Pathophysiology of multiple sclerosis

From Wikipedia, the free encyclopedia

Multiple sclerosis is a disease in which the myelin (a fatty substance which covers the axons of nerve cells, important for proper nerve conduction) degenerates. This includes not only the usually known white matter demyelination, but also demyelination in the cortex and deep gray matter (GM) nuclei, as well as diffuse injury of the normal-appearing white matter.[1] GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[2]

Contents

[edit] Demyelination process

Demyelinization by MS. The Klüver-Barrera colored tissue show a clear decoloration in the area of the lesion (Original scale 1:100)
Demyelinization by MS. The Klüver-Barrera colored tissue show a clear decoloration in the area of the lesion (Original scale 1:100)
Demyelinization by MS. The CD68 colored tissue shows several Macrophages in the area of the lesion. Original scale 1:100
Demyelinization by MS. The CD68 colored tissue shows several Macrophages in the area of the lesion. Original scale 1:100

According to the view of most researchers, a special subset of lymphocytes, called T cells, plays a key role in the development of MS. Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies. Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS[3] and in the degeneration of the axons[4].

Normally, there is a tight barrier between the blood and brain, called the blood-brain barrier (BBB), built up of endothelial cells lining the blood vessel walls. It should prevent the passage of antibodies through it, but in MS patients it does not work. For unknown reasons leaks appear in the blood-brain barrier. These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins such as matrix metalloproteinases. The final result is destruction of myelin, called demyelination. Whether BBB dysfunction is the cause or the consequence of MS[5] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins [6]

A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite.[7] The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions,[8] but not in the grey matter lesions.[9]. Besides, uric acid levels are lower during relapses[10].

The axons themselves can also be damaged by the attacks.[11] Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS. Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.[12]

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas[13]

[edit] Blood-brain barrier disruption

A healthy blood-brain barrier shouldn't allow T-cells to enter the nervous system. Therefore BBB disruption has always been considered one of the early problems in the MS lesions. Recently it has been found that this happens even in non-enhancing lesions[14], and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption [15].

Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions and in NAGM in SPMS. They persist in inactive lesions, particularly in PPMS[16]

Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins [17]. In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule), also called CD166, and is under study as therapeutic target[18]. Other protein also involved is CXCL12[19].

Haemodynamics of the lesions has been measured and distortion has been found related to plaque distribution[20]. It was measured through transcranial color-coded duplex sonography (TCCS). The permeability of two cytokines, IL15 and LPS, could be involved in the BBB breakdown[21].

The importance of vascular misbehaviour in MS pathogenesis has been confirmed by seven-tesla MRI[22]

[edit] Spinal cord damage

Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability[23]. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues[24]

[edit] Retina and optic nerve damage

There is axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography[25]. This measure can be used to predict disease activity.[26]

[edit] Brain tissues abnormalities

Brain normal tissues (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM) show several abnormalities under MRI. This is currently an active field of research with no definitive results. These abnormalities can be studied with Magnetization transfer multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype[27]. It has been found that grey matter injury correlates with disability[28] and that there is high oxidative stress in lesions, even in the old ones. [29]. Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls[30]

Cortical lesions also appear. They can be detected by double inversion recovery MRI. They have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women[31]. These lesions can partly explain cognitive deficits. It is known that two parameters of the cortical lesions, fractional anisotropy (FA) and mean diffusivity (MD), are higher in patients than in controls[32].

[edit] Neural and axonal damage

The axons of the neurons are damaged probably by B-Cells[33], though currently no relationship has been established with the relapses or the attacks[34].

A relationship between neural damage and N-Acetyl-Aspartate concentration has been established, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy[35]

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy[36].

[edit] Blood and CSF abnormalities

Since long time ago it is known that glutamate is present at higher levels in CSF during relapses[37] compared to healthy subjects and to MS patients before relapses. Also a specific MS protein has been found in CSF, chromogranin A, possibly related to axonal degeneration. It appears together with clusterin and complement C3, markers of complement-mediated inflammatory reactions[38]. Also Fibroblast growth factor-2 appear higher at CSF[39].

Blood serum also shows abnormalities. Creatine and Uric acid levels are lower than normal, at least in women[40]. Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior[41], and relapses are associated with CD8(+) T Cells[42].

MS patients are also known to be CD46 defective, and this leads to Interleukin 10 deficiency, being this involved in the inflammatory reactions[43]. Levels of IL-2, IL-10, and GM-CSF are lower in MS females than normal. IL6 is higher instead. These findings do not apply to men[44].

Varicella-zoster virus remains have been found in CSF of patients during relapses, but this particles are virtually absent during remissions[45]. Plasma Cells in the cerebrospinal fluid of MS patients could also be to blame, because they have been found to produce myelin-specific antibodies[46].

[edit] Demyelination patterns

Also known as Lassmann patterns[47], it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases.

The four identified patterns are [20]:

Pattern I 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.[48]
Pattern II 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.[49]
Pattern III 
The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis.
Pattern IV 
The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneous disease. Others maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution. Anyway, the heterogeneity could be true only for the early stage of the disease[50]. Recently some lesions have shown mitocondrial defects and this could also be a difference between types of lesions[51]

[edit] Correlation with clinical courses

No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study [52] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy)[53]. Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions[54].

[edit] Correlation with MRI and MRS findings

The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease “sub-types” of underlying pathologies. It is possible that such “sub-types” of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments.

It seems that Pulsed magnetization transfer imaging [PMID 16964602], diffusion Tensor MRI [PMID 16385020] and VCAM-1 enhanced MRI [21] could be able to show the pathological differences of these patterns.

Together with MRI, magnetic resonance spectroscopy will allow in the future to see the biochemical composition of the lesions.

[edit] Correlation with CSF findings

Teams in Oxford and Germany, [22] [PMID 11673319] found correlation with CSF and progression in November 2001, and hypothesis have been made suggesting correlation between CSF findings and pathophysiological patterns[55]. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found [56], though this is disputed[57]. High levels of anti-nuclear antibodies are found normally in patients with MS. Antibodies against Neurofascin–186 could be involved in a subtype of MS [58]

[edit] Response to therapy

It is known that 30% of MS patients are non-responsive to Beta interferon[59]. The heterogeneous response to therapy can support the idea of hetherogeneous aetiology. It has also been shown that IFN receptors and interleukins in blood serum predicts response to IFN therapy[60][61]. Besides:

  • Pattern II lesions patients are responsive to plasmapheresis, while others are not [23] [24][25].
  • The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.[PMID 12027786]
  • People non-responsive to interferons are the most responsive to Copaxone [26][27]
  • In general, people non-responsive to a treatment is more responsive to other [62]
  • There are genetic differences between responders and not responders [PMID 18195134] Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior[63]

[edit] Subgroups by molecular biomarkers

Differences have been found between the proteines expresed by patients and healthy subjects, and between attacks and remisions. Using DNA microarray technology groups of molecular biomarkers can be stablished[64].

[edit] Discovery

The National MS society launched The Lesion Project to classify the different lesion patterns of MS.

Claudia F. Lucchinetti, MD from Mayo Clinic and collaborators from the U.S., Germany and Austria were chosen to conduct this study for their previous contributions in this area. They have amassed a large collection of tissue samples from people with MS through brain biopsies or autopsy. Claudia Lucchinetti was appointed director of this project. The group has reported promising findings on samples from 83 cases. They found four types of lesions, which differed in immune system activity. Within each person, all lesions were the same, but lesions differed from person to person.

The first article about pathophysiological heterogeneity was in 1996 [PMID 8864283] and has been confirmed later by several teams. Four different damage patterns have been identified by her team in the scars of the brain tissue. Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions.

According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

Apart of this, recent achievements in related diseases, like neuromyelitis optica have shown that varieties previously suspected different from MS are in fact different diseases. In neuromyelitis optica, a team was able to identify a protein of the neurons, Aquaporin 4 as the target of the immune attack. This has been the first time that the attack mechanisme of a type of MS has been identified [65].

The investigators are now trying to identify the types of cells involved with tissue destruction, and examining clinical characteristics of the individuals from whom these tissues were taken.

The MS Lesion Project has just been renewed with a commitment of $1.2 million for three years. It is now part of the Promise 2010 campaign.

[edit] Research

Until recently, most of the data available came from post-mortem brain samples and animal models of the disease, such as the experimental autoimmune encephalomyelitis (EAE), an autoimmune disease that can be induced in rodents, and which is considered a possible animal model for multiple sclerosis.[66] However, since 1998 brain biopsies apart from the post-mortem samples were used, allowing researchers to identify the previous four different damage patterns in the scars of the brain.[67]


[edit] See also

[edit] References

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