Pathophysiology of multiple sclerosis

Structure of a typical neuron
Myelin sheath of a healthy neuron

Multiple sclerosis (MS) is a condition where the CNS of a person present a special kind of distributed glial scars (sclerosis) [1] which are a remaining of a previous inflammatory demyelination. MS pathophysiology is complex and still under investigation and there is no agreement about its scope. Some authors[2] consider it a pathological entity, while others consider it a clinical entity. From a pathological point of view, the demyelinating lesions can be classified as encephalomyelitis, and sometimes the disease is known as encephalomyelitis disseminata.

There are two phases for how an unknown underlying condition may cause damage in MS: First some MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM). Second, there are leaks in the blood–brain barrier where immune cells infiltrate causing the known demyelination[3] and axon destruction.[4] Some clusters of activated microglia, transection of axons and myelin degeneration is present before the BBB breaks down and the immune attack begins[5][6][7]

Pathophysiology is a convergence of pathology with physiology. Pathology is the medical discipline that describes conditions typically observed during a disease state; whereas physiology is the biological discipline that describes processes or mechanisms operating within an organism. Referring to MS, the physiology refers to the different processes that lead to the development of the lesions and the pathology refers to the condition associated with the lesions.

Pathology

Multiple sclerosis can be pathologically defined as the presence of distributed scars (or sclerosis) in the central nervous system disseminated in time (DIT) and space (DIS).[8] These sclerosis are the remainings of previous demyelinating lesions in the CNS white matter of a patient (encephalomyelitis) showing special characteristics, like for example confluent instead of perivenous demyelination.[9]

Multiple sclerosis differs from other idiopathic inflammatory demyelinating diseases in its confluent subpial cortical lesions, being a hallmark exclusively present in MS patients,[10]

Normally the WM lesions appear along to other kind of damage such as NAWM (normal appearing white matter) and grey matter lesions, but MS main findings take place inside the white matter, and lesions appear mainly in a peri-ventricular distribution (lesions clustered around the ventricles of the brain), but apart from the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter.[11] MS is active even during remission periods.[12] GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[13]

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the blood–brain barrier also outside of active lesions.[14] The scars that give the name to the condition are produced by the astrocyte cells healing old lesions.[15]

Physiology of MS

In multiple sclerosis there is an inflammatory condition together with a neurodegenerative condition. Clinical trials with humanized molecular antibodies have shown that the inflammation produces the relapses and the demyelination, and an independent neurodegeneration (axonal transection) produces the accumulative disability. Degeneration has been shown to advance even when inflammation and demyelination are detained.[16]

The lesion development process

Currently it is unknown what the primary cause of MS is. Current models can be divided into two groups: Inside-out and Outside-in. In the first ones, it is hypothesized that a problem in the CNS cells produces an immune response that destroys myelin and finally breaks the BBB. In the second models, an external factor produces BBB leaks, enters the CNS, and destroys myelin and axons.[17] Some authors claim that NAWM comes before the BBB breakdown [18] and some others point to adipsin as a factor of the breakdown[19]

Whatever the underlying condition for MS is, some damage is triggered by a CSF unknown soluble factor, which is produced in meningeal areas and diffuses into the cortical parenchyma. It destroys myelin either directly or indirectly through microglia activation.[10]

Confluent subpial cortical lesions are the most specific finding for MS, being exclusively present in MS patients, though currently it can only be detected at autopsy.[10]

The lesions are driven mainly by T-cells. Nevertheless, recently it has been found that B-cells are also involved[20]

Blood–brain barrier disruption

The blood–brain barrier (BBB) is a protective barrier that denies the entrance of foreign material into the nervous system. BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions.[21]

The BBB is composed of endothelial cells which line the blood vessel walls of the central nervous system. Compared to normal endothelial cells, the cells lining the BBB are connected by occludin and claudin which form tight junctions in order to create a barrier to keep out larger molecules such as proteins. In order to pass through, molecules must be taken in by transport proteins or an alteration in the BBB permeability must occur, such as interactions with associated adaptor proteins like ZO-1, ZO-2 and ZO-3.[22] The BBB is compromised due to active recruitment of lymphocytes and monocytes and their migration across the barrier. Release of chemokines allow for the activation of adhesion molecules on the lymphocytes and monocytes, resulting in an interaction with the endothelial cells of the BBB which then activate the expression of matrix metalloproteinases to degrade the barrier.[22] This results in disruption of the BBB, causing an increase in barrier permeability due to the degradation of tight junctions which maintain barrier integrity. Inducing the formation of tight junctions can restore BBB integrity and reduces its permeability, which can be used to reduce the damage caused by lymphocyte and monocyte migration across the barrier as restored integrity would restrict their movement.[23]

After barrier breakdown symptoms may appear, such as swelling. Activation of macrophages and lymphocytes and their migration across the barrier may result in direct attacks on myelin sheaths within the central nervous system, leading to the characteristic demyelination event observed in MS.[24] After demyelination has occurred, the degraded myelin sheath components, such as myelin basic proteins and Myelin oligodendrocyte glycoproteins, are then used as identifying factors to facilitate further immune activity upon myelin sheaths. Further activation of cytokines is also induced by macrophage and lymphocyte activity, promoting inflammatory activity as well continued activation of proteins such as matrix metalloproteinases, which have detrimental effect on BBB integrity.[25]

Recently it has been found that BBB damage happens even in non-enhancing lesions.[26] MS has an important vascular component.[27]

Postmortem BBB study

Postmortem studies of the BBB, specially the vascular endotelium, show immunological abnormalities. Microvessels in periplaque areas coexpressed HLA-DR and VCAM-1, some others HLA-DR and urokinase plasminogen activator receptor, and others HLA-DR and ICAM-1.[28]

In vivo BBB study

As lesions appear (using MRI) in "Normal-appearing white matter" (NAWM), the cause that finally triggers the BBB disruption is supposed to be there.[18] The damaged white matter is known as "Normal-appearing white matter" (NAWM) and is where lesions appear.[3] These lesions form in NAWM before blood–brain barrier breakdown.[29]

BBB can be broken centripetally or centrifugally, the first form being the most normal.[30] Several possible biochemical disrupters have been proposed. Some hypothesis about how the BBB is compromised revolve around the presence of different compounds in the blood that could interact with the vascular vessels only in the NAWM areas. The permeability of two cytokines, Interleukin 15 and LPS, could be involved in the BBB breakdown.[31] The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain.[32] Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase[33]

Using iron nanoparticles, involvement of macrophages in the BBB breakdown can be detected.[34] A special role is played by Matrix metalloproteinases. These are a group of proteases that increase T-cells permeability of the blood–brain barrier, specially in the case of MMP-9,[25] and are supposed to be related to the mechanism of action of interferons.[35]

Whether BBB dysfunction is the cause or the consequence of MS[36] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins.[37] Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins.[37] (Adhesion molecules could also play a role in inflammation[38]) 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.[39] Other protein also involved is CXCL12,[40] which is found also in brain biopsies of inflammatory elements,[41] and which could be related to the behavior of CXCL13 under methylprednisolone therapy.[42] Some molecular biochemical models for relapses have been proposed.[43]

Normally, gadolinium enhancement is used to show BBB disruption on MRIs.[44] Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions, and gray matter in SPMS. They persist in inactive lesions, particularly in PPMS.[45]

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.[46] 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,[47] but not in the grey matter lesions.[48] Besides, uric acid levels are lower during relapses.[49]

Normal-appearing tissues and their origin

Some areas that appear normal under normal MRI look abnormal under special MRI, like magnetisation transfer MTR-MRI. These are called Normal Appearing White Matter (NAWM) and Normal Appearing Grey Matter (NAGM).

The cause why the normal appearing areas appear in the brain is unknown. Historically, several theories about how this happens has been presented.

Old blood flow theories

Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins.[50] Some other authors like Tracy Putnam[51] pointed to venous obstructions.

Some authors like Franz Schelling proposed a mechanical damage procedure based on violent blood reflux.[52] Later the focus moved to softer hemodynamic abnormalities, which were showing precede changes in sub-cortical gray matter[53] and in substantia nigra.[54] However, such reports of a "hemodynamic cause of MS" are not universal, and possibly not even common. At this time the evidence is largely anecdotal and some MS patients have no blood flow issues. Possibly vascular problems may be an aggravating factor, like many others in MS. Indeed, the research, by demonstrating patients with no hemodynamic problems actually prove that this is not the only cause of MS.

Endothelium theories

Other theories point to a possible primary endothelial dysfunction.[55] The importance of vascular misbehaviour in MS pathogenesis has also been independently confirmed by seven-tesla MRI.[56] It is reported that a number of studies have provided evidence of vascular occlusion in MS, which suggest the possibility of a primary vascular injury in MS lesions or at least that they are occasionally correlated.[57]

Some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency.[58]

It has also been pointed out that some infectious agents with positive correlation to MS, specially Chlamydia pneumoniae, can cause problems in veins and arteries walls[59]

CCSVI

The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. Instead of intracranial venous problems he described extracranial blockages, and he stated that the location of those obstructions seemed to influence the clinical course of the disease.[60] According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.[61] Zamboni's results were criticized as some of his studies were not blinded and they need to be verified by further studies.[60][61] As of 2010 the theory is considered at least defensible[62]

A more detailed evidence of a correlation between the place and type of venous malformations imaged and the reported symptoms of multiple sclerosis in the same patients was published in 2010.[63]

Haemodynamic problems have been found in the blood flow of MS patients using Doppler,[64] initially using transcranial color-coded duplex sonography (TCCS), pointing to a relationship with a vascular disease called chronic cerebro-spinal venous insufficiency (CCSVI).[65][66] In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.[67][68][69][70] but is important to note that positives have appeared among the blinded studies.

CSF flow theories

Other theories focus in the possible role of cerebrospinal fluid flow impairment.[71] This theory could be partially consistent with the previous one[72]

Currently a small trial with 8 participants has been performed[73]

CSF composition: Kir4.1 and Anoctamin-2

Whatever the underlying primary condition is, it is expected to be a soluble factor in the CSF,[10] maybe an unknown cytokine or ceramide, or a combination of them. Also B-cells and microglia could be involved[74][75]

It has been reported several times that CSF of some MS patients can damage myelin in culture[76][77][78][79][80] and mice[81][82] and ceramides have been recently brought into the stage.[83] Whatever the problem is, it produces apoptosis of neurons respecting astrocytes[84]

In 2012 it was reported that a subset of MS patients have a seropositive anti-Kir4.1 status,[85] which can represent up to a 47% of the MS cases, and the study has been reproduced by at least one other group.[86]

In 2016 a similar association was reported for anti-Anoctamin-2[87]

If the existence of any of these subsets of MS is confirmed, the situation would be similar to what happened for Devic Disease and Aquaporine-4. MS could be considered a heterogeneous condition or a new medical entity will be defined for these cases.

Primary neuro-degeneration theories

Some authors propose a primary neurodegenerative factor. Maybe the strongest argument supporting this theory comes from the comparison with NMO. Though autoimmune demyelination is strong, axons are preserved, showing that the standard model of a primary demyelination cannot be hold.[88] The theory of the trans-synaptic degeneration, is compatible with other models based in the CSF biochemistry.[89]

Others propose an oligodendrocyte stress as primary dysfunction, which activates microglia creating the NAWM areas[90] and others propose a yet-unknown intrinsic CNS trigger induces the microglial activation and clustering, which they point out could be again axonal injury or oligodendrocyte stress.[91]

Finally, other authors point to a cortical pathology which starts in the brain external layer (pial surface) and progresses extending into the brain inner layers[92]

MS biomarkers

Diagnosis of MS has always been made by clinical examination, supported by MRI or CSF tests. According with both the pure autoimmune hypothesis and the immune-mediated hypothesis,[93] researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments.[94] As of 2014 no biomarker with perfect correlation has been found,[95] but some of them have shown a special behavior like an autoantibody against the potassium channel Kir4.1.[96] Biomarkers are expected to play an important role in the near future[97]

As of 2014, the only fully specific biomarkers found to date are four proteins in the CSF: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin-T (a phosphodiesterase)[98] Nevertheless, abnormal concentrations of non-specific proteins can also help in the diagnosis, like chitinases[99]

Biomarkers are also important for the expected response to therapy. Currently it has been proposed the protein SLC9A9 (gen Solute carrier family 9) as biomarker for the response to interferon beta[100]

Molecular biomarkers in blood

Blood serum of MS patients shows abnormalities. Endothelin-1 shows maybe the most striking discordance between patients and controls, being a 224% higher in patients than controls.[101]

Creatine and Uric acid levels are lower than normal, at least in women.[102] Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior,[103] and relapses are associated with CD8(+) T Cells.[104] There is a set of differentially expressed genes between MS and healthy subjects in peripheral blood T cells from clinically active MS patients. There are also differences between acute relapses and complete remissions.[105] Platelets are known to have abnormal high levels.[106]

MS patients are also known to be CD46 defective, and this leads to Interleukin-10 (IL-10) deficiency, being this involved in the inflammatory reactions.[107] 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.[108] This IL-10 interleukin could be related to the mechanism of action of methylprednisolone, together with CCL2. Interleukin IL-12 is also known to be associated with relapses, but this is unlikely to be related to the response to steroids[109]

Kallikreins are found in serum and are associated with secondary progressive stage.[110] Related to this, it has been found that B1-receptors, part of the kallikrein-kinin-system, are involved in the BBB breakdown[111][112]

There is evidence of Apoptosis-related molecules in blood and they are related to disease activity.[113] B cells in CSF appear, and they correlate with early brain inflammation.[114] There is also an overexpression of IgG-free kappa light chain protein in both CIS and RR-MS patients, compared with control subjects, together with an increased expression of an isoforms of apolipoprotein E in RR-MS.[115] Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis.[116]

Recently, unique autoantibody patterns that distinguish RRMS, secondary progressive (SPMS), and primary progressive (PPMS) have been found, based on up- and down-regulation of CNS antigens,[117] tested by microarrays. In particular, RRMS is characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. These antibodies patterns can be used to monitor disease progression.[118][119]

Finally, a promising biomarker under study is an antibody against the potassium channel protein KIR4.1.[120] This biomarker has been reported to be present in around a half of MS patients, but in nearly none of the controls.

MS types by genetics

By RNA profile

Also in blood serum can be found the RNA type of the MS patient. Two types have been proposed classifying the patients as MSA or MSB, allegedly predicting future inflammatory events.[121]

By transcription factor

The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease.[122] The importance of this discovery is that the expression of these genes appears in blood and can be measured by a simple blood analysis.

In blood vessels tissue

Endothelial dysfunction has been reported in MS[123] and could be used as biomarker via biopsia. Blood circulation is slower in MS patients and can be measured using contrast[124] or by MRI[125]

Interleukin-12p40 has been reported to separate RRMS and CIS from other neurological diseases[126]

In Cerebrospinal Fluid

It has been known for quite some time that glutamate is present at higher levels in CSF during relapses[127] and to MS patients before relapses compared to healthy subjects. This observation has been linked to the activity of the infiltrating leukocytes and activated microglia, and to the damage to the axons[128] and to the oligodendrocytes damage, supposed to be the main cleaning agents for glutamate[129]

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.[130] Also Fibroblast growth factor-2 appear higher at CSF.[131]

CSF also shows oligoclonal bands (OCB) in the majority (around 95%) of the patients. Several studies have reported differences between patients with and without OCB with regard to clinical parameters such as age, gender, disease duration, clinical severity and several MRI characteristics, together with a varying lesion load.[132] Free kappa chains in CSF are documented and have been proposed as a marker for MS evolution[133]

Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions.[134] Plasma Cells in the cerebrospinal fluid of MS patients could also be used for diagnosis, because they have been found to produce myelin-specific antibodies.[135] As of 2011, a recently discovered myelin protein TPPP/p25, has been found in CSF of MS patients[136]

A study found that quantification of several immune cell subsets, both in blood and CSF, showed differences between intrathecal (from the spine) and systemic immunity, and between CSF cell subtypes in the inflammatory and noninflammatory groups (basically RRMS/SPMS compared to PPMS). This showed that some patients diagnosed with PPMS shared an inflammatory profile with RRMS and SPMS, while others didn't.[137]

Other study found using a proteomic analysis of the CSF that the peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients[138]

As of 2014 it is considered that the CSF signature of MS is a combination of cytokines[139] CSF lactate has been found to correlate to disease progression[140]

Micro-RNA as biomarker

Micro-RNA are non-coding RNA of around 22 nucleotides in length. They are present in blood and in CSF. Several studies have found specific micro-RNA signatures for MS[141]

Biomarkers in brain cells and biopsies

Abnormal sodium distribution has been reported in living MS brains. In the early-stage RRMS patients, sodium MRI revealed abnormally high concentrations of sodium in brainstem, cerebellum and temporal pole. In the advanced-stage RRMS patients, abnormally high sodium accumulation was widespread throughout the whole brain, including normal appearing brain tissue.[142] It is currently unknown whether post-mortem brains are consistent with this observation.

The pre-active lesions are clusters of microglia driven by the HspB5 protein, thought to be produced by stressed oligodendrocytes. The presence of HspB5 in biopsies can be a marker for lesion development.[6]

Biomarkers by MRI

Recently SWI adjusted magnetic resonance has given results close to 100% specificity and sensitivity respect McDonalds CDMS status[143] and Magnetization transfer MRI has shown that NAWM evolves during the disease reducing its magnetization transfer coeficient[144]

Biomarkers for the clinical courses

Currently it is possible to distinguish between the three main clinical coursesusing a combination of four blood protein tests with an accuracy around 80% [145]

Currently the best predictor for clinical multiple sclerosis is the number of T2 lesions visualized by MRI during the CIS, but it has been proposed to complement it with MRI measures of BBB permeability[146] It is normal to evaluate diagnostic criteria against the "time to conversion to definite".

Subgroups by molecular biomarkers

Differences have been found between the proteines expressed by patients and healthy subjects, and between attacks and remissions. Using DNA microarray technology groups of molecular biomarkers can be established.[147] For example, it is known that Anti-lipid oligoclonal IgM bands (OCMB) distinguish MS patients with early aggressive course and that these patients show a favourable response to immunomodulatory treatment.[148]

It seems that Fas and MIF are candidate biomarkers of progressive neurodegeneration. Upregulated levels of sFas (soluble form of Fas molecule) were found in MS patients with hypotense lesions with progressive neurodegeneration, and also levels of MIF appeared to be higher in progressive than in non-progressing patients. Serum TNF-α and CCL2 seem to reflect the presence of inflammatory responses in primary progressive MS.[149]

As previously reported, there is an antibody against the potassium channel protein KIR4.1[120] which is present in around a half of MS patients, but in nearly none of the controls, pointing towards an heterogeneous etiology in MS. The same happens with B-Cells[150]

Biomarkers for response to therapy

Response to therapy is heterogeneous in MS. Serum cytokine profiles have been proposed as biomarkers for response to Betaseron[151] and the same was proposed to MxA mRNA[152]

See also

References

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