docThe immunopathogenesis of multiple sclerosis
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The immunopathogenesis of multiple sclerosis
The immunopathogenesis of multiple sclerosis Olaf Stüve, M.D., Ph.D. Neurology Section VA North Texas Health Care System Dallas VA Medical Center Departments of Neurology and Neurotherapeutics University of Texas Southwestern Medical Center at Dallas Disclosures • Dr. Stüve has received research funding from Teva Pharmaceuticals • Dr. Stüve is on the editorial boards of Clinical and Experimental Immunology, JAMA Neurology, Multiple Sclerosis, and Therapeutic Advances in Neurological Disorders Learning objectives A. To understand the role of the adaptive immune system in the initiation of relapsing-remitting MS B. To learn about factors that cause relapses in relapsing-remitting MS C. To comprehend events that lead to remission in relapsing-remitting MS Multiple Sclerosis • Inflammatory, demyelinating, neurodegenerative disease of the central nervous system • Unknown etiology • Presumed autoimmune pathogenesis Multiple Sclerosis Stüve O, Zamvil SS. In: Lange: Medical Immunology (tenth edition). 2001. http://www.mmorris.com/ms/MRI/multiple_sclerosis_news%20MRI%20Images.htm Multiple Sclerosis What starts the disease? Stüve O, Zamvil SS. In: Lange: Medical Immunology (tenth edition). 2001. Underlying Factors of MS Infectious agent Genetic predisposition Environmental factors Abnormal immunologic response MS DeLorenze et al. Arch Neurol. 2006. Multiple Sclerosis • Peak age of onset: Between 20 and 40 years of age • Female preponderance Canada Denmark North-East Ireland Saskatoon Oslo Cardiff UAA Iran Isfahan Japan French West Indies Greater Hobart Sellner et al. Autoimmunity Reviews. 2011. Underlying Factors of MS Infectious agent Genetic predisposition Environmental factors Abnormal immunologic response MS Complex genetic diseases • Unknown genetic parameters and mode of inheritance • Substantial role of non-genomic factors Selected familial risks for MS Regions of overlap between whole genome scans in multiple sclerosis US 2p23 UK Canada 1p36-p33 1p36-p33 2p23-p21 2p23-21 3p14-p13 3p14-p13 3q22-q24 4q31-qter * 3q22-q24 3q22-q24 5p14-p12 5p14-22 4q31-qter 5q13-q23 5q12-q13 5q12-q13 6p21 6p21 6p21 (LD) 6q27 6q22-27 7q11-q22 6p21 7q21-q22 17q22 18p11 19q13 Finland 17q22-24 18p11 19q12-13 19q13 19q13 Multiple Sclerosis What causes a relapse? Stüve O, Zamvil SS. In: Lange: Medical Immunology (tenth edition). 2001. Neuropathol-web.org Circulation Central Nervous System T cell T-cell extravasation B cell T cell T cell T cell B-cell – T-cell cross-activation Chemoattraction T cell Plasma cell CNS APC T cell Antibodies & Complement T-cell adhesion T-cell reactivation T cell Memory B cell Inflammatory mediators T-cell rolling T cell K+ Na+ Inflammation APC T cell T-cell activation Hypoxia, ischemia Activation of Na+ channels Oligodendrocyte NA+ Energy depletion Ca2+ Na+ Reverse Na+ Ca2+ exchange Etiology of Multiple Sclerosis • Two particular circumstances have been associated with clinical MS exacerbations: Etiology of Multiple Sclerosis • Two particular circumstances have been associated with clinical MS exacerbations: – Postpartum period Etiology of Multiple Sclerosis • Two particular circumstances have been associated with clinical MS exacerbations: – Postpartum period – Febrile infections Experimental Autoimmune Encephalomyelitis (EAE) myelin Ag./CFA s/c +myelin Ag. CD4+ Th1 Nitin Karandikar, UTSW. VLA-4 α4 1 Natalizumab Circulation T cell Central Nervous System B cell T cell T cell T cell B cell – T cell cross-activation T cell adhesion Chemoattraction T cell Plasma cell CNS APC T cell Antibodies & Complement T cell re-activation T cell Memory B cell Inflammatory mediators T cell rolling T cell K+ Na+ Inflammation APC T cell T cell activation NA+ Energy depletion Hypoxia, ischemia Activation of Na+ channels Ca2+ Na+ Reverse Na+ Ca2+ exchange Oligodendendrocyte Stüve et al. Ann Neurol. 2006. Fingolimod – Believed to modulate sphingosine 1-phosphate (S1P) receptors on lymphocytes and other tissues1,2 Presumed MOA/CNS impact • S1P receptors are widely expressed, including in cardiac tissue, vascular endothelium, and pulmonary endothelium2,3 – Prevents lymphocytes from leaving the lymph nodes and entering the bloodstream and CNS compartment1,4,5 Proinflammatory Th1 cells (MS-specific) Naïve T cells Anti-inflammatory Th2 cells (MS-specific) – The mechanism by which fingolimod exerts therapeutic effects in MS is unknown1 1. Gilenya™ (fingolimod) prescribing information. Novartis Pharmaceuticals Corporation. 2. Chun J, et al. Clin Neuropharm. 2010;33(2):91-101. 3. Szczepaniak WS, et al. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L137-L145. 4. Lopez-Diego RS, et al. Nat Rev Drug Discovery. 2008;7(11):909-920. 5. Kappos L, et 35al. N Engl J Med. 2010;362(5):387-401. Kowarik et al. Neurology. 2011. Circulation Central Nervous System T cell T-cell extravasation B cell T cell T cell T cell B-cell – T-cell cross-activation Chemoattraction T cell Plasma cell CNS APC T cell Antibodies & Complement T-cell adhesion T-cell reactivation T cell Memory B cell Inflammatory mediators T-cell rolling T cell K+ Na+ Inflammation APC T cell T-cell activation Hypoxia, ischemia Activation of Na+ channels Oligodendrocyte NA+ Energy depletion Ca2+ Na+ Reverse Na+ Ca2+ exchange Hauser et al. NEJM. 2008. VLA-4 α4 1 Natalizumab Stüve et al. Ann Neurol. 2006. Stüve et al. Ann Neurol. 2006. Circulation Central Nervous System T cell T-cell extravasation B cell T cell T cell T cell B-cell – T-cell cross-activation Chemoattraction T cell Plasma cell CNS APC T cell Antibodies & Complement T-cell adhesion T-cell reactivation T cell Memory B cell Inflammatory mediators T-cell rolling T cell K+ Na+ Inflammation APC T cell T-cell activation Hypoxia, ischemia Activation of Na+ channels Oligodendrocyte NA+ Energy depletion Ca2+ Na+ Reverse Na+ Ca2+ exchange Multiple Sclerosis What causes remission? Stüve O, Zamvil SS. In: Lange: Medical Immunology (tenth edition). 2001. VLA-4 α4 1 Natalizumab O’Connor et al. Neurology. 2010. Stüve et al. Neurol. 2009. Conclusion • During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes Conclusion • During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes • Much of our knowledge on the immunology in relapsing-remitting MS stems from observations made with specific pharmacotherapies Conclusion • During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes • Much of our knowledge on the immunology in relapsing-remitting MS stems from observations made with specific pharmacotherapies • There is an intricate interplay between many cellular subsets Conclusion • CD4+ T cells and B cells are thought to be key players in MS pathogenesis Conclusion • CD4+ T cells and B cells are thought to be key players in MS pathogenesis • Some T cells and B cells also have regulatory function Conclusion • CD4+ T cells and B cells are thought to be key players in MS pathogenesis • Some T cells and B cells also have regulatory function • Regulatory cells may be used therapeutically The End
