Ana sayfa | MS’in Derinliği  | MS Slide Resource

Overview of the immune system

The immune system is very complex and involves many cells types and molecules.^33,34,35 Cells of particular importance to an understanding of MS immunopathology include T-lymphocytes, B-lymphocytes, and monocytes/macrophages. Important molecules in this respect include antibodies, complement, certain cytokines and human leukocyte antigen (HLA).

T-lymphocytes

Each T-lymphocyte recognizes a specific antigen and lies dormant until that antigen is presented to it by an antigen presenting cell. The T-lymphocyte then becomes activated, multiplies, and its many daughter cells roam the body looking for their target antigen. T-lymphocytes perform several different functions. They may have cytotoxic, helper or suppressor roles. Cytotoxic T-lymphocytes chemically attack other cells bearing their target antigen. Helper T-lymphocytes have recently been subdivided into two different populations. The T_H1 cells mainly activate macrophages and augment the T-lymphocyte response, whereas the T_H2 cells help trigger antibody production in B-lymphocytes. Suppressor T-lymphocytes suppress, and thereby control, the immune response of other immune cells directed against the target antigen.

B-lymphocytes

Each B-lymphocyte recognizes a specific antigen and expresses on its surface an antibody that binds to that antigen. The B-lymphocyte lies dormant until the antigen stimulates the B-lymphocyte to multiply. The daughter cells transform into plasma cells and produce antibody which freely disperses from the cell in search of the target antigen. When antibodies bind to target antigens, they help macrophages to engulf them and complement to attack them.

Monocyte/macrophage system

Monocytes circulate in the blood. When they come to rest in a tissue they transform into macrophages. Their two major functions are phagocytosis and antigen presentation. Macrophages do not recognize specific antigens. They engulf foreign material and other debris which they destroy internally with enzimler . They are particularly attracted to material with antibody or complement attached. Once they have phagocytosed material, they can process its antigens and present them, linked with HLA molecules (see below), to lymphocytes.

Complement

Complement is a series of serum proteins. Under certain conditions, these assemble on cell membranes to attract macrophages, and to puncture holes in the cell membranes thus allowing a massive calcium ion influx which results in cell death (membrane attack complex). Complement can be activated and assembled by either of two pathways, termed 'classical' and 'alternative'. These converge in a common final 'lytic' pathway. The 'classical' pathway is triggered by antigen-antibody complexes on cell membranes. The 'alternative' pathway can begin spontaneously on the surface of foreign cells. By-products of complement assembly attract macrophages and promote the inflammatory response in other ways e.g. by causing vasodilation.

Cytokines

Cytokines are soluble mediators secreted by immune cells (e.g. macrophages and lymphocytes). Some affect immune cells and immune molecules by modifying their activities, and others damage target cells. For example, on encountering their antigen, helper T-lymphocytes produce cytokines that stimulate the proliferation and differentiation of B-lymphocytes.

There are a large number of cytokines. Of particular importance in multiple sclerosis is interferon gamma, which promotes inflammation. Interferon beta counteracts the effects of interferon gamma. Tumour necrosis factors alpha and beta (TNF and ß) are important also, they promote inflammation and cause cell damage. Interferon alpha, interleukins, and transforming growth factor beta are other cytokines that may be involved in MS immunopathology.

The major histocompatibility complex

The major histocompatibility complex (MHC) genes code for proteins called HLA molecules, which are involved in self recognition. There are lymphocytes in the body that have the potential to react against the body's own constituents. However, for immune cells to attack, their target antigen must be presented to them by antigen presenting cells. To be presented to T-lymphocytes, the antigen must be bound to HLA molecules on the surface of antigen presenting cells. This system ensures that autoreactive lymphocytes normally remain dormant, never attacking self-constituents. However, under some circumstances autoimmunity (self attack) can occur.

Immunity and the blood-brain barrier

CNS immune surveillance

The CNS is a delicate tissue that has a poor capacity to regenerate. Consequently, it is particularly vulnerable to damage from immune reactions, which must therefore be kept to a minimum.⁸ Nevertheless, immune cells are found in the CNS under normal conditions, but they are present in very low numbers.³⁶ The most abundant are microglial cells, which form a network throughout the CNS. They are probably derived from monocytes that colonize the CNS during embryonic and neonatal life.³⁷

In addition to these resident cells, the CNS is under immune surveillance by lymphocytes.⁸ Adhesion molecules on endothelial cells allow activated T-lymphocytes to enter the CNS in search of their target antigen (if it is not present they pass through without incident).³⁸ Resting (non-activated) T-lymphocytes are excluded from the CNS.³⁷ This greatly reduces the number of immune cells patrolling the CNS, as only a minority of circulating T-lymphocytes are in an activated state.⁸ Thus, lymphocyte traffic through the CNS is more selective than in other organs.³⁷

Inflammation and blood-brain barrier breakdown in the CNS

Despite the low level of immune etkinligini in the CNS under normal circumstances, immune reactions appear to be involved in several brain and spinal cord diseases.⁹ Activated T-lymphocytes survey the CNS until they discover their target antigen being presented by an antigen presenting cell. Then, when a sufficient number of T-lymphocytes are present, inflammation begins.³⁶

Once this process has begun, the blood-brain barrier opens and a full inflammatory reaction can occur. Molecular signals attract other lymphocytes, microglia multiply, and other cells from the circulation, as well as immunoglobulins, coagulation and complement factors, join the inflammatory process.³⁶

Such blood-brain barrier breakdown can occur in MS plaques. It can be seen using MRI scanning enhanced by Gd-DTPA, a molecule that can only enter the brain where the blood-brain barrier is abnormal.¹⁶

The role of particular immune system components in MS

T-lymphocytes in MS

T-lymphocyte origin and activation in MS

The normal immune system contains dormant T-lymphocytes that could attack auto-antigens if activated. The body has a mechanism that normally prevents these cells from becoming activated and initiating autoimmune disease. In MS, they become activated by some as yet unknown mechanism, and enter the CNS.³⁹

T-lymphocyte distribution in the CNS of MS patients

Early in the development of an active plaque, activated T-lymphocytes accumulate around small venules. These are predominantly the helper variety of T-lymphocyte (those that augment T-lymphocyte and macrophage activation). Later, myelin degeneration occurs with marked perivenular inflammation, in which T-lymphocytes are predominantly the suppressor or cytotoxic variety of T-lymphocyte (suppressing the immune response or engaging in chemical attack). T-lymphocytes also occur at the edges of plaques and in the white matter surrounding plaques.^40,41

Antigen presentation to T-lymphocytes in MS

T-lymphocytes cannot recognize their target antigen unless it is presented to them by antigen presenting cells. Such cells ingest the target antigen and cleave it into fragments, some of which they present on their surface linked to HLA molecules so that the fragments are recognizable to T-lymphocytes.³⁹

In actively demyelinating MS plaques, macrophages ingest myelin and then form intimate contacts with small lymphocytes. This is probably an example of antigen presentation to T-lymphocytes.⁴⁰

What is the target antigen of T-lymphocytes in MS?

Identifying target antigens must be done indirectly, by examining the receptors on the T-lymphocyte surface.³⁵ The receptors that T-lymphocytes use to bind to their antigen consist of two glycoprotein sub-units out of four available - alpha () usually pairs with beta (ß), and gamma () with delta ().³⁴ Hence there are ß T-lymphocytes and T-lymphocytes.

Many of the ß T-lymphocytes involved in MS have identical receptor arrangements, implying they may be recognizing a particular common antigen (i.e. they may be a clone).⁴⁰ Nevertheless, a polyclonal ß T-lymphocyte repertoire does occur in MS lesions. This is not surprising, since breakdown of the blood-brain barrier is likely to lead to recruitment of large numbers of T-lymphocytes against many antigens. They would swamp the minority of T-lymphocytes that specifically attack the target antigen involved in disease initiation.⁴¹

The ß T-lymphocytes are likely to be specific for myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein. Such cells are present in blood. Moreover, T-lymphocytes with the same specificities are thirty to seventy times more frequent in the CSF.³⁵

T-lymphocytes may also be important in MS pathogenesis. This type of lymphocyte has been described in MS plaques, where they multiply in clones. In vitro, T-lymphocytes lyse oligodendrocytes, possibly by recognising antigens known as 'heat shock proteins' that are expressed by stressed oligodendrocytes.^40,42,43

One possible scenario is that ß T-lymphocytes initiate the inflammatory process by attacking myelin. This stresses oligodendrocytes which consequently express heat shock proteins. T-lymphocytes are then recruited and may further destroy oligodendrocytes.⁴³

B-lymphocytes in MS

Animal models suggest that antibodies directed against myelin may play a role in demyelination. When sera taken from animals sensitized to CNS antigens is injected into the CSF of other animals, demyelination occurs. However, two conditions must be met before antibody can initiate demyelination under these circumstances. The antibody must be directed against a myelin surface antigen, and it must gain access to the CNS. The latter condition can be met by damage to the blood-brain barrier or intrathecal antibody synthesis.⁴⁴

B-lymphocytes and antibodies in the CSF and serum in MS

Plasma cells producing antibody occur in high numbers in the CSF of MS patients. Electrophoresis of the CSF shows oligoclonal bands of IgG type antibody in over 90% of patients, indicating the presence of clones of antibodies directed against specific antigens. Typically around ten bands occur. Antibodies produced in the CSF are partly directed against myelin antigens: myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein. Myelin basic protein antigen is released into the CSF following any type of brain insult, including MS.^34,35

Although antibody synthesis in MS occurs mainly within the CNS, IgG synthesis by peripheral blood B-lymphocytes is increased in MS patients, especially during relapse.³⁴

B-lymphocytes and antibodies in brain tissue in MS

MS plaques also contain B-lymphocytes and plasma cells.³⁴ These cells are much more numerous within plaques than in normally myelinated tissue. Consistent with CSF studies, these cells contain predominantly IgG. Some plaques produce a preponderance of either kappa or lambda light chains (sub-units of antibodies), suggesting that plaques may contain B-lymphocyte clones. This would imply that there is an antigenic stimulus to B-lymphocytes within the plaques.⁴⁵

B-lymphocyte/T-lymphocyte co-operation in MS

Some T-lymphocytes enhance polyclonal B-lymphocyte responses, either directly or through the release of cytokines; others suppress B-lymphocyte responses.³⁴ Conversely, B-lymphocytes may affect T-lymphocytes, by expressing HLA Class II antigens and presenting antigens to T-lymphocytes.³⁵

In experimental animal models, demyelination can be induced by T-lymphocytes reactive against myelin basic protein. However, this response is significantly enhanced by antibody directed against myelin surface antigens.⁴⁴ Supporting this, B-lymphocyte-deficient animals may fail to develop experimental demyelinating diseases.³⁵

Antibody/complement co-operation in MS

Oligodendrocytes are unduly sensitive to complement.³⁴ Antibodies directed against myelin surface antigens may aid demyelination by activating complement via the classical pathway.³⁵

Antibody/macrophage co-operation in MS

In experimental animal models, demyelination seems to depend on the phagocytosis of myelin by macrophages attracted to antibodies on myelin surfaces.³⁴ This may be important in MS also.³⁵

Complement in MS

Evidence for complement involvement in MS

There is currently much interest in the role that complement may play in MS, since experimental animal models have shown that complement may cause myelin injury. In these models, animals depleted of complement do not develop demyelinating disease, even though they show blood-brain barrier damage and T-lymphocyte infiltration. The role of complement is supported further by in vitro studies. These show complement component C9 attached to the surface of oligodendrocytes that have been exposed to autoreactive serum.³⁴

In patients with MS, CSF studies suggest a role for complement in the disease process. Two short-lived by-products of complement activation, called C3a and C4a, can be detected in the CSF of MS patients. Also, complement component C9 (part of the membrane attack complex) is depleted from the CSF of MS patients.

During periods of clinical improvement following treatment with high-dose intravenous prednisolone, the CSF concentration of C9 increases. In addition, C9 concentration is inversely proportional to IgG synthesis.³⁴ This implies that complement assembly is occurring in response to antibody production. Finally, antigens of the membrane attack complex have been detected in the CSF of MS patients.⁴⁶

The complement membrane attack complex in MS

Complement injures oligodendrocytes in vitro. This is due to the formation of membrane attack complexes on oligodendrocyte surfaces. They allow rapid entry of excess calcium into the cell. This is greater when antibody and complement are used together. The addition of antibody (as occurs in MS) may be sufficient to cause permanent damage.

Different antimyelin antibodies encourage complement-dependent calcium influx to varying degrees. Antibodies against surface myelin antigens (e.g. myelin oligodendrocyte glycoprotein) promote greater complement-mediated calcium influx than those against internal myelin antigens (e.g. myelin basic protein).³⁴

Complement's effect on macrophages in MS

By-products of the complement pathways attract and activate macrophages.³⁴ Also, complement may act as an opsonin on the myelin surface⁴⁷ - opsonins encourage macrophages to phagocytose cells to which they attach.

In MS, as complement activation proceeds, macrophages may be recruited and contribute to oligodendrocyte and myelin injury by phagocytosis and the release of cytokines. Although oligodendrocyte lysis can occur in vitro without macrophages, in vivo macrophages appear to be important. In MS, antibody, complement and macrophages may all act together in synergy.³⁴

Macrophages in MS

Evidence for macrophage involvement in MS

Much evidence suggests that activated macrophages are involved in demyelination.⁴⁸ Macrophages are some of the most abundant infiltrating cells found in histopathological studies of MS. Myelin breakdown occurs mainly in the presence of infiltrating macrophages and local macrophage etkinligini.^12,48 Moreover, macrophages in the inflammatory perivenular cuffs of MS plaques contain myelin degradation products.⁴⁹

As with complement, animals depleted of macrophages do not develop clinically manifest demyelinating disease, even though they show blood-brain barrier damage and T-lymphocyte infiltration.³⁴

Macrophage sources and movements in MS

There is controversy concerning the source of the macrophages present in MS plaques.³⁴ One possible source is resident microglial cells, another the blood monocytes.

During development, macrophages enter the CNS and become resident microglial cells.³⁴ These are a very stable pool of cells, which in the adult are rarely replaced by new cells arriving from the blood.⁵⁰ In MS, microglial cells situated near active plaques may turn into phagocytic macrophages.⁴⁹

The CNS is continuously patrolled by small numbers of monocytes. Monocytes from the blood slowly replace monocytes in the meninges and brain perivascular spaces. During brain inflammation, antibody and complement attract circulating monocytes through the blood-brain barrier, thus increasing turnover.^12,34,50

Phagocytosis by macrophages in MS

The primary role of macrophages is phagocytosis. Much evidence suggests that, in MS, macrophages physically remove myelin from axons by phagocytosis.³⁴

In the early stages of demyelination, superficial layers of myelin can be seen attached to receptor-rich areas on the surface of macrophages (these areas are called coated pits). This suggests that receptor-mediated phagocytosis is taking place. Afterwards, myelin can be seen incorporated into elongated vesicles within the macrophages. In MS, non-immune mediated phagocytosis probably occurs as well as antibody- and complement-mediated phagocytosis.^12,34

It remains unclear whether macrophages initiate the damage to myelin and oligodendrocytes, or merely remove tissue already damaged by other immune mechanisms.³⁴ However, no consistent changes in myelin are known to precede phagocytosis of myelin in MS. This suggests that macrophages may initiate the demyelination.¹²

Chemical attack by macrophages in MS

Substances secreted by activated monocytes/macrophages include:

• tumour necrosis factor (TNF-)

• interleukin-1

• interleukin-6

• leucotrienes

• oxygen-free radicals

• proteolytic enzimler .

Several of these substances damage myelin, either directly or via oligodendrocyte injury.^12,34,48

Antigen presentation by macrophages in MS

In MS plaques, macrophages may function as antigen presenting cells.⁴⁹ HLA Class II expression occurs mainly on microglial/macrophage-like cells.³⁵

Cytokines in MS

Cytokines are soluble chemical messengers and effector molecules. They are involved in immune cell movements, activation, antigen recognition, and effector etkinligini. Several cytokines appear to play a central role in the immune pathogenesis of MS.⁵¹

Interferon gamma in MS

Interferon gamma has antiproliferative, antiviral and immunoregulatory functions.⁵² It can be found in the CNS of MS patients, where its primary role is probably immune regulation.^35,53

In MS patients, interferon gamma is produced by T-lymphocytes in response to myelin antigens, especially during relapses. Moreover, the T-lymphocytes from these patients produce interferon gamma more readily than T-lymphocytes from subjects without MS.^5,35

Systemic administration of interferon gamma causes the clinical condition of MS patients to deteriorate.⁵² Several immune mechanisms could be involved in its detrimental effects.

Interferon gamma may potentiate the immune response by activating other T-lymphocytes,⁵² and attracting them into plaques.⁵¹ Experimental injection of interferon gamma into the spinal cord recruits T-lymphocytes to the injection site.³⁵ It may do this by inducing adhesion molecules which help lymphocytes to cross the blood-brain barrier and control their migration to sites of inflammation.⁵¹

Similarly, interferon gamma may potentiate the immune response by activating macrophages. It induces macrophages to express HLA Class II molecules, permitting them to present myelin antigens to activated T-lymphocytes.^52,53 In addition, interferon gamma stimulates macrophages to produce another cytokine: TNF (see below), thereby enhancing myelin destruction.⁵⁴

Interferon gamma can potentiate antibody-mediated demyelination also.

In MS there is a relationship between acute exacerbations and common viral infections.⁵² This may be an immunological side-effect as a result of the body producing interferon gamma for its antiviral properties.⁵³

Tumour necrosis factor alpha in MS

Tumour necrosis factor alpha (TNF) is secreted by activated macrophages,⁵⁴ and occurs in active MS plaques.³⁵ It may damage myelin and oligodendrocytes directly through an effect on ion channels.⁵⁴

Levels of TNF correlate well with blood-brain barrier damage in the brains of MS patients. It may cause blood-brain barrier disruption by damaging vascular endothelial cells.

Finally, TNF acts synergistically with interferon gamma to induce HLA Class II molecules.⁵³ Therefore it may promote the inflammatory response by stimulating antigen presentation.

Tumour necrosis factor beta (lymphotoxin) in MS

Tumour necrosis factor beta (TNFß) is produced by activated T-lymphocytes. Chemically it is a close relative of TNF. Thus, lymphocytes and macrophages may have similar cytokine-mediated cytotoxic effects.⁵⁴

Interferon beta in MS

Interferon beta tends to inhibit the etkinligini of interferon gamma. This may account for clinical findings that the recombinant product, interferon beta-1b, suppresses exacerbations in relapsing/remitting MS patients.⁵⁶

Interferon beta has its effect via several mechanisms. It down-regulates interferon gamma production.³⁵ In addition, it decreases cytokine release from T-lymphocytes, and, by counteracting interferon gamma's augmentation of MHC-derived proteins, it inhibits T-lymphocyte proliferation.⁵ However, interferon beta also improves suppressor T-lymphocyte function.⁵¹

Other cytokines in MS

Other cytokines that may be involved in regulating MS pathology, either positively or negatively, are interleukin-1, interleukin-2, interferon alpha, and transforming growth factor beta.^35,51,57

Evidence for autoimmunity in MS

Evidence that MS is an autoimmune disease is strong but circumstantial.⁵⁸

Immune components and antigen specificity

Within the immune system, there are many dormant T- and B-lymphocytes directed against self-antigens. There is a risk that the mechanisms preventing these lymphocytes from becoming active may fail, resulting in self-attack (autoimmune disease). Several such diseases have already been identified (e.g. juvenile diabetes).³³

In MS, autoreactive T- and B-lymphocytes and antibodies occur in the peripheral blood, CSF and brain tissue. These are directed against several myelin antigens. These findings suggest that MS may be a myelin-specific autoimmune disease, but do not prove it. They could be secondary phenomena, since tissue damage in the CNS can induce T- and B-lymphocyte autoimmunity against the same myelin antigens³⁵ (i.e. the disease could be responsible for generating autoimmunity in the same way that myocardial infarction induces anticardiac antibodies).³³ This possibility is supported by the finding that the T-lymphocytes in MS are directed against several antigens. However, animal models that are clearly autoimmune also show lymphocytes directed against more than one myelin antigen.

A further line of evidence suggests that autoimmunity is the cause of MS. Brain lesions very similar to those found in MS occur following autosensitization of humans with CNS tissue (seen following vaccination with vaccines grown on CNS-tissue or 'cell therapy').⁵⁹

Animal models

One way to test whether a disease is autoimmune in nature, is to induce autoimmunity experimentally in animals and see if a similar disease develops.³³ Most clinical, immunopathological and immunochemical features of MS can be reproduced in the animal model of MS called experimental allergic encephalomyelitis (EAE).^15,35 This provides further evidence that MS is an autoimmune disease.

HLA Class II associations

In most autoimmune diseases, extrinsic factors trigger the disease in genetically susceptible individuals.³⁴ Virtually all autoimmune diseases show an association with the MHC genes.³³ The part of the MHC expressed by antigen presenting cells is the HLA Class II (DP, DQ and DR). In Caucasians, MS is associated with HLA DW2 and DR2. Various other associations have been recorded in populations of MS patients.³⁵

Extrinsic factors

In the case of MS, many extrinsic factors have been proposed as the triggering factor. Some researchers suggest that individuals develop MS because they are exposed to a particular extrinsic factor during a brief window of susceptibility in late childhood.³⁴

Further evidence

MS is more common in females than males and has a relapsing/remitting course. Both of these features are typical of autoimmune diseases.⁶⁰

Bu sayfadaki bilginin en son güncellendiği/doğrulandığı tarih:

11/09/2001

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