MS Symptoms + Diagnosis + etiology + pathogenesis

Oligodendrocyte forming ? in the CNS

Electron micrograph showing oligodendrocyte (OL) in the spinal cord, which has myelinated two axons (A1, A2). ×6,600. The inset shows axon A1 and its myelin sheath at higher magnification. The myelin is a spiral of oligodendrocyte membrane that surrounds the axon. Most of the oligodendrocyte cytoplasm is extruded from the myelin. Because the myelin is compact, it has a high electrical resistance and low capacitance so that it can function as an insulator around the axon. ×16,000.

Conduction in unmyelinated vs. myelinated axons

Nerve action potential. The upstroke of the action potential results from increased Na+ conductance. Repolarization results from a declining Na+ conductance combined with an increasing K+ conductance; afterhyperpolarization is due to sustained high K+ conductance. B. Action potential propagation. Local current flow causes the threshold potential to be exceeded in adjacent areas of the neuron membrane. Because the upstream region is refractory, an action potential is only propagated downstream. In myelinated axons, action potentials propagate faster by "jumping" from one node of Ranvier to the next node by saltatory conduction. ARP, absolute refractory period; RR

Nodes of Ranvier (arrows) are between?

Neurons and glia in the CNS. A typical neuron has a cell body (or soma) that receives the synaptic responses from the dendritic tree. These synaptic responses are integrated at the axon initial segment, which has a high concentration of voltage-gated sodium channels. If an action potential is initiated, it propagates down the axon to the synaptic terminals, which contact other neurons. The axon of long-range projection neurons are insulated by a myelin sheath derived from specialized membrane processes of oligodendrocytes, analogous to the Schwann cells in the peripheral nervous system. Astrocytes perform supportive roles in the CNS, and their processes are closely associated with neuronal synapses.

Immunological genes associated with MS

*Disease-associated genes are tentatively stratified into three functional groups: immunological, neuronal and other or unknown function. This stratification has its limitations, as some genes have many functions or are expressed by multiple cell types, and for most it remains to be proven that they are involved in disease pathogenesis by exclusively affecting a certain pathway. ACCN1; amiloride-sensitive cation channel 1, neuronal; ALK, anaplastic lymphoma kinase; ANKRD15; ankyrin-repeat domain 15; CLEC16A, C-type lectin domain family 16, member A; DBC1, deleted in bladder cancer 1; EVI5, ecotropic viral integration site 5; FAM69A, family with sequence similarity 69, member A; IL2RA, interleukin-2 receptor -chain; KIF1B, kinesin family member 1B; LFA3, lymphocyte function-associated antigen 3; ND, not determined; PDE4B, phosphodiesterase 4B, cAMP specific; RPL5, ribosomal protein L5; SNP, single nucleotide polymorphism; TYK2, tyrosine kinase 2.

Central and peripheral N cell tolerance

A. Central B-cell tolerance: As T cells do in the thymus, B cells rearrange their B-cell receptor (BCR) in the bone marrow. Unproductive rearrangements drive pre-B cells to apoptosis. Functional rearrangements allow expansion and expression of IgM. Next, similar to T-cell clonal deletion, immature B cells that strongly bind self antigens in the bone marrow are eliminated by apoptosis. Some autoreactive immature B cells, instead of becoming apoptotic, however, resume rearrangements of their L-chain genes, attempting to reassemble new allelic κ or λ genes (BCR editing). Soluble self antigens presumably generate weaker signals through the BCR of immature B cells; they do not cause apoptosis but make cells unresponsive to stimuli (anergy). These anergic B cells migrate to the periphery, expressing IgD, and may be activated under special circumstances. Only immature B cells with no avidity for antigens become mature B cells, expressing both IgM and IgD. These are the predominant cells that make it to the periphery. B. Peripheral B-cell tolerance: In the "absence" of antigen (top right), mature B cells are actively eliminated by activated T cells via Fas-FasL and CD40-CD154 interactions. In the "presence" of specific self antigen but "without T-cell help," antigen recognition by BCRs induces apoptosis or anergy on mature B cells. If self antigen and specific autoreactive T-cell help are provided, two events develop (center): (1) The B cell becomes an IgM-secreting plasma cell (top left), and, in the presence of the appropriate cytokines after expression of CD40 (for TH cell CD154 interaction), class switching occurs (bottom left). (2) Further somatic hypermutation of the Ig-variable region genes, which changes affinity of BCRs, occurs. Mutants with low-affinity receptors undergo apoptosis, while improved-affinity BCRs are positively selected. In the presence of CD40 ligation of CD154, antigen-stimulated B cells become memory B cells. These two events are the same as in foreign antigen recognition.

Central and peripheral T cell tolerance

A. Central T-cell tolerance: Mechanisms of central tolerance (at the thymus level) are depicted. From top to bottom, pre-T cells first rearrange their TCR. Unproductive (nonfunctional) rearrangements lead to apoptosis, while productive ones engage pre-T cells in self-antigen recognition. Clonal deletion indicates elimination of cells based on their high or no avidity for self antigen (apoptosis). Surviving low-avidity cells reach the periphery as mature CD4 and CD8 cells. B. Peripheral T-cell tolerance: May be accomplished through any of the five depicted mechanisms. 1. Clonal deletion: After encountering self antigen in the context of self-MHC molecules and simultaneous delivery of a second signal (CD80/86-CD28) by APCs (top left), autoreactive T cells become activated. These activated T cells express Fas molecules on their surface but are resistant to Fas ligand (FasL)-mediated apoptosis because of the simultaneous expression of Bcl-xL (not shown) induced by CD28 ligation during activation. Several days after activation, when Bcl-xL presence has declined, CD4 cells become susceptible to FasL-mediated apoptosis. Natural killer cells (NK-T) may then accomplish the task of eliminating these autoreactive T cells. 2. Anergy: Anergy may be induced via CD80/86-CD152 interaction 48 to 72 hours following activation or may result from the lack of a second costimulatory signal from APCs presenting self antigen (nonprofessional APCs). 3. Active suppression: Active suppression is thought to occur when nonhematopoietic cells (stimulated by IFN-γ) present antigen in an MHC class II-restricted fashion to CD4 T-suppressor cells (TS, also known as CD4 + CD25 + FOXP3 + T regs). Before becoming unresponsive, these cells may induce specific CD8 TS cells. In turn, these CD8 TS cells may suppress antigen-specific autoreactive T cells. 4. Ignorance (top right): Some autoreactive T cells may never encounter self antigen because it may be sequestered from the immune system. Although they may persist in the circulation, they never become activated. 5. Immune deviation: Under specific circumstances, noninflammatory TH2 responses could suppress inflammatory (autoreactive) TH1 responses (see text).

Saltatory conduction is disrupted following ?

A: Saltatory conduction in a myelinated axon. The myelin functions as an insulator because of its high resistance and low capacitance. Thus, when the action potential (cross-hatching) is at a given node of Ranvier, the majority of the electrical current is shunted to the next node (along the pathway shown by the broken arrow). Conduction of the action potential proceeds in a discontinuous manner, jumping from node to node with a high conduction velocity. B: In demyelinated axons there is loss of current through the damaged myelin. As a result, it either takes longer to reach threshold and conduction velocity is reduced, or threshold is not reached and the action potential fails to propagate.

Demyelination at 3 can result in ?

A: Section through the medulla, stained for myelin, from a patient with multiple sclerosis. Notice the multiple demyelinated plaques (labeled 1-4) that are disseminated throughout the central nervous system (CNS). B: Even a single lesion can interfere with function in multiple neighboring parts of the CNS. Notice that plaque 3 involves the hypoglossal root (producing weakness of the tongue) and the medial lemnisci (causing an impairment of vibratory and touch-pressure sense). Figure 7-7B shows, for comparison, a diagram of the normal medulla at this level.

Activation of T cells

Activation and roles of T lymphocytes in the pathogenesis of MS and EAE 1. In contrast to most organs, the brain and spinal cord do not contain defined lymphatic channels; nevertheless, lymphatic drainage for the CSF and the interstitial fluid of the brain parenchyma to the cervical lymph nodes does take place (Laman and Weller 2013). Soluble CNS antigens and professional APCs, such as dendritic cells, that have engulfed myelin or neuronal antigens can travel from the CNS to the cervical lymph nodes (CLN) (Mohammad et al. 2014). 2. Mature APCs that have engulfed myelin or neuronal antigens are detected in cervical lymph nodes obtained from MS patients and EAE animals (Laman and Weller 2013). These APCs can efficiently activate CNS-reactive CD4 and CD8 T lymphocytes. Different regulatory T lymphocyte subsets have been shown to reduce the development and severity of EAE (Kleinewietfeld and Hafler 2014; Sinha et al. 2014). Several groups reported that regulatory T cell subsets from MS patients have impaired regulatory functions compared to healthy donors (Kleinewietfeld and Hafler 2014; Sinha et al. 2014). 3. Activated myelin or neuronal-specific T lymphocytes exit into the peripheral blood to perform immunosurveillance. CNS reactive CD4 and CD8 T lymphocytes obtained from the peripheral blood of MS patients exhibit enhanced activation properties compared to those from health donors. 4. Activated autoreactive T lymphocytes have an enhanced capacity to cross the BBB given their elevated expression of mediators such as chemokine receptors, adhesion molecules, integrins, and cytokines (Goverman 2009; Larochelle et al. 2011). 5. Once in the CNS, T lymphocytes can be reactivated by local APCs (macrophages, microglia and dendritic cells, or B lymphocytes), which are present in human and mouse CNS lesions (Greter et al. 2005; Frohman et al. 2006; Pierson et al. 2014). This antigen-specific reactivation has been shown to be essential to license activated autoreactive T lymphocytes to enter the CNS parenchyma (Bartholomaus et al. 2009). 6. CNS infiltrating Th1, Th17, and CD8 T lymphocytes, and macrophages as well as inflamed microglia secrete soluble mediators (e.g., inflammatory cytokines, free radical, etc.). Moreover, cross-talk between T cells and microglia/macrophages contribute to perpetuate the inflammatory milieu within the CNS. 7. These soluble mediators can injure oligodendrocyte/myelin and axon/neuron structures. Moreover, activated microglia/macrophages can directly phagocyte oligodendrocytes. Similarly, CD8 T lymphocytes have been detected in close proximity to oligodendrocytes and demyelinated axons with polarization of their cytolytic granules (Neumann et al. 2002; Wulff et al. 2003; Lassmann 2004; Saikali et al. 2007). Activated T cells have the capacity to kill oligodendrocytes or neurons (Jurewicz et al. 1998; Sauer et al. 2013; Zaguia et al. 2013). Finally, such damage causes the release of additional CNS antigens that can be further phagocytosed and presented to new waves of CNS-specific T lymphocytes

Treatments for MS

Article available. Schematic representation of multiple sclerosis (MS) pathophysiology indicating points of treatment intervention. APC antigen presenting cell; BBB blood brain barrier; C5b-9 complement complex 5b-9; CNS central nervous system; DHODH dihydroorotate dehydrogenase; FasL Fas ligand; GA glatiramer acetate; IFN interferon; IL2R interleukin 2 receptor; MHC I major histocompatibility complex I; NO nitrous oxide; Nrf2 nuclear factor (erythrocyte derived) related factor 2; S-1-P1 sphingosine-1-phosphate 1; TCR T cell receptor; VCAM-1 vascular cell adhesion molecule 1; VLA-4 very late antigen 4.

More severe meningeal and perivascular inflammation results in ? in PPMS patients

Clinicopathological comparisons revealed that a more severe clinical course was associated with greater inflammation at death in primary progressive multiple sclerosis. (A) Kaplan-Meier survival curves of age at death plotted against inflammatory rating (mild 0+, moderate +, substantial ++) revealed that cases rated as ++ for meningeal and perivascular inflammation had a younger age at death, in comparison with cases rated 0+ [mean age ± SEM (years): ++ = 51.8 ± 3.8, + = 63.8 ± 4.9, 0 = 71.1 ± 3.4; one-way ANOVA P < 0.05 for ++ versus 0+]. (B) Cases characterized by substantial (++) meningeal/perivascular inflammation had a significantly reduced mean disease length in comparison to cases rated as mild (0+) (mean duration ± SEM ++ = 14.6 ± 3.0, + = 24.8 ± 2.4, 0+ = 32.7 ± 4.0; one-way ANOVA P < 0.01 for ++ versus 0+).

Disease modifying therapies are effective for relapsing remitting MS but generally are not effective for progressive forms of disease

Disease-modifying therapies in development target the pathology underlying the stage of multiple sclerosis (MS). Clinical course is indicated by the black line with stepwise increases in disability in early disease caused by relapses and, later, by gradual progression of disability in secondary progressive MS (SPMS) and from disease onset in primary progressive MS (PPMS). Anti-inflammatory therapies are effective in relapsing-remitting MS and SPMS when relapses are still present. Neuroprotective therapies target neurodegeneration in SPMS without relapses and PPMS.

Mitochondrial Changes

Electron transport chain gene expression is decreased in parietal and frontal cortex in MS. Changes in transcript expression were determined by RT-PCR for the Complex I NADH dehydrogenase ubiquinone Fe-S protein 4 (NDUFS4) gene, the Complex III genes, lowmolecularmass ubiquinone binding protein (QP-C) and ubiquinol-cytochrome c reductase core protein II (UQCRC2), the Complex IV genes, cytochrome c oxidase assembly protein (COX11) and cytochrome c oxidase subunit Va (COX5A), the Complex V genes, ATP synthase H+ transporting subunit c (ATP5G3) and ATP synthase,H+ transporting,mitochondrial F0 complex, subunit B1 (ATP5F1), and for the cytochrome c gene. Data are the average % decrease for message isolated fromthreeMS compared to three control samples for parietal cortex and twoMS compared to two control samples for frontal cortex. Expressionwas standardizedwith levels of expression obtained with 18S RNA primers. Levels of mRNA from MS samples are expressed as % control. Error bars represent SEM and are from three separate experiments. ⁎pb0.05.

Cortical Lesion in MS

Fluid-attenuated inversion-recovery scan (left) demonstrating a hyperintense lesion (arrow) that is confirmed on the co-registered modified driven equilibrium Fourier transform scan (right) to show hypointensity (arrow) and involve the cerebral cortex. This is from a patient with relapsing-remitting MS (29-year-old woman, disease duration = 11 years, Expanded Disability Status Scale score = 2). Fluid-attenuated inversion-recovery scan (left) demonstrating a hyperintense lesion (arrow) that is confirmed on the co-registered modified driven equilibrium Fourier transform scan (right) to show hypointensity (arrow) and involve the cerebral cortex. This is from a patient with relapsing-remitting MS (29-year-old woman, disease duration = 11 years, Expanded Disability Status Scale score = 2).

Remyelination

Following demyelination in the CNS, a demyelinated axon has two possible fates. The normal response to demyelination, at least in most experimental models, is spontaneous remyelination involving the generation of new oligodendrocytes. The myelin sheaths that are generated in remyelination are typically thinner and shorter than those that are generated during developmental myelination. Nevertheless, they are associated with recovery of function. In some circumstances, however, and notably in multiple sclerosis, remyelination fails, leaving the axons and even the entire neuron vulnerable to degeneration that largely accounts for the progressive clinical decline that is associated with demyelinating diseases. For this reason, therapies that increase the chances of the regenerative outcome of demyelination are keenly sought. b | A well-established and effective means of identifying remyelination is to embed well-fixed tissue in resin and examine semi-thin sections by light microscopy. The images in this series are transverse sections from the adult rat cerebellar white matter, showing normally myelinated axons of various diameters in the left-hand panel, demyelinated axons (plus debris-filled macrophages) following injection of ethidium bromide in the middle panel and remyelinated axons with typically thin myelin sheaths four weeks after the induction of remyelination in the right-hand panel.

MS pathogenesis: Periphery

From: Rocio S. Lopez-Diego & Howard L. Weiner Power point slide available. Nature Reviews Drug Discovery 7, 909-925 (November 2008) Immature dendritic cells are central players in innate immune responses and are involved in the maintenance of peripheral tolerance by means of promotion of suppressor regulatory T cell and anti-inflammatory T helper 2 (TH2) cell responses. Abnormally activated (mature) antigen-presenting dendritic cells can be found in patients with multiple sclerosis (MS). This activation results in increased production of pro-inflammatory cytokines that lead to aberrant activation of TH1 and TH17 pro-inflammatory responses. Activated encephalitogenic adaptive immune effectors (such as TH1 cells, TH17 cells, CD8+ cells and B cells) express surface molecules that allow them to penetrate the blood-brain barrier and to enter the central nervous system (CNS). The presence of autoreactive immune effectors, together with abnormally activated CNS astrocytes and microglia, lead to increased production of reactive species, excitotoxicity, autoantibody production and direct cytotoxicity, which are all involved in demyelination, axonal and neuronal damage that is present in patients with MS. Potential therapeutic interventions at different levels of the immunopathological cascade are depicted in filled yellow boxes. CTL, cytotoxic T lymphocyte; IFN-, interferon-; IL, interleukin; IL2R, IL2 receptor; MHC II, major histocompatibility complex class II; MMPs, matrix metalloproteinases; NO, nitric oxide; ODG, oligodendrocyte; S1PR, sphingosine 1-phosphate receptor; TGF-, transforming growth factor-; TNF, tumour-necrosis factor; TReg cell, regulatory T cell; VCAM1, vascular cellular adhesion molecule 1; VLA4, very late antigen 4 (also known as 41 integrin).

Gray matter lesions molecular

Gray matter lesions in multiple sclerosis. Meningeal infiltrates are characterized by the presence of lymphocytes intermingled with stromal cells and macrophages. The core of these lymphoid organs consists of B cells whose maturation process is supported by FDCs, while the cortex of the tertiary lymphoid organ consists of T cells and macrophages. Meningeal infiltrates (especially in deep cortical sulci) are associated with extensive microglia activation in the underlying cortex and gray matter damage. The most likely justification for the association of microglial activation in the cortex and meningeal inflammation is a soluble factor produced within the meningeal inflammatory infiltrate and accumulated in the cerebrospinal fluid. Abbreviations: FDCs: follicular dendritic cells.

Immune mediated demyelination and associated axonal transection

Immune-mediated demyelination and axonal transectionAxonal ovoids are hallmark of transected axons. Abundant axonal ovoids were detected in MS tissue (a) when stained for myelin protein (red) and axons (green). There are areas of demyelination (arrowheads), mediated by microglia and hematogenous monocytes. One of the axons ends in a large swelling (arrow) or axonal retraction bulb (arrow). (b-c) Schematic of axonal response during and following transection. Demyelination is an immune-mediated or immune cell assisted process leading to axonal transaction. When transected, the distal end of the axon rapidly degenerates while the proximal end connected to the neuronal cell body survives and transported organelles accumulate at the transection site and form an ovoid (arrows). (Reproduced from(Trapp and Nave, 2008)

Perivascular inflammation: T and B cells

Meningeal and perivascular inflammation in primary progressive multiple sclerosis. Haematoxylin and eosin stained sections (14 blocks per case) were examined and the maximum degree of meningeal (A) and white matter perivascular (B) inflammation was used to determine the inflammatory rating of the case as mild (0+), moderate (+) or severe (++). Cases classified as containing at least a single example of ++ rated meningeal or perivascular inflammation were further sampled as these were the most likely to harbour significant immune cell aggregates and lymphoid-like structures. Double immunostaining for CD3-positive (blue) T cells and CD20-positive (brown) B cells (C and D) was used to screen for the presence of immune cell aggregates. A dense aggregate of CD3-positive T cells partially separated from an aggregate of CD20-positive B cells is shown in the meninges (C) together with a large mixed perivascular infiltrate of T and B cells in the white matter

White matter plaques (loss of myelin)

Multiple sclerosis. A, This section of the brain contains several opaque vaguely gelatinous areas in the white matter, which represent areas of demyelination, also known as plaques (arrows). As in the two on the left side of this image, the plaques are characteristically found at the corner of the cerebral ventricles. B, In the left upper corner of this image is gray matter. The purple band immediately adjacent to it is normally staining white matter. The remainder of the image (right lower half of photomicrograph) is white matter, which is poorly stained due to the loss of myelin. This image is a photomicrograph of an inactive plaque. Luxol-fast blue, 40×.

What does myelin do?

Myelin is the multilayered compacted cell membrane wrapped around axons by glial cells to form electrical insulation that speeds conduction of nerve impulses. (a) In the brain, myelin is wrapped around axons by oligodendrocytes, which have 20 or more cellular processes to insulate multiple axons. (b) An oligodendrocyte (green) is shown at the initial stage of wrapping myelin membrane around several axons (red), in cell cultures equipped with electrodes to stimulate axons for investigations of the role of impulse activity in regulating myelination [87]. (c) An electron micrograph of an axon from the corpus callosum of rat brain is shown in cross-section to reveal the multiple layers of myelin membrane surrounding the axon. Up to 150 layers of myelin are formed on large-diameter axons. Image in (b) courtesy of Varsha Shukla, NICHD and in (c) courtesy of Andrea Nans, NYU School of Medicine. Myelin basic protein (green); neurofilament protein (red). Figure modified from Fields [1].

MS pathogenesis: CNS

Power Point slide available. From: Rocio S. Lopez-Diego & Howard L. Weiner Nature Reviews Drug Discovery 7, 909-925 (November 2008) Immature dendritic cells are central players in innate immune responses and are involved in the maintenance of peripheral tolerance by means of promotion of suppressor regulatory T cell and anti-inflammatory T helper 2 (TH2) cell responses. Abnormally activated (mature) antigen-presenting dendritic cells can be found in patients with multiple sclerosis (MS). This activation results in increased production of pro-inflammatory cytokines that lead to aberrant activation of TH1 and TH17 pro-inflammatory responses. Activated encephalitogenic adaptive immune effectors (such as TH1 cells, TH17 cells, CD8+ cells and B cells) express surface molecules that allow them to penetrate the blood-brain barrier and to enter the central nervous system (CNS). The presence of autoreactive immune effectors, together with abnormally activated CNS astrocytes and microglia, lead to increased production of reactive species, excitotoxicity, autoantibody production and direct cytotoxicity, which are all involved in demyelination, axonal and neuronal damage that is present in patients with MS. Potential therapeutic interventions at different levels of the immunopathological cascade are depicted in filled yellow boxes. CTL, cytotoxic T lymphocyte; IFN-, interferon-; IL, interleukin; IL2R, IL2 receptor; MHC II, major histocompatibility complex class II; MMPs, matrix metalloproteinases; NO, nitric oxide; ODG, oligodendrocyte; S1PR, sphingosine 1-phosphate receptor; TGF-, transforming growth factor-; TNF, tumour-necrosis factor; TReg cell, regulatory T cell; VCAM1, vascular cellular adhesion molecule 1; VLA4, very late antigen 4 (also known as 41 integrin).

Mechanisms of neuronal degeneration

PowerPoint slide available. From: Geurts and Barkhof. Lancet 2008; 7(9): 841-851 Schematic representation of disease processes currently believed to underlie grey matter damage in MSGrey matter damage could occur secondarily to white matter pathology. Several secondary disease mechanisms (blue boxes) have been proposed, including the "virtual hypoxia" theory by Stys and colleagues.115 This theory postulates that axonal degeneration in the grey matter might result from inflammatory activity in white matter lesions, combined with subsequent axonal demyelination and reorganisation of sodium channels and an inadequate mitochondrial energy supply. Moreover, glutamate excitotoxicity might aggravate neuroaxonal damage in the grey matter. [116], [117], [118], [119], [120] and [121] This degeneration of axons and neurons in grey matter might in turn lead to demyelination and the lesions visible under the microscope in grey matter areas. Alternatively, pathological processes affecting grey matter areas primarily (green boxes), without intervening effects from white matter damage, might arise as a result of meningeal inflammation and the concomitant release of a myelinotoxic substance, ultimately leading to subpial cortical demyelination.105 This might cause demyelination of axons in the grey matter, which in turn could result in neuroaxonal degeneration. Furthermore, primary cortical degeneration might occur in specific predilection sites, as is seen in dementias; for example, animal studies have shown that the cholinergic system is specifically involved in the disease. Led by functional and cortical thinning studies, consistently active brain areas (eg, default-mode networks) could be hypothesised to be specifically subject to neurodegeneration (the "use-it-and-lose-it" principle). Of note, the primary and secondary disease processes proposed do not imply sequentiality, but are instead likely to develop largely independently, with cumulative effects on grey matter damage in MS. View thumbnail images

Epitope spreading

PowerPoint slide available. From: Stephen D. Miller, Danielle M. Turley & Joseph R. Podojil. Nature Reviews Immunology 7, 665-677 (September 2007 Animal models of multiple sclerosis (MS) have helped to identify putative mechanisms by which epitope spreading occurs. In relapsing-remitting experimental autoimmune encephalomyelitis (EAE), the activation of the autoreactive CD4+ T cells that are specific for the initiating antigen epitope (CD4+ T cell depicted in green) occurs in the draining lymph node. Following activation, the effector CD4+ T cells enter the circulation and extravasate into the CNS. Once in the CNS, the autoreactive CD4+ T cells initiate myelin destruction through the activation of resident and infiltrating antigen-presenting cells (APCs). The activated infiltrating immune cells secrete cytokines and chemokines that not only recruit immune cells into the central nervous system (CNS), but also help to open the blood-brain barrier (BBB). Besides the re-activation of the CD4+ T cells that are specific for the initiating antigen, myelin antigens are released, phagocytosed, processed, and presented principally within the CNS by peripherally derived myeloid dendritic cells (DCs) to naive CD4+ T cells, both of which can enter through the compromised BBB. For example, in proteolipid protein (PLP) peptide PLP139-151-induced relapsing-remitting EAE in SJL/J mice the initiating epitope is PLP139-151, and the population of CD4+ T cells that recognize this peptide is responsible for the initial acute phase of disease. During the acute phase of disease the destruction of myelin allows for the release of both PLP and myelin basic protein (MBP). Due to antigen availability and CD4+ T-cell precursor frequency, the activation of the secondary population of CD4+ T cells specific for PLP178-191 occurs during the primary relapse (known as intramolecular epitope spreading). During the secondary relapse, CD4+ T cells specific for MBP84-104 are activated (known as intermolecular epitope spreading). TCR, T-cell receptor.

Probability maps of multiple sclerosis patients

Probability maps of multiple sclerosis patients. Probability maps of multiple sclerosis patients ( A , C and E ) and age-matched controls ( B , D and F ). The colour codes indicate the probability of finding lesions (in % of cases A and B ), the cumulative frequencies of neurons affected by retrograde neurodegeneration ( C / D ) and the cumulative frequencies of meningeal inflammatory cells ( E / F ) in a specific location of this virtual brain slice. ( A ) The probability of demyelinating lesions in the white and grey matter of multiple sclerosis patients. ( B ) The probability of leukoaraiosis in control subjects. ( C ) The cumulative number of neurons with retrograde degeneration in multiple sclerosis patients. ( E ) The accumulated number of inflammatory cells in the leptomeninges of multiple sclerosis patients. The highest incidence of demyelination ( A ) in the white matter is seen in the so-called watershed areas, which are located at the borders of the supply territories of the major cerebral arteries. In contrast, cortical lesions are mainly concentrated in invaginations of the cortical surface, such as the cortical sulci, in regions with high incidence of meningeal inflammatory infiltrates ( E ). Retrograde neurodegeneration is mainly seen in the deep cortical layers and the deep grey matter and in part follows the putative fibre projection from white matter lesions into the cortex ( C ). In age-matched controls no plaques of primary demyelination were present, but there were areas of diffuse white matter alterations (leukoaraiosis) in 43% of the cases investigated (blue areas in B ). Cortical neurodegeneration was much less pronounced compared to that seen in multiple sclerosis ( D ), but showed a topographically similar distribution compared to that seen in multiple sclerosis patients. Inflammatory infiltrates were also seen in low numbers and incidence in the meninges of the age-matched controls ( F ). Definitions of regions of interest: ( G ) venous density atlas from Grabner et al. (2014) depicts the density of veins (red) in different brain areas. Brains were scanned in a 7 T MRI and a venous map of the normal human brain was created. ( H ) Turnbull staining showing the iron distribution throughout the brain. ( I ) Our regions of interest in one hemisphere of the virtual brain map. Areas of low CSF flow are indicated by blue, watershed area in purple and the basal ganglia in pink.

Neuronal loss in gray matter lesions in PPMS

Slide available. From: Choi et al., Brain. 2012 Aug 20. [Epub ahead of print] Neuronal loss in primary progressive multiple sclerosis. Images captured from cortical layers III and V of neuronal nuclei (NeuN) and SMI32-positive double-stained sections were used to quantify the density of neurons within normal appearing and demyelinated grey matter (A). Pyramidal cells were identified by the long apical dendrite and distinct morphology (B and C) and only NeuN- and SMI32 double positive neurons with visible haematoxylin stained nuclei were counted. Neuronal densities in layers III and V in grey matter lesions were significantly reduced in comparison with controls (D and E). ANOVA and Dunns multiple comparison post-test; *P < 0.05, **P < 0.01. Scale bars: A = 100 μm, C = 25 μm. GML = grey matter lesion; NAGM = normal appearing grey matter.

Glutamate toxicity

Slide available. From: Lawrence Steinman & Scott Zamvil. Nature Reviews Immunology 2003; 3, 483-492 T cells and antigen-presenting cells (APCs) such as macrophages produce glutamate, a toxic substance, which injures oligodendroglial cells and underlying axons. The activation of T cells can be blocked by various approaches, including statins and altered peptide ligands (APLs). Statins also inhibit the secretion of metalloproteases, and it has been suggested that they might, therefore, also act to block T cells from entering the central nervous system (CNS). Antibodies specific for 4-integrin also block the movement of T cells into the brain. OPN, osteopontin.

Inflammatory mechanisms - antibodies and complement

Slide available. From: Lawrence Steinman & Scott Zamvil. Nature Reviews Immunology 2003; 3, 483-492 T cells, B cells and antigen-presenting cells (APCs), including macrophages, enter the central nervous system (CNS), where they secrete certain chemicals known as cytokines that damage the oligodendroglial cells. These cells manufacture the myelin that insulates the neuronal axon. The injured myelin cannot conduct electrical impulses normally, just as a tear in the insulation of a wire leads to a short circuit. Lymphocytes diapedese into the CNS through use of a surface receptor known as 4-integrin. This step is impeded by antibodies specific for 4-integrin or by interferon- (IFN-). Once the blood-brain barrier is breached, other inflammatory cells accumulate in the white matter. Inside the brain, T cells and accompanying macrophages and microglial cells release osteopontin (OPN), interleukin-23 (IL-23), IFN- and tumour-necrosis factor (TNF), all of which damage the myelin sheath. Also, the presence of OPN might lead to the attraction of T helper 1 (TH1) cells. T-cell activation can be blocked by altered peptide ligands (APLs), such as copaxone, or by statins. Concomitantly, B cells (plasma cells) produce myelin-specific antibodies, which interact with the terminal complex in the complement cascade to produce membrane-attack complexes that further damage oligodendroglial cells. DNA vaccination can be used to tolerize T- and B-cell responses to myelin.

MRI - white matter lesions

Slide available. MRI Images in MS (A) Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS. (B) Sagittal T2-weighted fluid attenuated inversion recovery (FLAIR) image in which the high signal of CSF has been suppressed. CSF appears dark, while areas of brain edema or demyelination appear high in signal as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease. (C) Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the mid thoracic spinal cord. (D) Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows).

Structure of myelin

The molecular architecture of the myelin sheath illustrating the most important disease-related proteins. The illustration represents a composite of central nervous system (CNS) and peripheral nervous system (PNS) myelin. Proteins restricted to CNS myelin are shown in green, proteins of PNS myelin are lavender, and proteins present in both CNS and PNS are red. In the CNS, the X-linked allelic disorders, Pelizaeus-Merzbacher disease and one variant of familial spastic paraplegia, are caused by mutations in the gene for proteolipid protein (PLP) that normally promotes extracellular compaction between adjacent myelin lamellae. The homologue of PLP in the PNS is the P0 protein, mutations in which cause the neuropathy Charcot-Marie-Tooth disease (CMT) type 1B. The most common form of CMT is the 1A subtype caused by a duplication of the PMP22 gene; deletions in PMP22 are responsible for another inherited neuropathy termed hereditary liability to pressure palsies (Chap. 459). In multiple sclerosis (MS), myelin basic protein (MBP) and the quantitatively minor CNS protein, myelin oligodendrocyte glycoprotein (MOG), are likely T cell and B cell antigens, respectively (Chap. 458). The location of MOG at the outermost lamella of the CNS myelin membrane may facilitate its targeting by autoantibodies. In the PNS, autoantibodies against myelin gangliosides are implicated in a variety of disorders, including GQ1b in the Fisher variant of Guillain-Barré syndrome, GM1 in multifocal motor neuropathy, and sulfatide constituents of myelin-associated glycoprotein (MAG) in peripheral neuropathies associated with monoclonal gammopathies (Chap. 460).

Loss of myelin(plaques)

This is a section from the forebrain of a patient who died with multiple sclerosis. The section is stained with luxol fast blue to reveal areas of myelination in the subcortical white matter. The green arrows indicate three areas from which the myelin stain is absent, representing three foci or plaques of chronic demyelination. The demyelinated axons in these lesions are vulnerable to atrophy. The red arrows indicate 'shadow plaques', in which the demyelinated axons have undergone remyelination. This section illustrates two important points: first, that remyelination can occur as a spontaneous regenerative response in the adult human brain; and second, that this process does not always occur and many lesions remain demyelinated.