This produces a clinical deficit. Conduction failure in demyelinated axons is now known to result not only from loss of the insulating myelin, but also from the molecular organization of the axon membrane.
Following damage to the myelin, internodal parts of the axon membrane which had previously been covered by myelin are uncovered. Prior to the last decade, axonal dysfunction in demyelinating diseases was considered to be due entirely to the loss of the myelin insulation. It is now known that although the schema described above is partially correct, it is not the whole story.
The axon itself exhibits an elegant molecular architecture, and following damage to the myelin, this architecture is disrupted. The molecular architecture of the axon is manifest by the placement of specialized protein molecules, called ion channels, within the membrane of the axon.
Sodium channels act as tiny molecular batteries, which produce the depolarization that is necessary for the generation of action potentials. In contrast, potassium channels act as molecular brakes, damping electrical activity. Within myelinated axons, these two types of ion channels have a complementary structure.
Sodium channels are clustered in high density in the axon membrane at small gaps in the myelin called nodes of Ranvier, where they support the produc-. Their numbers there are too low to support secure conduction, which contributes to conduction failure. Potassium channels, on the other hand, tend to be located in the internodal parts of the axon membrane, beneath the myelin sheath; as a result of this, they are masked by the.
Current concept of pathogenesis of neurological dysfunction associated with acute multiple sclerosis lesion in relapsing-remitting MS patient. Normal myelinated fibers A are demyelinated by inflammatory process B , which causes conduction block. Given that impulse conduction fails in demyelinated axons and that this contributes to clinical deficits, how do remissions occur? It is now clear that demyelinated axons possess a remarkable capability to rebuild themselves at the molecular level.
In the weeks following demyelination, demyelinated axons acquire, within regions where myelin has been lost, a density of sodium channels that is high enough to support action potential conduction even in the absence of insulating myelin.
The demyelinated nerve fibers insert additional amplifiers sodium channels in their membranes so that they are able to conduct action potentials reliably even though there is a short circuit. This is a striking example of neuronal plasticity, in this case at the molecular level. How do neurons control the synthesis and deployment of sodium channels?
What turns on the genes for sodium channels and ensures that the correct types of sodium channels there are nearly a dozen different types, which are like different types of batteries are produced following demyelination? Also, how are sodium channels transported and inserted into the correct parts of the axon membrane so that they can function normally? These questions have important therapeutic implications and are currently under study.
The presence of axonal degeneration in MS was recognized even in the early descriptions of this disease, 36 but its presence has recently been reemphasized Figure 2. As a step toward the development of neuroprotective strategies in MS, it will be important to delineate the mechanisms that underlie axonal injury in this disorder. Is it a consequence of demyelination? Alternatively, is the axonal damage a by-product of the inflammatory or immune processes involved in triggering demyelination?
Understanding the pathogenesis of the process might lead to the development of new therapeutic targets for MS. These questions are being approached in models of other neurological diseases such as trauma and cerebrovascular disease, including stroke, and should be actively pursued in MS research as well.
Axonal transection during inflammatory demyelination. According to this schema, axonal transection during A is a consistent feature of inflammatory demyelinating lesions. This results in degeneration of the distal axonal segment B and irreversible loss of neuronal function. Axonal degeneration as a result of chronic demyelination. This model posits that axonal viability depends upon oligodendrocyte-derived trophic effect.
Chronically demyelinated axons A may undergo nerve transection B or wallerian degeneration C , which are caused by lack of myelin trophic support. MS is defined as a demyelinating disease because the myelin sheaths and their parent cells, the oligodendroglia, are major targets of immune-mediated damage Figure 2. These predominantly white matter lesions occur in multiple brain regions and appear at different times throughout the disease. Common syndromes correlated with lesions in specific areas include visual deficits, weakness and spasticity, eye movement abnormalities, and ataxia Table 2.
Lesions are often described as active or chronic, depending on whether there are signs of active inflammation, usually associated with ongoing demyelination, or whether the lesion is stable and does not show signs of inflammatory activity. Active Lesions. Disruption of the blood-brain barrier that normally insulates the brain from pathogenic blood-borne substances is an early event in the development of MS lesions Figure 2.
This can be detected on contrast-enhanced MRI. A plaque is characterized by loss of myelin sheath and infiltration by macrophages which show myelin basic protein and myelin-associated glycoprotein immunoreactivities. As the. The mechanisms causing myelin damage are not completely known. Possible mechanisms include a direct toxic effect of tumor necrosis factor TNF on myelin upper panel or macrophage-mediated damage through either phagocytosis, in which the cell is engulfed and destroyed, or apoptosis, in which cells are induced to self-destruct lower panel.
Berlex Laboratories. Frequently associated with plaques involving connections between the brainstem nuclei subserving eye movements. One of the consequences of lesions involving the spinal cord or descending motor tracts in the white matter of internal capsule or brainstem. Scattered B cells and plasma cells are also sometimes associated with these lesions.
Immunocytochemical analysis has suggested that there may be leakage of immunoglobulins and complement from vessels at the margins of active plaques. There is evidence for upregulation of a variety of cytokines within MS plaques including various interleukins IL-1, 2, 4, 6, 10, and 12 ; beta-interferon; tumor necrosis factor TNF ; and transforming growth factor TGF.
Their involvement in any disease is complex. They can initiate, sustain, or terminate various aspects of disease processes and are particularly involved in inflammatory responses. Specific chemokine receptors are expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. These results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.
Some investigators have emphasized that the pattern of pathology suggests a dying-back oligodendrogliopathy those parts of the cell, such as the most distal process, farthest from the cell body are the most vulnerable. Subsequently, there might be partial recruitment of oligodendrocyte precursors that may, in part, repopulate the margins of the plaque and contribute to remyelination.
Chronic Lesions. Trapp and colleagues have emphasized that the relapsing-remitting course is intimately related to the inflammatory demyelination and classical plaques, while more chronic progressive forms of the disease are linked to transection, or severing, of axons at sites of inflammation and demyelination.
They have shown that severed axons were a consistent component in the lesions of individuals with MS and suggest that the number of these injured axons is correlated to the magnitude of the inflammation within the lesion. Axonal damage might be a pathological correlate of irreversible neurological deficits that occur in patients with progressive MS.
Demyelination can be incomplete. The density of axons may be significantly reduced. There is usually astrogliosis within these lesions. It is not clear exactly how the axonal damage that occurs at later stages plays into this complex evolving pathology, but the extent of axonal damage appears to be a critical determinant of whether a person recovers from an attack or not. Lack of recovery from attacks and disease progression are more likely when axons are more severely damaged and repair mechanisms fail.
The tight seal of the cells lining the blood vessels forms a blood-brain barrier that keeps many substances out of the brain. Leaky blood vessels in the body allow many molecules to cross through to other tissues, but the tight construction of the vessels in the head guards against entry of most molecules into the brain.
Normally, only certain molecules, for example, blood gases such as oxygen and small nutritional molecules, can cross the blood-brain barrier, but this barrier breaks down when the brain is injured or in certain diseases, such as MS. A correlation between demyelination and axonal degeneration observed at autopsy is supported by imaging studies, including those that compare the concentrations of N -acetyl aspartate.
The brains of MS patients showed significantly greater side-to-side differences in levels of NAA, indicating decreased neuronal integrity on the side of the brain with lower NAA levels. There was a correlation between this asymmetry in motor function and the asymmetry of NAA concentrations in the internal capsule. Gliosis is a prominent feature of the MS lesion, but it is best regarded as a secondary phenomenon.
The response is broadly the same whatever the source of injury, although the details vary somewhat with different types of pathology. Formation of the glial scar after CNS injury generally occurs over a period of weeks. Microglia are typically the first cell types to enter the lesion.
In the normal brain, they are quiescent with short, branched processes. Following injury, they exhibit various changes, including activation, cell division, and migration to the injury site. The final glial scar is made up mainly of a meshwork of tightly interwoven astrocyte processes, attached to one another by tight junctions and gap junctions and surrounded by extracellular matrix reviewed in by Fawcett and Asher Astrocytes are irregularly star-shaped, background structural cells of the nervous system.
Gliosis is usually restricted to the area of demyelination, but it sometimes extends beyond that area. There is no specific way to identify the presence and extent of gliosis in MS lesions through MRI, although the T1 signal might be more sensitive to gliosis than the T2 signal. The role of astrocytes in gliosis is not completely known. Finally, although gliosis is generally considered harmful, there is also evidence that the gliotic ensheathment of demyelinated axons might favor the restoration of nerve conduction.
The relapsing-remitting form of MS appears to be related to the demyelination of axons during relapses, followed by the remodeling and remyelination with consequent restoration of conduction that underlies remission. Remyelination is carried out by surviving oligodendrocytes or by the proliferation of progenitor cells that are then stimulated to become oligodendrocytes. Molecular remodeling of demyelinated axons, in terms of their redistributing their sodium channels along the axon, might act as a form of adaptive plasticity; this process may represent a target for future therapies.
In contrast, the progressive form of the disease, which appears clinically as an unremitting accumulation of deficits, might reflect the superimposition of axonal injury or degeneration on multiple chronic foci of demyelinated axons. The finding that axonal damage can occur frequently in MS and the suggestion that these lesions contribute to persistent neurological deficits are important issues in MS research.
It will also be important to search for molecules that promote the regrowth of injured axons to their appropriate targets. Some of the lessons from studies of the repair of spinal cord injury are likely to be relevant here. Progenitor cells, those either already present in an individual or provided from another source by injection, can produce myelin in demyelinated foci in experimental animals.
The most striking pathology in MS is the immune system's attack and destruction of the body's own myelin sheath, which is why it is believed to be an autoimmune disease, although this has not yet been definitively proven Box 2. The pathogenic trigger that first causes the immune system to attack myelin is unknown, but the immunopathology, or pathological activity of the immune system, that ensues after that initial attack is becoming clearer.
The immune system defends the body against foreign invaders such as bacteria and viruses. Normally, the immune system reacts only to non-self invaders, not to its own tissues. Unfortunately, this process is not foolproof. Autoimmunity is an immune response mounted against antigens that are naturally produced within the body, or self-antigens, to cause lasting tissue damage.
In the strictest sense, an autoimmune disease must meet several criteria. First, the disease must be reproduced by transfer of autoantibodies or autoreactive T lymphocytes T cells from affected to unaffected individuals. Second, the self-antigen that elicits the immune attack must be identified. Third, this antigen or a closely related one should cause a similar disease in an animal model.
Scientifically, it would be best to show that the antigen caused the disease in humans, but it would be unethical to intentionally infect humans, hence, the compromise for evidence in animals. It is now feasible to transfer human genes into animals in an attempt to satisfy these criteria. One of the first so-called transgenic studies that introduced certain human genes into an animal without MS led to the development of a disease resembling MS.
This type of study begins to confirm the autoimmune nature of MS. Human autoimmune diseases, however, are generally classified as such without meeting these three stringent criteria. Circumstantial evidence often is marshaled for classification. For example, patients are classified as having autoimmune disease if they have high levels of autoantibody or autoreactive T cells, or because there is a correlation between the level of immune activity and disease severity.
Some examples of autoimmune diseases are listed in Table 2. Why does the immune system have autoreactive lymphocytes? During development, the immune system randomly builds a vast repertoire of cells that respond to a multitude of foreign antigens. At the same time, the immune system must weed out those cells that react to self-antigens. Most self-reactive B cells and T cells are removed early during development.
Other regulatory mechanisms exist to keep self-reactive lymphocytes unresponsive later on. These are among the normal regulatory mechanisms resulting in immunological tolerance to most self-antigens. Even though there are usually small numbers of autoreactive lymphocytes in a normal adult, most do not cause disease, and some might even serve a currently unknown beneficial purpose.
Autoimmune disease thus can be thought of as a failure of normal regulatory mechanisms that guard against autoimmunity. What causes a pathological autoimmune response? The causes of autoimmune response in MS and most other autoimmune diseases are unknown but likely include a combination of genetic susceptibility and exposure to environmental agents.
For most autoimmune diseases, the actual genes and environmental agents are unknown. Gender also plays a role because women are disproportionately affected by autoimmune disease. The reasons for the gender difference are also unknown but appear to relate to distinct immune environments in women and.
How can genes and environment trigger autoimmune pathology? Genes control many properties of the immune system. Theoretically, autoimmune disease can occur if any of the genes controlling the immune system's ability to distinguish self from non-self are defective.
The genes often suspected of predisposing to autoimmune disease encode proteins, such as histocompatibility antigens, that participate in this complex process of self versus non-self recognition. Environmental or infectious agents can stimulate pathological autoimmune reactions through at least two possible mechanisms: molecular mimicry, superantigens, and bystander damage Figure 2.
Molecular mimicry occurs when a bacterial or viral epitope—the fragment of an antigen that elicits an immune response—is very similar to a self-epitope. This can occur following an infection where an immune cell targeting an epitope on a bacterium subsequently cross-reacts with a self-antigen. Unlike most antigens, which activate only a specific T cell, superantigens activate approximately one out of every ten T cells. In bystander damage, a virus upregulates a nonspecific immune response that then leads to pathology; for example, proinflammatory cytokines might activate Th1 cells or macrophages that contribute to the immunopathology.
Once damage occurs, new cellular epitopes become exposed and trigger an immune response in a process called epitope spreading, which can also lead to autoimmune pathology. During an immune response against a particular epitope, the number of lymphocytes that recognize the epitope normally multiplies. Yet, in epitope spreading, the immune response escalates to target other epitopes on the same antigen or on related antigens. The underlying basis for epitope spreading in autoimmune diseases is poorly understood.
Another way to produce a pathological autoimmune response is for autoreactive lymphocytes to gain access to a target antigen from which they are ordinarily separated. The brain is one example of an anatomical sanctuary site, because it is protected by the blood-brain barrier of the central nervous system. Normally, T cells that might react against myelin do not pass across this barrier into the central nervous system.
In MS, however, T cells become activated, which enables them to penetrate the blood-brain barrier and reach their targets—myelin antigens—thereby generating an autoimmune response. One of the first pathological processes leading up to MS attacks is thought to be activation of autoreactive T lymphocytes, or T cells, and their migration into the central nervous system. Many cells and molecules of the immune system—likely unleashed by T-cell activation—participate in demyeli-.
This simplified outline shows interactions that occur in response to a foreign antigen. The antigen could be an epitope from a virus particle, bacterium, or other foreign agent. The antigen-presenting cell APC ingests the antigen or in the case of an infecting virus, it may already be within the cell and processes it into peptide fragments. The major histocompatibility complex MHC, the cell surface structure characteristic of each individual presents this target to a resting T cell. When T and B lymphocytes are activated by a specific antigen, they undergo proliferation, producing more cells with their same antigen specificity.
This serves to amplify the immune response against the foreign antigen. Immune response against topoisomerase I leads to increased formation of collagen in the skin and internal organs. Antibodies against presynaptic calcium channel of the neuromuscular junction NMJ disrupt function. Antibodies against postsynaptic acetylcholine receptor of the NMJ disrupt function.
Antibodies against subunit of ionotropic glutamate receptor lead to degeneration of one cerebral hemisphere. Although no virus has yet been shown to contribute to the etiology of MS, there are several ways in which this could occur, and one of these is shown in this figure.
Activated T cells cross the blood-brain barrier following activation by a microbe with a structural similarity to a component of the myelin sheath. Once inside the brain, these cells attack self-antigens, such as the various myelin proteins that are attacked in MS. Adapted from Wucherpfennig and Strominger, The entire cascade of immune system events eventually culminates in myelin destruction.
The key features of this cascade are not fully understood, including the precise ordering of events, the antigens targeted by T cells, and the contributions of B lymphocytes, or B cells, and other cells of the immune system. Yet, as this section explains, much insight has been gained into the immunopathology of MS. This knowledge has been—and continues to be—fundamental for devising therapies targeted to the immunopathology of MS Chapter 5.
As much as a century ago, researchers observed that T cells were particularly abundant in MS lesions. These and related findings gave credence to the hypothesis that autoreactive T cells played a dominant role in MS. After all, immunologists have long known that T cells are capable of orchestrating a multifaceted autoimmune attack. However, this was not enough to explain MS pathology. First, elevations in certain types of autoreactive T cells were not unique to MS patients.
Second, and more critically, T cells were necessary but not sufficient to cause demyelinating disease in animal models. The transfer of myelin-specific T cells into normal animals initiated only inflammation, not demyelination. Possibly involved in myelin compaction. PLP spans the myelin membrane, providing increased stability. The major mediator of axonal-glial contacts essential for the initiation of myelination. Major constituent of glial filaments in astrocytes, providing structural stability.
Rapidly synthesized in response to CNS trauma or disease. Broad class of stress-responsive proteins that are normal components of the myelin sheath. The prime autoantigen that elicits the autoimmune response in MS is not known. While there are many candidate autoantigens, as yet none is preeminent. Much MS research focused on myelin basic protein MBP , located at the inner surface of the myelin membrane. Clinical studies were shaped by research on experimental allergic encephalomyelitis EAE , the classic animal model of demyelinating disease.
In many species, MBP acts as a classical encephalitogenic autoantigen an antigen capable of serving as the focus of an inflammatory attack in the brain. EAE research further established that in some strains of mice and rats, the autoimmune response to MBP displays two unique features.
Second, the encephalitogenic T cells in EAE use an unusually narrow repertoire of genes for their antigen receptors. These two features raised hopes for developing immune-based therapies because a more limited range of therapies might succeed in combating MS in early stages. Unfortunately, these features turned out to be much less prominent in humans with MS. First, human T cells respond to a broader set of MBP epitopes. While there might be a relatively dominant epitope in the central portion of the MBP molecule, there are clearly many other target epitopes along the full sequence of this large polypeptide.
However, when more definitive assay systems were used, increased frequencies of activated MBP-specific T cells were found in MS patients. More direct assays, such as those that use binding of oligomeric class II-peptide complexes to specific T cells, 41 might resolve the problem.
To add a further degree of complexity, MBP does not appear to be the only autoantigen in MS: there are a number of additional myelin and nonmyelin proteins that are potential autoantigens in MS. Earlier hypotheses had implicated MBP on the basis of two lines of research. First, studies of EAE had suggested that MBP was indeed the most important, if not the only, encephalitogenic myelin autoantigen.
Second, due to its particularly convenient molecular properties, MBP was the only myelin protein available both at high purity and in large. Later studies established that many, if not all, myelin proteins are potentially encephalitogenic. Especially interesting among these newly recognized autoantigens is myelin oligodendrocyte glycoprotein MOG. As one of the few myelin proteins accessible to humoral autoantibodies, MOG is a target for demyelinating immunoglobulins see next section.
In addition, MOG is a very effective autoantigen in rodents and in primates for encephalitogenic T cells. It is also important to investigate whether different subtypes of MS, which are distinguished by divergent clinical, genetic, and morphological features, are associated with enhanced T-cell responses against different target autoantigens.
The role of heat shock proteins in the development of the MS lesion is unknown, but there are various possibilities. Some of these proteins might act as a target autoantigen, as has been shown in autoimmune diabetes. They might also reflect inflammatory stress inflicted on local CNS cells, or they might be determinants of beneficial anti-inflammatory control mechanisms.
Even though the precise pathological roles of T cells and their autoantigens are unresolved, this line of research has generated many approved or emerging therapies. These include vaccination strategies, which use either attenuated myelinspecific T cells 33 or peptides representing myelin-specific T-cell receptors 9 as vaccines to strengthen the body's own regulatory responses against pathogenic T cells reviewed in Zhang et.
B cells also known as B lymphocytes have been detected in MS lesions for many years, although less consistently than T cells. It now appears that both types of lymphocytes actively contribute to MS immunopathology. Autoreactive T cells are thought to launch inflammation and, through their release of cytokines, to stimulate B cells to secrete antibodies that cause demyelination.
In MS patients, levels in cerebrospinal fluid of the type of protein known to consist of antibodies immunoglobulin are often higher than in healthy people. The increased immunoglobulin is due to production by only a few different clones of B cells that have been induced to proliferate. B cells from the CSF of MS patients have been reported to contain mutations in the DNA sequences that encode antibodies, which is consistent with the notion of an antigen-driven selection of antibodies with high-affinity antigen-binding sites.
One recent study using sophisticated immunocytochemistry furnished direct evidence of a pathologic role for autoantibodies. For the first time, MOG-specific antibodies were demonstrated to be bound to myelin debris in active MS lesions. Cytokines are soluble proteins produced and released by T cells, macrophages, and certain other cell types. They generally act as intercellular signaling molecules that regulate.
Some function as pro-inflammatory, others as anti-inflammatory agents. Some even have divergent functions during different phases of disease. Proinflammatory cytokines and other secretory products of immune cells are proposed in several neurological diseases—including MS—to be toxic to neurons and oligodendrocytes if they are secreted in sufficiently high concentrations over a sustained period of time.
In MS, the initial entry of autoreactive T cells into the CNS is thought to trigger the local production of cytokines and chemokines, which in turn begins the inflammatory process and enhances the permeability of the blood-brain barrier. Thus, understanding the roles of cytokines and their temporal sequence of activation is crucial to modifying the course of MS.
Much of our present understanding of cytokine action in demyelinating disease comes from studies of animal models, including EAE. A large body of research is being compiled on the expression and possible function of cytokines as pro- and anti-inflammatory mediators in MS. Some studies have used in situ immunocytochemistry and in situ hybridization to visualize gene expression in lesions, whereas others have relied on the activation of inflammatory cells T cells, B cells, macrophages in vitro.
Much of the research is comparing material from MS patients with or without treatment with immunomodulatory agents, especially glatiramer acetate and beta-interferon. Pro-inflammatory cytokines within active MS lesions have been localized to both infiltrating immune cells and glia. Understanding of cytokines and their diverse roles throughout the course of disease, although still incomplete, has nevertheless spawned new treatments. One explanation for the success of glatiramer acetate and beta-interferon relates to their control over cytokine expression: they can induce T cells to switch from a pro-inflammatory phenotype Th1 to an anti-inflammatory phenotype Th2.
CNS tissues were traditionally thought to be exempt from active immune reactivity, but it is now known. Only activated and not resting T cells can cross the blood-brain barrier and interact with local CNS cells. Local glial cells can be stimulated by proinflammatory cytokines to express immunologically active molecules, such as the major histocompatability complex MHC products, cytokines, and chemokines required for local immune responses.
Neurons are capable of suppressing immune responses within the CNS. Thus, immune responses are more likely to occur in areas of neuronal degeneration than in intact CNS tissues. Immune reactivity within the CNS must hence be viewed as the balance between the proinflammatory signals contributed by activated T cells and other inflammatory cells entering the brain and the anti-inflammatory signals from functional neurons.
Epidemiologists define what causes a disease and what puts an individual at risk of getting this disease. They look for correlations such as whether Caucasians are more likely to have MS than Asians or whether residents of one county are more likely to get MS than residents of another. These correlations lead to hypotheses or working models as to which factors actually cause MS and which are only associated with it. These hypotheses or models can then be tested experimentally.
Epidemiological studies have limitations, but for a complex disease like MS, they can rule out some factors and highlight others. They are the first step toward finding a biological mechanism for MS, or possibly a cure.
Most epidemiological studies of MS have been observational and retrospective; researchers collected the information for example, ethnicity, age of onset from an individual or from records that had been diagnosed with MS.
Such studies rely on an individual's ability to accurately recall information from years ago, for example, the infections that she or he had before the age of five. Other sources of data, such as death certificates, can contain incorrect information.
Despite these shortcomings, a few factors consistently correlate with MS prevalence. Determining how these factors lead to an increased risk of MS has proven more difficult. The risk of MS increases with increasing distance from the equator.
In the United States, this is seen as a gradient of risk, with higher risk in northern regions and a lower risk in the south. Individuals who have moved from a region with one risk level to a region with a higher or lower risk, in general, adopt the risk level of their new home. Studies carried out in the s and s suggested that this geographical effect had a defined susceptibility period before age Although these data still. Most recently, a study comparing the prevalence of MS among native-born Australians and Australian immigrants from the United Kingdom thereby providing a rough control for genetic background suggests that rather than being established around age 15, environmental risk factors operate over many years and into early adulthood.
Although the migrational studies suggest an environmental correlation with MS, the root cause of this latitude effect is unknown. Differences in diet or sunlight 1 , 97 , have been proposed, but neither has been supported by rigorous studies. Alternatively, the geographical distribution of MS could result from the migration either of a viral agent or of individuals perhaps originally Scandinavians who carried a pool of susceptible genes.
Ethnicity is another definite risk factor. MS is more prevalent among Caucasians than other groups. In a study of 5, U. MS is almost absent among black Africans. African Americans, however, show a low risk of MS; this might be due to genetic mixing with Caucasian Americans or to an environmental effect.
When applied to a complex disorder such as MS, conclusions derived from epidemiologic data of this type must be interpreted cautiously because inapparent explanations may be present. For example, a higher-than-expected incidence of MS observed in South Vietnamese immigrants a low-risk group residing in France a moderate-risk area superficially suggest a modifying role of the environment on MS. However, this immigrant population was in fact racially mixed and contained substantial numbers of individuals with mixed French and Asian ancestry.
Thus, the higher-than-expected MS incidence in these immigrants could have been due to either genetic or environmental factors. Neither factor can be ruled out. On the other hand, the increased incidence of MS observed in Japanese-Americans compared to individuals residing in Japan is not easily explained by racial admixture and does support a role of the environment on MS risk.
As in other autoimmune diseases, women are much more likely to get MS than men, suggesting that hormonal or genetic factors are involved. The ratio of women to men with MS is about MS ranges between 10 and 59 years, 56 with the highest incidence occurring among individuals in their mids to early 30s, depending on the population examined.
This results, at least in part, from an increase in the percentage of males with the primary progressive variant. This form of MS has a later onset than other types and affects approximately 15 percent of patients. The ratio of males to females with primary progressive MS is approximately Epidemiological studies have provided conflicting data as to whether an infectious agent viral or bacterial either causes or triggers MS.
The occurrence of MS epidemics has suggested that an infectious agent might be at work. Both, however, are open to multiple interpretations. Coincident with the stationing of foreign soldiers, the population of the Faroe Islands received increased medical services 56 and changed its diet.
No infectious agent has been associated with either of these MS clusters. Another area of investigation has explored whether environmental factors contribute to the onset of MS or the probability of MS attacks. Some studies suggest that MS attacks are more likely to occur in the spring and fall than in the winter or summer. Such a finding, if true, suggests that a relationship exists between some viral infections and the risk of exacerbations.
Many patients with MS are also at heightened risk for urinary tract, pulmonary, or skin infections, yet the relationship between these potentially preventable infections and the course of MS has never been adequately studied. Additional research in this area is needed. Perhaps the most clear-cut epidemiologic link to MS attacks is the effect of pregnancy and the postpartum period.
Pregnancy is associated with a decrease in the risk for MS attacks, particularly during the third trimester. The postpartum period is, conversely, associated with a significant increase in risk. An immunosuppressive state in the pregnant mother is created by increased numbers of regulatory T cells Th2 cells which, presumably, dampen the autoimmune reaction that produces attacks of MS. The explanation for the increase in attack risk during the postpartum period is less clear but might involve immunostimulation by prolactin, the hormone responsible for milk production.
The absence of supporting evidence does not prove that a virus is not connected with the disease. Unrelated individuals in the case of the adoptee and conjugal studies may differ in their susceptibilities to infectious agents. Researchers have isolated a variety of viruses from individual MS patients, but to. Researchers continue to look for causative infectious agents.
The aggregation of MS in some geographic areas, ethnic populations, or families could be explained by a common environmental exposure, a shared genetic background, or a combination of both environmental and genetic susceptibility. It is likely that in MS, as in other complex disorders, both factors contribute.
It is also possible that the relative contributions of environment versus genetics might vary in different situations, depending on the degree to which an individual is genetically susceptible and the specific environmental context. The role of genetic factors in MS is discussed in the next section. MS is not considered a genetic disease in the classic sense because it usually occurs sporadically. However, population and family studies are consistent with a principal pathogenic role for genetic risk factors in MS etiology.
This genetic component is indicated primarily by the increased relative risk to siblings of affected individuals compared with the general population. In addition, twin studies from different populations consistently indicate that a monozygotic twin of an MS patient is at higher risk 25 to 30 percent concordance for MS than a dizygotic twin 2 to 5 percent , , providing additional evidence for a significant but complex genetic etiology.
Finally, the frequent occurrence of MS in some ethnic populations particularly those of northern European origin compared to others African and Asian groups , irrespective of geographic location, also provides evidence for a complex genetic etiology.
A simple genetic model for the inheritance of MS is unlikely to be valid. Such a single-gene hypothesis is at odds with concordance data in twin and family studies and with the observed nonlinear decrease in disease risk as the genetic distance from the relative with MS is increased. It is likely that susceptibility is determined by multiple independent genetic loci polygenic inheritance , each with a relatively modest contribution to overall risk.
It is also possible that there are different genetic causes of susceptibility to MS genetic heterogeneity. Finally, the genes that contribute to MS susceptibility are likely to be normal, common variants or alleles of genes rather than obviously defective mutations. Most individuals who carry such susceptibility genes would have no obvious deleterious consequences.
For example, the DR2 gene described below is the most important genetic contributor to MS susceptibility identified to date. Approximately half of patients with MS have this gene, but so do 15 to 20 percent of healthy Caucasians. Thus, only approximately 1 in people who have DR2 develop MS. The cumulative action of several susceptibility genes, each with weak effects and limited penetrance, is thought to underlie genetic susceptibility to MS.
Penetrance refers to the likelihood that a person carrying an allele will develop specific manifestations caused by that gene. The effects of individual susceptibility genes may also be influenced by interactions with other genes and by specific environmental exposures. Locus heterogeneity is also likely, meaning that there are different susceptibility genes in different MS patients.
The possibility that MS is a heterogeneous disease with different causes or pathological processes adds an additional level of complexity to the analysis. In addition to MS, similar issues are present in other autoimmune diseases such as diabetes mellitus that are genetically complex, and common research tools will be needed to decipher specific disease genes in these different conditions.
Major Histocompatibility Complex. The genetic region most clearly associated with MS susceptibility is the major histocompatibility complex MHC, or HLA [human leukocyte antigen] in humans locus on the short arm of chromosome 6 6p21 Box 2. This association has been seen in different population studies that have relied primarily on sporadic patients.
Many of the MHC genes are extraordinarily variable or polymorphic, reflecting the importance of genetic variation of these critical antigen-presenting molecules in the maintenance of a heterozygous advantage and the need to effectively present a diverse array of antigens if immune homeostasis is to be maintained. Immune homeostasis refers to the capacity of the immune system to respond appropriately to a diverse number of infectious pathogens and tumors without initiating unhealthy responses against self-constituents auto-.
The major histocompatibility complex is a chromosomal region that contains more than genes, many of which make proteins involved in the immune system. It is named for the role it plays in rejecting tissue transplants histo- means tissue. In humans, this region resides on chromosome 6 and is called the human leukocyte antigen gene complex. The terminology is slightly confusing because. The role of the immune system is to differentiate between self and non-self.
This allows it to tell the difference between, for example, muscle tissue self and an invading virus non-self and to respond appropriately. To do this, the immune system relies on several different proteins that specifically bind antigens. This process is analogous to a lock and key. This discussion focuses on T-cell receptors and MHC molecules. T-cell receptors sit on the surface of T cells and bind to antigens outside the cell.
In the case of T-cell receptors and MHC molecules, antigens are small protein fragments. Binding to an antigen signals the T cell either to die, to do nothing, or to become active. The signal context, such as whether the antigen is self or non-self, determines which of these signals is relayed. However the T cell cannot bind the antigen alone. It needs the help of an MHC molecule. MHC molecules sit on the surface of other cells.
The MHC molecule, like two outstretched arms, holds onto an antigen and presents it to a T-cell receptor. There are two major classes of MHC molecules. Each arm of the MHC molecule is made up of a separate protein. Each MHC molecule can bind many but not all of the thousands of antigens that confront the immune system. The immune system relies on diversity among the MHC proteins to help stack the odds in its favor.
The gene for each MHC protein chain comes in different varieties, or alleles. The proteins vary just enough that although they all function as MHC proteins, they can bind different antigens. Any one person will have two alleles, at most, for a particular MHC protein there are two copies of each gene in human cells , but across a population of individuals, this variety becomes more important.
Researchers hypothesize that because HLA-B53 can protect people from the most severe forms of malaria, it is more prevalent in Gambia. Scientists still do not understand how HLA-DR2 predisposes individuals to MS, but this might have to do with the MHC molecule's ability to present specific antigens for example, a fragment of myelin basic protein to T cells. In Caucasian MS populations of northern European descent, the critical MS-associated genetic region is thought to reside near the class II locus and is comprised of a group of genes with specific polymorphisms alleles that tend to occur in certain fixed combinations, termed haplotypes.
DR molecules are comprised of alpha and beta chains encoded by A and B genes, respectively , and the polymorphisms are predominantly present in the beta chain. Of the more than beta-chain sequence variations identified in humans, only one , also designated as DR2 is associated with MS. How can the DR2 association with MS be explained? The DR2 molecule itself may have a propensity to bind peptide antigens of myelin and stimulate disease-inducing T cells.
X-ray crystallography of the DR2-MBP peptide complex revealed that the DR2 molecule contains a distinctive hydrophobic pocket in its antigen-binding region, created by a unique alanine residue at the B71 position into which glutamic acid at position 93 of MBP is tightly bound, anchoring the MBP-DR2 complex. Glatiramer acetate copolymer 1 , a currently available disease-modifying therapy for MS, is a random synthetic protein composed of four amino acids, including tyrosine.
The tyrosine residues of processed copolymer peptides likely also bind to the hydrophobic pocket of DR2, perhaps interfering with presentation of this key MBP peptide to encephalitogenic T cells. It is surprising that no data exist on the interaction of DR2 and the response to glatiramer acetate in MS. DR2 is also linked to other diseases. Besides MS, narcolepsy is the disease most strongly linked to DR2. In various studies, the HLA region has been estimated to confer somewhere between 10 percent and half of the inheritability of MS.
To date, no other genes of major effect have been identified in genomic screens. Several studies appear to demonstrate that a deletion mutation in the CCR5 chemokine receptor gene a coreceptor for HIV on chromosome 3 confers a later age of onset or a more benign course of MS; this mutation is also associated with protection against HIV. This is particularly important because the expression of CCR5, which is increased in MS brain lesions, is thought to attract inflammatory cells into tissue.
A polymorphism near the gene for myelin basic protein on chromosome 21 was reported to be linked to MS in a family from Finland, but not in other populations. Some studies have suggested linkages or. The inability to confirm some genetic regions as containing MS susceptibility genes might reflect the small genetic contribution of these putative genes or genetic heterogeneity; alternatively, the original claim might have been spurious.
As noted above, it is likely that an additive model consisting of multiple independent genes, each with small effects, explains the non-MHC genetic contributions to MS. It should be emphasized, however, that the identification of specific genes that have even very minor genetic effects on MS can have an enormous payoff, both in terms of helping to decipher the underlying biology of MS and in pointing to new potential treatments. For example, the genetic studies discussed earlier that identified a role for the CCR5 chemokine receptor suggest that therapies aimed at this receptor could be investigated in people with MS.
Perhaps the strongest indication that MS is a heterogeneous disorder comes from HLA studies showing an absence of DR2 association in particular ethnic groups or perhaps in some clinical variants. Lesions in the non-DR2-associated condition are frequently more severe and necrotizing than in the disseminated form. A number of relatively small studies failed to show any association between PPMS and DR2, although a recent larger study from northern Ireland appeared to show an association; it is possible that PPMS represents more than one underlying disorder.
Evidence for genetic heterogeneity is not limited to case-control HLA association studies but is also derived from formal linkage studies. Analysis of the MHC locus in an American multiple affected member MS data set confirmed the significant genetic linkage to this region lod score of 4.
This indicated most likely the presence of locus heterogeneity in familial MS in Caucasians. A related. The extent to which distinct clinical forms of MS are associated with different susceptibility genes, as may be the case in EAE see discussion of animal models , is not known. Also unknown is whether specific genes interact with certain causative agents or triggers. Genetic studies have the potential to answer these questions, particularly when the information is analyzed in combination with epidemiologic, clinical, and neuroimaging data.
There are several human and animal diseases of known etiology or pathogenesis that resemble either the clinical or the pathological features of MS Table 2. Animal diseases that resemble MS are discussed under animal models. CNS demyelinating diseases include those mediated by immune responses, infection, and toxins, as well as inherited disorders. Infectious agents can induce direct injury of oligodendrocytes and their myelin membranes, as well as indirect injury via the immune system.
A variety of toxins, such as diphtheria, lysolecithin, cuprizone, and ethidium bromide, have been associated with demyelinating lesions. Many of these toxins induce lysis of the oligodendrocyte, with demyelination as a secondary effect. In addition, nutritional deprivation can be associated with demyelination in the central and peripheral nervous system.
Acute disseminated encephalomyelitis ADEM , also known as post vaccination encephalomyelitis, occurs as a consequence of vaccination with neural antigens. EAE, the most widely used animal model of MS, is the animal counterpart of this human disease. ADEM is characterized pathologically by widespread perivenular inflammation and demyelination. The uniformity of lesions differs from the multi-age lesions found in even the most acute case of MS. Post vaccination immune-mediated damage can also affect the peripheral nervous system.
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