* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download HLA-DRB1*1501 - The Neurology Report
Survey
Document related concepts
Innate immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Rheumatoid arthritis wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Neuromyelitis optica wikipedia , lookup
Multiple sclerosis signs and symptoms wikipedia , lookup
Management of multiple sclerosis wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Transcript
Advances in Basic and Translational Science Research in Multiple Sclerosis Salim Chahin, MD, MSCE University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania A REPORT FROM THE 66TH ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY (AAN 2014) © 2014 Direct One Communications, Inc. All rights reserved. 1 Neuropathology of Multiple Sclerosis © 2014 Direct One Communications, Inc. All rights reserved. 2 The Dynamic Nature of MS Pathology Active lesions are characterized by relative axonal preservation and macrophage infiltration. » Early active demyelination—minor myelin proteins (MAG, MOG) » Late active lesions—major myelin proteins (proteolipid protein and MBP). Smoldering lesions have an inactive center and a rim of activated macrophages and microglia. Inactive lesions have substantial axonal loss and are completely demyelinated. Shadow lesions represent remyelinated areas. Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Popescu BF et al. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):901 © 2014 Direct One Communications, Inc. All rights reserved. 3 The Dynamic Nature of MS Pathology Stages of demyelination Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185 © 2014 Direct One Communications, Inc. All rights reserved. 4 The Dynamic Nature of MS Pathology Relationship to disease course » Active lesions—RRMS and SPMS with relapses » Inactive and smoldering lesions—SPMS and PPMS » Shadow lesions—similar rate in RR and progressive MS Remyelination » Thinly myelinated axons with short intermodal distances » Depends on availability of OPCs and inflammatory balance » Remyelination failure may be due to: • • • • Recurrent demyelination Axonal injury inhibiting remyelination Glial scarring Age-dependent loss of trophic support from microglia Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Popescu BF et al. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):901; Barkhof F et al. Arch Neurol. 2003;60:1073; Franklin RJ et al. Nat Rev Neurosci. 2008;9:839 © 2014 Direct One Communications, Inc. All rights reserved. 5 Heterogeneity of Early Active MS Plaques MS lesions can be classified into four immunopatterns Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185 © 2014 Direct One Communications, Inc. All rights reserved. 6 Pathologic Substrate of Disease Progression Axonal pathology » Occurs early in the disease » Correlates with degree of inflammation » Remains clinically silent until a threshold of axonal loss is reached where the compensatory capacity is surpassed Mitochondrial injury, oxidative stress, and iron accumulation » Mitochondrial injury triggered by reactive oxygen and nitrogen » » species leads to oligodendrocyte and neuronal damage. Iron, in liberated form, may generate reactive oxygen species and contribute to neurodegeneration. A decrease in iron in normal-appearing white matter has been observed in chronic MS. Bjartmar C et al. J Neurol Sci. 2003;206:165; Fischer MT et al. Brain. 2012;135(pt 3):886; Aboul-Enein F et al. Acta Neuropathol. 2005;109:49; Hametner S et al. Ann Neurol. 2013;74:848 © 2014 Direct One Communications, Inc. All rights reserved. 7 Pathologic Substrate of Disease Progression Cortical pathology » Can occur early in the disease process » Results from demyelination with the gray matter or through retrograde degeneration from white matter pathology » Meningeal inflammation may also contribute to gray matter pathology in MS » Types of cortical lesions: • Subpial lesions—from the pial surface to the deep cortical layers— common in chronic MS • Intracortical lesions—small perivascular lesions confined to the cortex • Leukocortical lesions—involve both gray and white matter at the gray-white matter junction Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Calabrese M et al. Nat Rev Neurol. 2010;6:438; Howell OW et al. Brain. 2011;134(pt 9):2755 © 2014 Direct One Communications, Inc. All rights reserved. 8 Pathologic Substrate of Disease Progression Neurodegeneration and inflammation » Studies have suggested that degeneration occurs separately from inflammation in MS. » However, it is more likely that degeneration occurs on an inflammatory background. » Cortical lesions, which are highly inflammatory, are present even early in the disease, suggesting a stronger role for inflammation at this early stage of the disease. » The process by which inflammation leads to degeneration is not completely understood. Popescu BF, Lucchinetti CF. Annu Rev Pathol. 2012;7:185; Dutta R, Trapp BD. Prog Neurobiol. 2011;93:1 © 2014 Direct One Communications, Inc. All rights reserved. 9 Epidemiology of Multiple Sclerosis © 2014 Direct One Communications, Inc. All rights reserved. 10 Epidemiology of Multiple Sclerosis MS in relatively common in the US, Europe, Canada, New Zealand, and parts of Australia. Lifetime risk is 1 in 400 in white non-Hispanic individuals. The incidence of MS follows a latitude gradient—risk is low in the tropics and increases with increasing latitude. Migration from a high- to low-risk area changes the risk of the disease in a graded, age-related fashion. Studies suggest a rising incidence in certain populations, especially women. Ascherio A et al. Nat Rev Neurol. 2012;8:602 © 2014 Direct One Communications, Inc. All rights reserved. 11 Known Environmental Risk Factors Epstein-Barr virus (EBV) » The geography and epidemiology of infectious mononucleosis are similar to those of MS. » Older age at EBV infection increases the risk for MS. » Pediatric studies have shown an association between EBV infection and the risk of developing MS. Other viruses » Contrary to EBV infections, cytomegalovirus (CMV) infections are associated with a lower risk of developing MS. » A complex relationship exists between infection with herpes simplex virus (HSV)-1 and genetic risk factors for MS (a strong interaction was observed with the gene HLA-DRB1). Ascherio A et al. Nat Rev Neurol. 2012;8:602; Henle W et al. Sci Am. 1979;241:48; Waubant E et al. Neurology. 2011;76:1989 © 2014 Direct One Communications, Inc. All rights reserved. 12 Known Environmental Risk Factors Risk of developing MS in children and adults Waubant E et al. Neurology. 2011;76:1989; Sundqvist E et al. Mult Scler. 2014;20:165 © 2014 Direct One Communications, Inc. All rights reserved. 13 Known Environmental Risk Factors Vitamin D » The geography of MS also correlates with degree of sun exposure (the primary source of vitamin D). » Vitamin D is hypothesized to play an immunomodulatory role in several diseases, including MS. » Several studies have shown a lower risk of MS in people with regular vitamin D intake or high serum levels of vitamin D. » Vitamin D deficiency may also contribute to a more severe disease course and progression in MS. » Several clinical trials are under way to further investigate the role of vitamin D in MS. Ascherio A et al. Nat Rev Neurol. 2012;8:602; Ebers GC. Lancet Neurol. 2008;7:268; Handel AE et al. Nat Rev Neurol. 2010;6:156 © 2014 Direct One Communications, Inc. All rights reserved. 14 Known Environmental Risk Factors Cigarette smoking » The risk of MS is higher in smokers compared with that in people who have never smoked. » Cigarette smoking also contributes to more rapid disease progression in patients with established MS. Dietary sodium intake » Sodium and increased dietary salt intake may be implicated in the pathogenesis of MS and may play a role in modulating the immune system and the development of autoimmune diseases such as MS. Hernan MA et al. Am J Epidemiol. 2001;154:69; Wingerchuk DM et al. Ther Adv Neurol Disord. 2012;5:13 © 2014 Direct One Communications, Inc. All rights reserved. 15 Genetics of Multiple Sclerosis © 2014 Direct One Communications, Inc. All rights reserved. 16 Genetic Susceptibility The genetic contribution to MS succeptibility is suggested by several observations » The risk of MS in monozygotic twins is 25%, whereas in dizygotic twins the risk is 5%. » Having a sibling with MS increases the risk 20–40 fold compared with the risk of MS in the general population. Multiple interacting polymorphic genes have been identified as contributing to the risk of MS. The strongest genetic risk is conferred by the HLADRB1*1501 allele. Genome-wide association studies have identified over 110 non-HLA genes involved in the risk of MS. Ascherio A et al. Nat Rev Neurol. 2012;8:602; Ebers GC. Nature. 1995;377:150; Beecham AH et al. Nat Genet. 2013;45:1353 © 2014 Direct One Communications, Inc. All rights reserved. 17 Environmental/Genetic Interactions MS is likely caused by a complex interaction between multiple genes and environmental factors. Examples of such interactions include: » The interaction between HSV-1 and HLA-DRB1. » The role of latitude in increased concordance among monzygotic twins. » The vitamin D response element located in the HLA-DRB1 promoter region. Future, more expansive studies are needed to further explore these interactions and understand better the pathophysiology of MS. Ascherio A et al. Nat Rev Neurol. 2012;8:602; Islam T et al. Ann Neurol. 2006;60:56; Waubant E et al. Neurology. 2011;76(23):1989 © 2014 Direct One Communications, Inc. All rights reserved. 18 Environmental/Genetic Interactions Role of epigenetic factors » The effect of environmental risk factors on genetic susceptibility can be explained by epigenetic modifications. » Epigenetic changes influence gene expression without altering the DNA sequence. » Examples of such epigenetic factors include such processes as: • DNA methylation • Histone modification • MicroRNA (miRNA) associated gene silencing • Heterochromatin Ascherio A et al. Nat Rev Neurol. 2012;8:602; Koch MW et al. Nat Rev Neurol. 2013;9:35 © 2014 Direct One Communications, Inc. All rights reserved. 19 Neuroimmunology of Multiple Sclerosis © 2014 Direct One Communications, Inc. All rights reserved. 20 T-Cell Involvement Studies have shown that auto-reactive, myelinspecific T lymphocytes can result in demyelination. T cells in MS patients have a greater proinflammatory phenotype. Both CD4+ and CD8+ T cells are implicated in the pathogenesis of MS. The suppressive capacity of CD8+ cells is reduced in MS patients during a relapse. In a clinical trial on altered peptide ligands, an increase in T cells responding to a component of myelin basic protein was observed. Pettinelli CB, McFarlin DE . J Immunol. 1981;127:1420; Lovett-Racke AE et al. J Clin Invest. 1998;101:725; Crawford MP et al. Blood. 2004;103:4222; Bielekova B et al. Nat Med. 2000;6:1167 © 2014 Direct One Communications, Inc. All rights reserved. 21 T-Cell Involvement T-cell phenotype in MS » T cells from MS patients produce inteferon-g, consistent with a T helper (Th) 1 cell response. » T cells from healthy individuals producde cytokines consistent with a Th2 response. » A subset of T cells (Th17) produce interleukin-17 (IL-17) and are triggered by IL-23. The differentiation of encephalitogenic Th1 and Th17 cells may differentiate between MS patients. These differences may also explain why some patients fail to respond to treatment with certain disease-modifying agents such as interferons. Pettinelli CB, McFarlin DE. J Immunol. 1981;127:1420; Trinchieri G et al. Immunity. 2003;19:641 © 2014 Direct One Communications, Inc. All rights reserved. 22 B-Cell and Humoral Involvement Cerebospinal fluid levels of B cells, plasma cells, and antibodies are increased in patients with MS. Evidence on the role of B cells in MS pathogenesis also comes from therapeutic trials that have shown successful results from targeting B cells. KIR4-1 antigen is an inward-rectifying potassium channel located on astrocytes and oligodendrocytes » Antibodies to KIR4-1 were present in 47% of patients with MS, compared with less than 1% of patients with other neurologic disorders. » Results were replicated in children with acute demyelinating disorders. Cepok S et al. Brain. 2005;128(pt 7):1667; Srivastava R et al. N Engl J Med. 2012;367:115; Kraus V et al. Neurology. 2014;82:470; Cross AH et al. J Neuroimmunol. 2006;180:63 © 2014 Direct One Communications, Inc. All rights reserved. 23 Epigenetics and the Role of MicroRNAs MicroRNAs have emerged as a leading epigenetic mechanism via regulation of gene expression and T-cell activation. MicroRNAs can be influenced by both genetic and environmental factors. Increased expression of three microRNAs (miR-128, miR-27a/b, and miR-340) has been identified in naïve T cells of patients with MS. These microRNAs target a transcription factor that drives Th2 differentiation and IL-4 expression. Keller A et al. PLoS One. 2009;4:e7440; Guerau-de-Arellano A et al. Brain. 2011;134(pt 12):3578 © 2014 Direct One Communications, Inc. All rights reserved. 24 Mechanisms of Action of Current and Future MS Therapies © 2014 Direct One Communications, Inc. All rights reserved. 25 Current and Future MS Therapies Type 1 interferons (interferon b-1a and b-1b) » The first disease-modifying therapies developed for the treatment of MS. » Although several mechanisms have been proposed, the exact mechanism of action remains unknown. » We have gained insight into how interferons work through knowledge of their effect in neuromyelitis optica (NMO). » Interferons may worsen disease status when the Th17 immune response is prominent. » Patients with NMO have elevated levels of IL-17 compared with MS patients; treating NMO with interferons can have devastating consequences. Borden EC et al. Nat Rev Drug Discov. 2007;6:975; Axtell RC et al. Trends Immunol. 2011;32:272 © 2014 Direct One Communications, Inc. All rights reserved. 26 Current and Future MS Therapies Glatiramer acetate » Several proposed mechanisms of actions » An anti-inflammatory monocyte, termed M2, is elicited in » response to glatiramer acetate. Results in increased secretions of anti-inflammatory cytokines, such as IL-10, and a shift from Th1 to INF-g response to a modulating pathway through Th2. Natalizumab » Humanized monoclonal antibody. » Targets a4 integrins. » Interferes with lymphocyte transmigration across the » blood-brain barrier. Impedes both T and B lymphocyte entry into the CNS. Weber MS et al. Nat Med. 2007;13:935; Rudick R et al. JAMA Neurol. 2013;70:172 © 2014 Direct One Communications, Inc. All rights reserved. 27 Current and Future MS Therapies Fingolimod » » » Sphingosine phosphate receptor agonist The S1P1 subtype is present on immune cells and neural cells. Fingolimod caused the S1P1 receptor to be internalized, trapping lymphocytes in the lymph nodes and impeding their egress. Teriflunomide » » » Active metabolite of leflunomide » Decreases lymphocyte proliferation and activation toward key myelin antigens in MS Complex mechanism of action Interferes with pyrimidine synthesis through reversible inhibition of dihydroorotate dehydrogenase. Brinkmann V et al. Nat Rev Drug Discov. 2010;9:883; O'Connor P et al. N Engl J Med. 2011;365:1293 © 2014 Direct One Communications, Inc. All rights reserved. 28 Current and Future MS Therapies Dimethyl fumarate » Likely affords cytoprotection from oxidative stress » May be beneficial in protecting against neuroinflammation, neurodegeneration, and oxidative stress. » Mainly works via activation of nuclear 1 factor (erythroidderived 2)-like2 (Nrf2) antioxidant pathways » Other potential mechanisms of action • Shifting dendritic-cell differentiation • Suppressing proinflammatory cytokines • Directly inhibiting proinflammatory pathways Gold R et al. N Engl J Med. 2012;367:1098; Fox RJ et al. N Engl J Med. 2012;367:1087 © 2014 Direct One Communications, Inc. All rights reserved. 29 Current and Future MS Therapies Alemtuzumab » Monoclonal antibody that targets CD52 receptors » Depletes T and B lymphocytes and monocytes mainly via » antibody-dependent cytotoxicity and complement-mediated cell lysis Alemtuzumab drives immune programming—when the cells repopulate, they don’t have the same autoimmune response. In 30% of cases, new autoimmune diseases (notably, immune thrombocytopenia) may emerge. Ocrelizumab » Recombinant humanized antibody that targets CD20 » receptors on B cells Results in antibody-dependent, cell-mediated cytotoxic effect Hersh CM, Cohen JA. Immunotherapy. 2014;6:249; Wiendl H, Kieseier B. Nat Rev Neurol. 2013;9:125; Kappos L et al. Lancet. 2011;378:1779 © 2014 Direct One Communications, Inc. All rights reserved. 30