Pathophysiology of multiple sclerosis 4930095 226022986 2008-07-16T14:08:36Z 213.170.46.90 T helper cells [[Multiple sclerosis]] is a disease in which the [[myelin]] (a [[lipid|fatty]] substance which covers the [[axon]]s of [[neuron|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.<ref>Lassmann H,Bruck W,Lucchinetti CF. The immunopathology of multiple sclerosis: an overview, Centre for Brain Research, Medical University of Vienna, Vienna, Austria, PMID 17388952</ref> GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS<ref>Pirko I, Lucchinetti CF, Sriram S, Bakshi R. Gray matter involvement in multiple sclerosis. Neurology. 2007 Feb 27;68(9):E9–10. PMID 17325269</ref> ==Demyelination process== [[Image:MS Demyelinisation KB 10x.jpg|thumb|300px|Demyelinization by MS. The Klüver-Barrera colored tissue show a clear decoloration in the area of the lesion (Original scale 1:100)]] [[Image:MS Demyelinisation CD68 10xv2.jpg|thumb|300px|Demyelinization by MS. The [[CD68]] colored tissue shows several [[Macrophage]]s in the area of the lesion. Original scale 1:100]] According to the view of most researchers, a special subset of [[lymphocyte]]s, called [[T helper cell]]s, specifically Th1 and Th17<ref>{{cite journal |author=Fransson ME, Liljenfeldt LS, Fagius J, Tötterman TH, Loskog AS. |title=The T-cell pool is anergized in patients with multiple sclerosis in remission |journal= |volume= |issue= |pages= |year= |pmid=18624727}}</ref>, play a key role in the development of MS. Under normal circumstances, these [[lymphocyte]]s 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 [[inflammation|inflammatory]] processes and stimulating other immune cells and soluble factors like [[cytokine]]s and [[antibody|antibodies]]. Recently other type of immune cells, [[B Cell]]s, have been also implicated in the pathogenesis of MS<ref>B-cell depletion with rituximab in relapsing-remitting multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/18272891?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]</ref> and in the degeneration of the axons<ref>Cause of nerve fiber damage in multiple sclerosis identified [http://www.physorg.com/news80230112.html]</ref>. Normally, there is a tight barrier between the blood and brain, called the [[blood-brain barrier]] (BBB), built up of [[endothelial cell]]s 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 [[edema|swelling]], activation of [[macrophages]], and more activation of cytokines and other destructive [[protein]]s such as [[matrix metalloproteinase]]s. The final result is destruction of myelin, called demyelination. <!--A study of MS lesions in post-mortem brains identified four patterns of damage; two affecting myelin and two affecting [[oligodendrocytes]]. This needs a reference.--> Whether BBB dysfunction is the cause or the consequence of MS<ref> {{cite journal |author=Waubant E |title=Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis |journal=Dis. Markers |volume=22 |issue=4 |pages=235–44 |year=2006 |pmid=17124345}}</ref> is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins <ref>[multiple sclerosis at emedicine.com http://www.emedicine.com/neuro/topic228.htm#target1]</ref> 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]].<ref>{{cite journal |author=Kean R, Spitsin S, Mikheeva T, Scott G, Hooper D |title=The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity |journal=J. Immunol. |volume=165 |issue=11 |pages=6511–8 |year=2000 |pmid=11086092}}Full article[http://www.jimmunol.org/cgi/content/full/165/11/6511]</ref> 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,<ref>{{cite journal |author=Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D |title=Serum uric acid and multiple sclerosis |journal=Clinical neurology and neurosurgery |volume=108 |issue=6 |pages=527–31 |year=2006 |pmid=16202511 |doi=10.1016/j.clineuro.2005.08.004}}</ref> but not in the grey matter lesions.<ref>van Horssen,Brink,de Vries,van der Valk,Bo. The Blood-Brain Barrier in Cortical Multiple Sclerosis Lesions. PMID 17413323</ref>. Besides, uric acid levels are lower during relapses<ref>Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment, Guerrero AL, Martín-Polo J, Laherrán E, Gutiérrez F, Iglesias F, Tejero MA, Rodríguez-Gallego M, Alcázar C.[http://www.ncbi.nlm.nih.gov/pubmed/18312403?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]</ref>. The [[axon]]s themselves can also be damaged by the attacks.<ref>{{cite journal |author=Pascual AM, Martínez-Bisbal MC, Boscá I, ''et al'' |title=Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis |journal=Neurology |volume=69 |issue=1 |pages=63–7 |year=2007 |pmid=17606882 |doi=10.1212/01.wnl.0000265054.08610.12}}</ref> 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 [[lesion]]s 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 NMR|Proton magnetic resonance]] spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.<ref>{{cite journal |author=Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman R, Scotti G, Comi G, Falini A |title=Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis |journal=Brain |volume=126 |issue=Pt 2 |pages=433–7 |year=2003 |pmid=12538409 |doi=10.1093/brain/awg038}}</ref> The [[oligodendrocyte]]s that originally formed a [[myelin sheath]] cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte [[stem cell]]s 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<ref>Wolswijk, G. ''Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells'' J Neurosci, 1998;18: 601-9. PMID 9425002</ref> ==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<ref>{{cite journal |author=Soon D, Tozer DJ, Altmann DR, Tofts PS, Miller DH |title=Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes |journal= |volume= |issue= |pages= |year=2007 |pmid=17468443 |doi=10.1177/1352458507076970}}</ref>, and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption <ref>{{cite journal |author=Petry KG, Boiziau C, Dousset V, Brochet B |title=Magnetic resonance imaging of human brain macrophage infiltration |journal=Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics |volume=4 |issue=3 |pages=434–42 |year=2007 |pmid=17599709 |doi=10.1016/j.nurt.2007.05.005}}</ref>. 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<ref>{{cite journal |author=Leech S, Kirk J, Plumb J, McQuaid S |title=Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis |journal=Neuropathol. Appl. Neurobiol. |volume=33 |issue=1 |pages=86–98 |year=2007 |pmid=17239011 |doi=10.1111/j.1365-2990.2006.00781.x}}</ref> Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins <ref>[multiple sclerosis at emedicine.com http://www.emedicine.com/neuro/topic228.htm#target1]</ref>. 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<ref>Alexandre Prat, Nicole Beaulieu, Sylvain-Jacques Desjardins, New Therapeutic Target For Treatment Of Multiple Sclerosis, Jan. 2008[http://www.medicalnewstoday.com/articles/94734.php]</ref>. Other protein also involved is [[CXCL12]]<ref>Pathological Expression of CXCL12 at the Blood-Brain Barrier Correlates with Severity of Multiple Sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/18276777?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]</ref>. Haemodynamics of the lesions has been measured and distortion has been found related to plaque distribution<ref>Intracranial Venous Haemodynamics in Multiple Sclerosis, Zamboni, Paolo; Menegatti, Erica; Bartolomei, Ilaria; Galeotti, Roberto; Malagoni, Anna M.; Tacconi, Giovanna; Salvi, Fabrizio [http://www.ingentaconnect.com/content/ben/cnr/2007/00000004/00000004/art00004;jsessionid=2t4etumjan81n.alexandra]</ref>. It was measured through transcranial color-coded duplex [[sonography]] (TCCS). The permeability of two [[cytokine]]s, [[IL15]] and [[Lipopolysaccharide|LPS]], could be involved in the BBB breakdown<ref>{{cite journal |author=Pan W, Hsuchou H, Yu C, Kastin AJ |title=Permeation of blood-borne IL15 across the blood-brain barrier and the effect of LPS |journal=J. Neurochem. |volume= |issue= |pages= |year=2008 |pmid=18384647 |doi=10.1111/j.1471-4159.2008.05390.x}}</ref>. The importance of vascular misbehaviour in MS pathogenesis has been confirmed by seven-tesla [[MRI]]<ref>{{cite journal |author=Ge Y, Zohrabian VM, Grossman RI. |title=Seven-tesla magnetic resonance imaging: new vision of microvascular abnormalities in multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |pmid=18541803 |doi=}}</ref> ==Spinal cord damage== Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability<ref>{{cite journal |author=Agosta F, Pagani E, Caputo D, Filippi M |title=Associations between cervical cord gray matter damage and disability in patients with multiple sclerosis |journal=Arch. Neurol. |volume=64 |issue=9 |pages=1302–5 |year=2007 |pmid=17846269 |doi=10.1001/archneur.64.9.1302}}</ref>. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues<ref>{{cite journal |author=Agosta F, Valsasina P, Rocca MA, Caputo D, Sala S, Judica E, Stroman PW, Filippi M. |title=Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis |journal= |volume= |issue= |pages= |year= |pmid=18429010 |doi=}}</ref> ==Retina and optic nerve damage== There is axonal loss in the retina and optic nerve, which can be meassured by [[Optical coherence tomography]]<ref>{{cite journal |author=Pueyo V, Martin J, Fernandez J, Almarcegui C, Ara J, Egea C, Pablo L, Honrubia F. |title=Axonal loss in the retinal nerve fiber layer in patients with multiple sclerosis |journal= |volume= |issue= |pages= |year= |pmid=18424482 |doi=}}</ref> or by [[Scanning laser polarimetry]]<ref>{{cite journal |author=Zaveri MS, Conger A, Salter A, Frohman TC, Galetta SL, Markowitz CE, Jacobs DA, Cutter GR, Ying GS, Maguire MG, Calabresi PA, Balcer LJ, Frohman EM. |title=Retinal Imaging by Laser Polarimetry and Optical Coherence Tomography Evidence of Axonal Degeneration in Multiple Sclerosis |journal= |volume= |issue= |pages= |year= |pmid=18625859 |doi=}}</ref>. This measure can be used to predict disease activity.<ref name="pmid17470751">{{cite journal |author=Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P |title=Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS |journal=Neurology |volume=68 |issue=18 |pages=1488–94 |year=2007 |month=May |pmid=17470751 |doi=10.1212/01.wnl.0000260612.51849.ed |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=17470751}}</ref> ==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<ref>{{cite journal |author=Laule C, Vavasour IM, Kolind SH, ''et al'' |title=Long T(2) water in multiple sclerosis: What else can we learn from multi-echo T(2) relaxation? |journal=J. Neurol. |volume=254 |issue=11 |pages=1579–87 |year=2007 |pmid=17762945 |doi=10.1007/s00415-007-0595-7}}</ref>. It has been found that grey matter injury correlates with disability<ref>{{cite journal |author=Zhang Y, Zabad R, Wei X, Metz LM, Hill MD, Mitchell JR |title=Deep grey matter 'black T2' on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis |journal= |volume= |issue= |pages= |year=2007 |pmid=17468444 |doi=10.1177/1352458507076411}}</ref> and that there is high oxidative stress in lesions, even in the old ones. <ref>{{cite journal |author=Holley JE, Newcombe J, Winyard PG, Gutowski NJ |title=Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes |journal= |volume= |issue= |pages= |year=2007 |pmid=17623739 |doi=10.1177/1352458507078064}}</ref>. Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls<ref>{{cite journal |author=Phuttharak W, Galassi W, Laopaiboon V, Laopaiboon M, Hesselink JR |title=Abnormal diffusivity of normal appearing brain tissue in multiple sclerosis: a diffusion-weighted MR imaging study |journal=J Med Assoc Thai |volume=90 |issue=12 |pages=2689–94 |year=2007 |pmid=18386722 |doi=}}</ref> 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<ref>{{cite journal |author=Calabrese M, De Stefano N, Atzori M, ''et al'' |title=Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis |journal=Arch. Neurol. |volume=64 |issue=10 |pages=1416–22 |year=2007 |pmid=17923625 |doi=10.1001/archneur.64.10.1416}}</ref>. 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<ref>{{cite journal |author=Poonawalla AH, Hasan KM, Gupta RK, ''et al'' |title=Diffusion-Tensor MR Imaging of Cortical Lesions in Multiple Sclerosis: Initial Findings |journal=Radiology |volume= |issue= |pages= |year=2008 |pmid=18195384 |doi=10.1148/radiol.2463070486}}</ref>. NAWM shows a decreased [[perfusion]] which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread [[astrocyte]] dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces<ref>{{cite journal |author=De Keyser J, Steen C, Mostert JP, Koch MW. |title=Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance |journal= |volume= |issue= |pages= |year=2008 |pmid=18594554 |doi=}}</ref>. Finally, it has been stablished that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at [[Thr97]] than normal individuals<ref>{{cite journal |author=Tait AR, Straus SK. |title=Phosphorylation of U24 from Human Herpes Virus type 6 (HHV-6) and its potential role in mimicking myelin basic protein (MBP) in multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |pmid=18616943 |doi=}}</ref>. ===Neural and axonal damage=== The axons of the neurons are damaged probably by B-Cells<ref>Cause of nerve fiber damage in multiple sclerosis identified [http://www.physorg.com/news80230112.html]</ref>, though currently no relationship has been established with the relapses or the attacks<ref>{{cite journal |author=Pascual AM, Martínez-Bisbal MC, Boscá I, ''et al'' |title=Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis |journal=Neurology |volume=69 |issue=1 |pages=63–7 |year=2007 |pmid=17606882 |doi=10.1212/01.wnl.0000265054.08610.12}}</ref>. A relationship between neural damage and [[N-acetylaspartate|N-Acetyl-Aspartate]] concentration has been established, and this could lead to new methods for early MS diagnostic through [[magnetic resonance spectroscopy]]<ref>Neuer Diagnose-Ansatz zur Früherkennung von MS [http://www1.uni-bonn.de/pressDB/jsp/pressemitteilungsdetails.jsp?detailjahr=2007&detail=365]</ref> Axonal degeneration at CNS can be estimated by [[N-acetylaspartate]] to [[creatine]] (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy<ref>{{cite journal |author=Mostert JP, Blaauw Y, Koch MW, Kuiper AJ, Hoogduin JM, De Keyser J |title=Reproducibility over a 1-month period of (1)H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients |journal=Eur Radiol |volume= |issue= |pages= |year=2008 |pmid=18389250 |doi=10.1007/s00330-008-0925-x}}</ref>. ==Blood and CSF abnormalities== Since long time ago it is known that [[glutamate]] is present at higher levels in CSF during relapses<ref>{{cite journal |author=Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. |title=Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid. |journal=Arch. Immunol. |year=2003 |pmid=12925363}}</ref> 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<ref>{{cite journal |author=Stoop MP, Dekker LJ, Titulaer MK, ''et al'' |title=Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry |journal=Proteomics |volume= |issue= |pages= |year=2008 |pmid=18351689 |doi=10.1002/pmic.200700446}}</ref>. Also [[Fibroblast growth factor]]-2 appear higher at CSF<ref>{{cite journal |author={{cite journal |author=Stoop MP, Dekker LJ, Titulaer MK, ''et al'' |title=Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry |journal=Proteomics |volume= |issue= |pages= |year=2008 |pmid=18351689 |doi=10.1002/pmic.200700446}} |title=Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients |journal=Neurosci Lett. |volume= |issue= |pages= |year=2008 |pmid=18353554 |doi=10.1002/pmic.200700446}}</ref>. Blood serum also shows abnormalities. [[Creatine]] and [[Uric acid]] levels are lower than normal, at least in women<ref>{{cite journal |author=Kanabrocki EL, Ryan MD, Hermida RC, ''et al'' |title=Uric acid and renal function in multiple sclerosis |journal=Clin Ter |volume=159 |issue=1 |pages=35–40 |year=2008 |pmid=18399261 |doi=}}</ref>. Ex vivo CD4(+) T cells isolated from the circulation show a wrong [[TIM]]-3 (Immunoregulation) behavior<ref>{{cite journal |author=Yang L, Anderson DE, Kuchroo J, Hafler DA |title=Lack of TIM-3 Immunoregulation in Multiple Sclerosis |journal=J. Immunol. |volume=180 |issue=7 |pages=4409–4414 |year=2008 |pmid=18354161 |doi=}}</ref>, and relapses are associated with [[Cytotoxic T cell|CD8(+) T Cells]]<ref>{{cite journal |author=Malmeström C, Lycke J, Haghighi S, Andersen O, Carlsson L, Wadenvik H, Olsson B. |title=Relapses in multiple sclerosis are associated with increased CD8(+) T-cell mediated cytotoxicity in CSF |journal=J Neuroimmunol. |volume= |issue=Apr.5 |pages=35–40 |year=2008 |pmid=18396337 |doi=}}</ref>. [[Platelet]]s are known to have abnormal high levels<ref>{{cite journal |author=Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A. |title=Evidence of platelet activation in multiple sclerosis |journal=J Neuroinflammation |volume= |issue= |pages= |year=2008 |pmid=18588683 |doi=}}</ref>. MS patients are also known to be [[CD46]] defective, and this leads to [[Interleukin 10]] deficiency, being this involved in the inflammatory reactions<ref>{{cite journal |author=Astier AL |title=T-cell regulation by CD46 and its relevance in multiple sclerosis |journal=Immunology |volume= |issue= |pages= |year=2008 |pmid=18384356 |doi=10.1111/j.1365-2567.2008.02821.x}}</ref>. 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<ref>{{cite journal |author=Kanabrocki EL, Ryan MD, Lathers D, Achille N, Young MR, Cauteren JV, Foley S, Johnson MC, Friedman NC, Siegel G, Nemchausky BA. |title=Circadian distribution of serum cytokines in multiple sclerosis |journal=Clin. Ter. |volume= |issue= |pages= |year=2007 |pmid=17566518 |doi=}}</ref>. [[Varicella-zoster virus]] remains have been found in CSF of patients during relapses, but this particles are virtually absent during remissions<ref>{{cite journal |author=Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B. |title=Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis |journal=Ann Neurol. |volume= |issue= |pages= |year=2008 |pmid=18306233 |doi=}}</ref>. Plasma Cells in the cerebrospinal fluid of MS patients could also be to blame, because they have been found to produce myelin-specific antibodies<ref>{{cite journal |author=von Büdingen HC, Harrer MD, Kuenzle S, Meier M, Goebels N. |title=Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies |journal= |volume= |issue= |pages= |year=2008 |pmid=18521957 |doi=}}</ref>. Finally, [[B cells]] in CSF appear, and they correlate with early brain inflammation<ref>{{cite journal |author=Kuenz B, Lutterotti A, Ehling R, Gneiss C, Haemmerle M, Rainer C, Deisenhammer F, Schocke M, Berger T, Reindl M. |title=Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |pmid=18596942 |doi=}}</ref>. ==Heterogeneity of the disease== ===Demyelination patterns=== Also known as '''Lassmann patterns'''<ref>Devic’s disease: bridging the gap between laboratory and clinic, Ralf Gold, Christopher Linington, Brain, Vol. 125, No. 7, 1425-1427, July 2002 [http://brain.oxfordjournals.org/cgi/content/full/125/7/1425]</ref>, 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 [http://www.neurologyreviews.com/aug02/nr_aug02_mslesion.html]: ; Pattern I : The scar presents [[T-cells]] and [[macrophages]] around blood vessels, with preservation of [[oligodendrocyte]]s, but no signs of [[complement system]] activation.<ref>{{cite web| url=http://immserv1.path.cam.ac.uk/~immuno/part1/lec10/lec10_97.html| title=Part 1B Pathology: Lecture 11 - The Complement System| accessdate=2006-05-10| first=Nick| last=Holmes| date=[[15 November]] [[2001]]}}</ref> ; 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.<ref>{{cite journal| url=http://brain.oxfordjournals.org/cgi/content/abstract/122/12/2279| journal=Brain| volume=122| issue=12| pages=2279–2295| month=December| year=1999| title=A quantitative analysis of oligodendrocytes in multiple sclerosis lesions - A study of 113 cases| first=Claudia| last=Lucchinetti| coauthors=Wolfgang Brück, Joseph Parisi, Bernd Scheithauer, Moses Rodriguez and Hans Lassmann| accessdate=2006-05-10| doi=10.1093/brain/122.12.2279}}</ref> ; Pattern III : The scars are diffuse with inflammation, distal [[oligodendrogliopathy]] and [[microglia]]l 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<ref>{{cite journal |author=Breij EC, Brink BP, Veerhuis R, ''et al'' |title=Homogeneity of active demyelinating lesions in established multiple sclerosis |journal=Ann Neurol |volume=63 |issue=1 |pages=16–25 |year=2008 |pmid=18232012 |doi=10.1002/ana.21311}}</ref>. Recently some lesions have shown [[mitocondria]]l defects and this could also be a difference between types of lesions<ref>{{cite journal |author=Mahad D, Ziabreva I, Lassmann H, Turnbull D. |title=Mitochondrial defects in acute multiple sclerosis lesions |journal= |volume= |issue= |pages= |year=2008 |pmid=18515320 |doi=}}</ref> === 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 <ref>Primary progressive multiple sclerosis [http://brain.oxfordjournals.org/cgi/content/full/125/12/2784]</ref> and nobody with RRMS was found with this pattern. [[Balo concentric sclerosis]] lesions have been classified as pattern III (distal oligodendrogliopathy)<ref>(Article in Spanish) Estudio longitudinal mediante imagen de resonancia magnética (RM) del efecto de la azatioprina[http://www.fedem.org/revista/n13/actualidad.html]</ref>. [[Neuromyelitis optica]] was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions<ref>The Mystery of the Multiple Sclerosis Lesion, Frontiers Beyond the Decade of the Brain, Medscape [http://209.85.135.104/search?q=cache:xLNFPncN2OkJ:doctor.medscape.com/viewarticle/433621+the+lesion+project+neuromyelitis+optica&hl=es&gl=es&ct=clnk&cd=7&client=firefox-a]</ref>. === 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 [http://www.admin.ox.ac.uk/po/news/2006-07/sep/24.shtml] 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. === Correlation with CSF findings === Teams in Oxford and Germany, [http://brain.oxfordjournals.org/cgi/content/abstract/124/11/2169] [PMID 11673319] found correlation with CSF and progression in November 2001, and hypothesis have been made suggesting correlation between CSF findings and pathophysiological patterns<ref>Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11673319&query_hl=8&itool=pubmed_docsum]</ref>. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found <ref>MOG antibodies in pathologically proven multiple sclerosis [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17294606&query_hl=13&itool=pubmed_docsum]</ref>, though this is disputed<ref>Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis, Belogurov AA Jr, Kurkova IN, Friboulet A, Thomas D, Misikov VK, Zakharova MY, Suchkov SV, Kotov SV, Alehin AI, Avalle B, Souslova EA, Morse HC 3rd, Gabibov AG, Ponomarenko NA [http://www.ncbi.nlm.nih.gov/pubmed/18178866?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]</ref>. High levels of [[Anti-nuclear antibody|anti-nuclear antibodies]] are found normally in patients with MS. Antibodies against [[Neurofascin]]–186 could be involved in a subtype of MS <ref>Early research into a treatment for progressive MS [http://www.mssociety.org.uk/news_events/news/research/linington_resear.html]</ref> ===Response to therapy=== It is known that 30% of MS patients are non-responsive to Beta interferon<ref>HLA class II and response to interferon-beta in multiple sclerosis. [http://www.ncbi.nlm.nih.gov/pubmed/16281922?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum]</ref>. The heterogeneous response to therapy can support the idea of hetherogeneous [[aetiology]]. It has also been shown that IFN receptors and [[interleukin]]s in blood serum predicts response to IFN therapy<ref>Pharmacogenomics of Interferon-ss Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients, van Baarsen LG, Vosslamber S, Tijssen M, Baggen JM, van der Voort LF, Killestein J, van der Pouw Kraan TC, Polman CH, Verweij CL. PLoS ONE. 2008 Apr 2 [PMID 18382694]</ref><ref>{{cite journal |author=Wiesemann E, Deb M, Hemmer B, Radeke HH, Windhagen A. |title=Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis |journal= |volume= |issue= |pages= |year=2008 |month= |pmid=18539537 |doi= |url=}}</ref>. Besides: * Pattern II lesions patients are responsive to [[plasmapheresis]], while others are not [http://www.neurologyreviews.com/mar00/nr_mar00_MSpatients.html] [http://www.nationalmssociety.org/Research-2005Aug19.asp][http://www.medicalnewstoday.com/medicalnews.php?newsid=29100]. * 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 [http://www.msworld.org/Resource_Center/news/n03switch.htm][http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17956447&ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] * In general, people non-responsive to a treatment is more responsive to other <ref>{{cite journal |author=Carrá A, Onaha P, Luetic G, ''et al'' |title=Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina |journal=Eur. J. Neurol. |volume=15 |issue=4 |pages=386–93 |year=2008 |pmid=18353125 |doi=10.1111/j.1468-1331.2008.02071.x}}</ref> * 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<ref>{{cite journal |author=Vandenbroeck K, Matute C |title=Pharmacogenomics of the response to IFN-beta in multiple sclerosis: ramifications from the first genome-wide screen |journal=Pharmacogenomics |volume=9 |issue=5 |pages=639–45 |year=2008 |month=May |pmid=18466107 |doi=10.2217/14622416.9.5.639 |url=}}</ref> === 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<ref>{{cite journal |author=Satoh J. |title=Molecular biomarkers for prediction of multiple sclerosis relapse |journal=Nippon Rinsho |volume= |issue= |pages= |year=2008 |month= |pmid=18540355 |doi= |url=}}</ref>. ===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 [[Devic's disease|neuromyelitis optica]] have shown that varieties previously suspected different from MS are in fact different diseases. In [[Devic's disease|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 <ref>The IgG autoantibody links to the aquaporin 4 channel [http://www.jem.org/cgi/content/abstract/202/4/473]</ref>. 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. ==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.<ref>{{cite web| url=http://www.mult-sclerosis.org/experimentalautoimmuneencephalomyelitis.html| title=Experimental Autoimmune Encephalomyelitis| year=08/13/2003| publisher=All About Multiple Sclerosis| accessdate=2006-05-10}}</ref> 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.<ref>Lucchinetti, C. Bruck, W. Parisi, J. Scherhauer, B. Rodriguez, M. Lassmann, H.''Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination'' Ann Neurol, 2000; 47(6):707-17. PMID 10852536</ref> ==See also== *[[Multiple sclerosis]] *[[Multiple sclerosis borderline]] ==References== {{reflist|2}} ==External links== *[http://www.nationalmssociety.org/Research-TargetedLesion.asp The lesion project page] *[http://www.thisisms.com Multiple sclerosis news] *[http://msnews.acceleratedcure.org MS News at Accelerated Cure Project] {{Multiple sclerosis}} [[Category:Neurology]] [[Category:Multiple sclerosis]] [[Category:Autoimmune diseases|Lesion Project]]