Lecture 6 Multiple Sclerosis

Transcription

1 Lecture 6 Multiple Sclerosis David Saffen, Ph.D. Professor/Senior Principal Investigator Institute of Brain Science Fudan University, Shanghai, China saffen@fudan.edu.cn

2 Multiple sclerosis (MS): pathogenesis and symptoms MS is a neuroinflammatory disease that damages myelin sheaths and axons of neurons in the central nervous system. Disease onset usually occurs in young adults, with more women affected than men (1.6 to 1). Symptoms, which include weakness, altered sensation, ataxia and loss of vision, are often variable and may be remitting and/or progressive in nature. Disability increases over time. There does not seem to be a unique cause. Rather, MS develops in genetically susceptible individuals in response to environmental exposures. The worldwide prevalence of MS is 1-150/100,000, with especially high prevalence in Northern Europe and low prevalence in Africa and East Asia, including Japan, Korea and China. Worldwide > 2.5 M individuals are affected by MS.

3 Jean-Martin Charcot ( ) Sclérose en Plaques disséminée lecture presented by Charcot and Vulpian on May 9, 1866 Presented three lectures on disseminated sclerosis (1868), describing: 1) Spinal, cephalic and bulbar forms 2) Charcot triad: of symptoms: intention tremor, nystagmus, scanning speech 3) Loss of CNS myelin, thickening of small blood vessels, fatty macrophages around vessels removing myelin residue, gliosis scar and damaged axons

4 Faces of multiple sclerosis Jacqueline du Pre ( ) Richard Prior Joan Didion b1934

5 MS damages the myelin sheaths of CNS neurons

6 Magnetic resonance imaging of MS scarring in brain MRI of the head of a 35-year-old man with relapsing remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation Lee AG, et al (2010): /article/ print/

7 MS prodrome and diagnostic categories Radiologically isolated syndrome (RIS) Clinically isolated syndrome (CIS) Relapsing-remitting MS (RRMS) Secondary progressive MS (SPMS) Primary progressive MS (PPMS) Progressive-relapsing MS (PRMS) Atypical MS RIS (20 years) 85% CIS 30% (median 5 years) rare RRMS SPMS 65% PPMS 10-15% PRMS rare Atypical MS Devic s disease Balo concentric sclerosis Schilder s diffuse sclerosis Marburg MS

8 Signs and Symptoms Changes in sensation, including loss of sensitivity or tingling, pricking or numbness (hypoesthesia and paraesthesia), muscle weakness, clonus, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis including phosphenes or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common. Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, exacerbations, bouts, attacks, or "flare-ups"), in a gradually progressive deterioration of neurologic function, or in a combination of both. Multiple sclerosis relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate rarely above one and a half per year. Some attacks, however, are preceded by common triggers. Relapses occur more frequently during spring and summer. Viral infections such as the common cold, influenza, or gastroenteritis increase the risk of relapse. Stress may also trigger an attack.

9 Histopathology MS is characterized by the presence of large, multifocal, demyelinated plaques with reactive glial scar formation. Demyelination is accompanied by inflammation with infiltrates composed of B-cells, T-cells, macrophages and activated microglia. Blood-brain barrier is also compromised. Demyelination can often be repaired by remyelination. Axons are also damaged or destroyed, particularly in the progressive stages of the disease. By contrast, damage or destruction of axons produces irreversible loss of function.

10 Demyelination & remyelination Forebrain section from MS patient stained with luxol fast blue to reveal areas of myelination in the subcortical white matter. Green arrows: areas from which the myelin stain is absent, representing three foci or plaques of chronic demyelination. Red arrows: 'shadow plaques', in which the demyelinated axons have undergone remyelination. Franklin RJ, 2002

11 Prodromal and potential causal pathways for MS Ramagopalan S et al, 2010

12 Genetic risk factors MS tends to aggregate in families First-degree relatives have greater risk than individuals from the general population Risk correlates with degree of kinship Genetic risk factors include: Human leukocyte antigen (HLA) subtypes Ethnic origin Parent-of-origin Sex

13 Age-adjusted percentage recurrence risks for relatives of MS probands 0.1% Ramagopalan S et al, 2010

14 HLA-DR locus: accounts for 40-50% of genetic risk for MS IMSGC, 2007 Chromosome 6 6p21 HFE F A B C HLA Class I TNF DP DQ DR HLA Class II

15 The HLA-DRA and B genes encode subunits of HLA class II molecules that present antigens to CD4+ T-cells T-cell (CD4+) TCR HLA-DR APC 6p21 CD28 B7 Co-stimulatory molecules antigen peptide presentation by the HLA-DR molecule CD4 = cluster of differentiation -4 (a cell-surface glycoprotein) CD4+ T-cells belong to the subclass of helper T-cells = T H cells; APC = antigen presenting cell; TCR = T cell receptor

16 HLA-DR locus

17 Specific HLA-DRB alleles increase risk or provide protection against MS HLA-DR haplotype (DRB1*1501, DQA1*0102, DQB1*0602) high-risk for European and North American Caucasians By contrast, HLA-DRB1*01, *10, *11, *14 alleles are protective. (note: the HLA-DRB1*14 allele is common in Asian populations) In addition to haplotypes, diplotypes are also important in determining risk. For example the increased risk associated with DRB1*1501 is greatly reduced when paired with DRB1*01.

18 Epistasis of HLA-RB1 alleles: genotypic odds ratios for MS for combinations of alleles [X = any allele other than HLA-DRB*1, *08, *10, *11, *14, *15 or *17] Handel AE et al, 2009

19 Additional MS susceptibility and protective genes IL-2 receptor alpha (IL2RA) 10p15 IL-7 receptor alpha (IL7RA) 5p13 Note: alleles at these loci account for only 0.2% of risk of developing MS; the HLA locus is by far the largest genetic risk factor. Thirteen additional genes have been linked to MS, but effect sizes are very small. IMSGC, 2007

20 Additional genetic influences Ethnic origin In North America, MS occurs at highest frequencies among individuals descended from Northern Europeans, with lower frequencies in African Americans, and individuals of Mexican, Puerto Rican and Japanese decent. MS occurs very infrequently among Chinese and Filipino Americans. Parent of origin Maternal half-siblings of MS patients have nearly double the risk of paternal half-siblings (2.35% vs 1.31%); Risk of maternal half-siblings similar to that of maternal full-siblings (2.35 vs 3.11%), suggesting that maternal effect significantly contributes to familial aggregation. Sex Frequency of MS for females is greater than for males. There is no evidence, however, for X-chromosome related genes; hormonal or environmental causes are suspected.

21 Environmental risk factors Smoking Odds ratio for smoking vs. never smoked = 1.51 (95% Confidence interval: ) Epstein-Barr virus (EBV) MS victims are almost always sero-positive for EBV, but not other viruses (>99% compared to 94% infection rate in the general population). Some authors have argued that late primary EBV infection (i.e., in adolescence or young adulthood) increases MS risk. Latitude/vitamin D These factors may be related: low sunlight exposure at higher elevations may result in vitamin D deficiency; effect of high latitude is offset by diet high in fish in costal Norway.

22 Epstein-Barr virus (EBV) EBV (aka: human herpes virus 4); genome = linear double-stranded DNA (172 kb); transmitted orally; infects B cells via interactions between viral surface antigens and the CR2/CD21 complement receptor and MHC class II molecules located on the surface of B cells. Propagation of EBV is restrained by circulating anti-ebv antibodies and by EBV-specific CD8+ T-cells, which kill EBV-infected B-cells. (CD8+ T-cells are cytotoxic T-cells = T C cells) In addition to MS, EBV is linked to infectious mononucleosis, B-cell tumors & several additional autoimmune diseases. Pender, 2010

23 EBV infected B cells in the brain in secondary progressive multiple sclerosis (MS) EBV-infected B-cells are localized in perivascular inflammatory infiltrates in the white matter and in meningeal inflammatory infiltrates overlying the cortex. The highest concentrations of EBV-infected B-cells are in meningeal infiltrates that resemble lymphoid follicles with germinal centers. The white areas in the cortex and white matter represent demyelinated regions. Pender M, 2010

24 7-dehydroxycholesterol Vitamin D: an immune system modulator with protective effects Pre-D 3 D 3 liver kidney 25(OH)D 3 1a-25(OH) 2 D 3

25 Latitude: Individuals living at higher or lower latitudes may not receive sufficient sunlight to prevent deficiencies of vitamin D; consumption of fish oil may be protective. Queensland: MS prevalence = 11/100,000 MS prevalence = 75.6/100,000

26 Hypothesis: EBV plays an essential role in the development of MS 1. Infection with EBV is essential for the development of MS. 2. EBV causes MS in genetically susceptible individuals by infecting auto-reactive B-cells, which enter the CNS, where they produce pathogenic auto-antibodies and provide co-stimulatory survival signals to auto-reactive CD4+T-cells (T H ) that would otherwise die in the CNS by apoptosis. The EBV-infected auto-reative B cells + autoreactive CD4+ T-cells produce antibodies and cytotoxic substances that damage myelin, oligodentrocytes and neuronal axons. 3. Susceptibility to develop MS after EBV infection is dependent on a genetically determined quantitative deficiency of the cytotoxic CD8+ T-cells that normally keep EBV infection under tight control. 4. Sunlight and vitamin D protect against MS by increasing the number of CD8+ T-cells available to control EBV infection. Pender M, 2010

27 Proposed role of Epstein-Barr virus (EBV) infection in the development of multiple sclerosis (MS) Step 1. EBV infects auto-reactive naive B-cells in the tonsil, driving them to enter germinal centers, where they proliferate intensely and differentiate into latently infected auto-reactive memory B-cells. Step 2. EBV-infected B-cells exit tonsil and circulate in blood. Step 3. The number of EBV-infected B- cells is normally controlled by EBVspecific cytotoxic CD8+ T-cells (T C ), which kill the infected B-cells, but not if there is a defect in this mechanism. Surviving EBV-infected auto-reactive memory B- cells enter the CNS, where they take up residence and produce pathogenic auto-antibodies, which attack myelin and other CNS components..

28 Step 4. Auto-reactive CD4+T-cells that have been activated in peripheral lymphoid organs by cross-reacting infectious antigens circulate in the blood and enter the CNS, where they are reactivated by EBV-infected auto-reactive B-cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules Step 5. After the auto-reactive CD4+T-cells have been reactivated by EBV-infected auto-reactive B-cells, they produce cytokines such as interleukin 2 (IL2), interferon-g (IFN-g) and tumor necrosis factor-b (TNF-b) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction Step 6. These EBV-infected B-cells provide co-stimulatory survival signals (B7) to the CD28 receptor on the auto-reactive T-cells and thereby inhibit the activation-induced T-cell apoptosis that normally occurs when auto-reactive T-cells enter the CNS and interact with nonprofessional antigen-presenting cells such as astrocytes and microglia, which do not express B7 co-stimulatory molecules Pender M, 2010

29 Proposed sequence of events leading to the development of multiple sclerosis (MS) In individuals with a genetic deficiency of cytotoxic CD8+ T-cells (T C ) (carried by autoimmune genes ) and with HLA class II genes predisposing to MS (e.g., HLA-DR1501), late EBV infection leads to the infection of auto-reactive B cells, which accumulate in the CNS, where they reactivate auto-reactive T-cells that orchestrate an autoimmune attack on the CNS Pender M, 2010

30 CD8+ T cells Hypothesis: susceptibility to MS is related to the number of CD8+ T- cells available to attack EBV-infected B-cells; lack of sunlight increases MS risk by reducing the number of cytotoxic CD8+ T-cells Age Pender M, 2010

31 Experimental autoimmune encephalomyelitis (EAE) model for MS A variety of mouse models have been developed, based on the injection of myelin, myelin proteins or other CNS tissues. Steinman & Zamil, 2005

32 Current therapies for MS Management of acute attacks intravenous or orally administered corticosteroids (e.g., prednisone) to suppress inflammation Disease-modifying treatments CIS: interferons RRMS: interferons b-1 and b-2 (modulates immune system) glatiramer acetate (random polymer of E, K, A,Y; may block immune attack on myelin) mitoxantrone (an immunosupressant) natalizumab (monoclonal antibody against a4b1 integrin) SPMS and PRMS: mitoxantrone and natalizumab PPMS: various experimental drugs Note: non-adherence rates to traditional treatments are in the range of 36-39%, possibly related to often severe side-effects of the above treatments. Alternative treatments Vitamin D, vitamin B 12, special diets, medical marijuana, herbal medicines (e.g., common rue derivatives that inhibit potassium channels in T cells), yoga

33 Targets for future MS therapies Steinman, 2003

34 (A) T-cells and B-cells penetrate the blood vessel endothelium. The key molecule in adhesion is a4b1 integrin on T and B cells. This integrin binds to VCAM, stimulating lymphocytes diapedesis and penetration of the extracellular matrix. Antibodies to a4b1 integrin inhibit the adhesion step. Matrix metalloproteases (MMPs) are crucial for this process. MMPs can be inhibited with IFN-b. (B) Once inside the brain, T-cells recognize myelin fragments in association with class II molecules of the MHC. The expression of these molecules, including MHC II and co-stimulatory molecules, such as CD80, CD86 and CD23, can be inhibited by CTLA4 antibodies, statins and PPAR agonists. Glatiramer can inhibit the interaction of MHC II with T cells. (C) Mast cells also have a role in the inflammatory response in MS. In EAE, histamine receptor antagonists and platelet activating factor (PAF) antagonists can prevent EAE. Anti-inflammatory cytokines, including IL-4 and IL-10, are also helpful in reducing inflammation. (D) Antibodies to protein and lipid components of the myelin sheath can activate complement, culminating in the production of membrane attack complexes, which damage the oligodendrocyte and lead to the stripping of myelin by activated macrophages. Administration of DNA vaccines and targeting of dendritic cells with small amounts of antigen has been successful in inducing tolerance, rather than immunogenic responses, in ECE models. (E) Destructive cytokines, such as IL-6, IL-12, TNF-a and IFN-g,, and the extracellular matrix component, osteopontin, amplify the inflammatory response in the brain. Some of these cytokines have Janus-like activities, both inducing pathology but also having key roles in recovery. E.g., TNF- is

35 References Ramagopalan S et al, Multiple sclerosis: risk factors, prodromes and potential causal pathways, The Lancet Neurology 9, , 2010 Oksenberg JR and Baranzini SE, Multiple sclerosis genetics is the glass half full, or half empty? Nature Reviews Neurology 6, , 2010 Dutta R and Trapp BD, Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis, Progress in Neurobiology, 2010 (in press) Stadelmann C et al, Inflammation, demyelination and degeneration Recent insights from MS pathology, Biochimica et Biophysica Acta, 2010 (in press) Emery B, Regulation of Oligodendrocyte differentiation and myelination, Science 330, , 2010 Franklin RJ, Why does remyelination fail in Multiple Sclerosis? Nature Reviews Neuroscience 3, , 2002 Peltonen L, Old suspects found guilty the first genome profile of multiple sclerosis, The New England Journal of Medicine 357, , 2007 The International MS Genetics Consortium, Risk alleles for multiple sclerosis identified by a genomewide study, The New England Journal of Medicine 357, , 2007

36 References Habek M et al, Genes associated with multiple sclerosis: 15 and counting, Expert Reviews 10, , 2010 Handel AE et al, Type 1 diabetes mellitus and multiple sclerosis: common etiological features, Nature Reviews Endocrinology 5, , 2009 Ascherui A et al, Vitamin D and multiple sclerosis, The Lancet Neurology 9, , 2010 Franciotto D et al, B cells and multiple sclerosis, The Lancet Neurology 7, , 2008 Pender MP, The essential role of Epstein-Barr virus in the pathogenesis of multiple sclerosis, The Neuroscientist, 2010 (in press) Steinman L and Zamil SS, Virtues and pitfalls of EAE for the development of therapeis for multiple sclerosis, Trends in Immunology 26, , 2005 Steinman L, Immune therapy for autoimmune diseases, Science , 2004 Fontoura P and Garren H, Multiple Sclerosis Therapies: Molecular Mechanisms and Future, Results and Problems in Cell Differentiation 51, , 2010

37 Journal Presentations Glass CK et al, Mechanisms Underlying Inflammation in Neurodegeneration, Cell 140, , 2010 Taveggia C et al, Signals to promote myelin formation and repair, Nature Reviews Neurology 6,

38 Internet resources National Multiple Sclerosis Society (US) Multiple Sclerosis Society (UK) The accelerated Cure project International Multiple Sclerosis Genetics Consortium