Immunopathogenesis of multiple sclerosis
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The document outlines the immunopathogenesis of multiple sclerosis (MS), detailing the roles of both innate and acquired immunity in the disease's progression. It discusses the mechanisms of autoimmunity, including the implications of T and B cells, cytokines, and the breakdown of tolerance. Additionally, the document addresses various therapeutic approaches and emerging treatments for MS.
Immunopathogenesis of multiple sclerosis
- 2. Amr Hasan, MD,FEBN Associate Professor of Neurology - Cairo University
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- 7. Immunity 7
- 8. First: INNATE IMMUNITY Cellular Defence Mechanisms: 8 1. Phagocytes • Particles, e.g. bacteria, entering the tissue fluids or blood are rapidly engulfed by phagocytic cells. • This process of engulfment (internalization) of particulate matter is termed phagocytosis. • There are 2 main types of phagocytic cells: Polymorphonuclear leucocytes (especially neutrophils) • Mononuclear phagocytes (monocytes in the blood and macrophages in the tissues).
- 10. First: INNATE IMMUNITY Cellular Defence Mechanisms: 10 2. Natural Killer cells (NK cells) • Large granular lymphocytes which can be distinguished from B and T lymphocytes. • They constitute 10-15% of peripheral blood lymphocytes. • They are capable of non-specific killing of tumour cells and virus- infected cells a manner similar to cytotoxic T cells, but differ from them in the way they recognize their target 3.Eosinophils
- 13. Second: Acquired Immunity (Adaptive immunity) 13 I.CELL MEDIATED IMMUNITY ( T CELL) II.HUMORAL IMMUNITY ( B CELLS)
- 14. Second: Acquired Immunity (Adaptive immunity) 14 I. T lymphocytes A. Produced in the bone marrow, but complete their maturation in the Thymus. B. They comprise around 75% of peripheral blood lymphocytes.
- 15. Second: Acquired Immunity (Adaptive immunity) 15 I. T lymphocytes There are two main kinds of T cells: A. Cytotoxic T (Tc) cells B. Helper T (Th) cells
- 16. Second: Acquired Immunity (Adaptive immunity) 16 There are two main kinds of T cells: A. Cytotoxic T (Tc) cells • These recognize body cells infected with virus. • Can kill tumour cells TV
- 17. Second: Acquired Immunity (Adaptive immunity) 17 There are two main kinds of T cells: B. Helper T (Th) cells a- T helper 1 (Th1) cells Secrete cytokines which help in activation of Macrophages making macrophages more capable of killing any bacteria inside them. b- T helper 2 (Th2) cells Secrete certain cytokines which help in activation of B cells plasma cells produce antibodies to deal with those extracellular pathogens.
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- 20. Second: Acquired Immunity (Adaptive immunity) 20
- 21. Second: Acquired Immunity (Adaptive immunity) 21 II. B lymphocytes • Produced in the Bone marrow, where they complete their maturation. They comprise around 10% of peripheral blood lymphocytes. • When B cells become active plasma cells antibodies, or immunoglobulins • When B cells become active plasma cells antibodies, or immunoglobulins. • B cells may act as APC
- 22. 22 B cell Surface Molecules
- 24. 24 • There are 5 main types: gamma (γ), alpha (α), mu (u), delta (δ) and epsilon (ε), corresponding to the 5 isotypes of Igs IgG, IgA, IgM, IgD and IgE respectively. Antibody classes and class switching
- 25. Activation of T cells 25 The Professional Antigen Presenting Cells: • These are the only cells capable of activating naive T cells. • They are concentrated in the peripheral lymphoid tissues, such as lymph nodes, where they trap antigen and present it to the recirculating T cells: 1. Dendritic cells • The most important &most efficient APCs. • Their only known function is antigen presentation. 2. Macrophages 3. B cells
- 26. 26 Naïve T cell
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- 28. Second: Acquired Immunity (Adaptive immunity) 28 Circulation of Lymphocytes between Blood and Lymph: • Lymphocytes which recognize a certain antigen undergo a series of changes ready to start working against the antigen . • The changes which occur are: .lymphoblaststhey becomectivation:Aa. rapid multiplication.roliferation:Pb. Effector cellthey change intoifferentiation:Dc.
- 30. CYTOKINES 30 Definition: • Cytokines are peptide or glycoprotein mediators that are produced by cells of the immune system and have an effect on the behaviour and properties of many cells. General Characteristics of Cytokines: 1. Highly potent, often acting at very low concentrations. 2. Not specific to antigens that induce their production. 3. Act through action high-affinity cell surface receptors. 4. Transient action. 5. They act mainly in an autocrine manner (affecting the cell which produced them) or in a paracrine manner (affecting cells close by). 6. They are pleiotropic, i.e. the same cytokine may have multiple effects.
- 31. 31 CYTOKINES Th1 Th2 Cytokines produced IL-2 IFN-Ɣ TNF-a and B GM-CSF IL-3 IL-4 ,IL-5 ,IL-6 ,IL-10, TGF-B GM-CSF IL-3 Development promoted by IL-12 &IFN-Ɣ Large doses of antigen IL-4 Small doses of antigen Development inhibited by IL-4 &IL-10 IFN-Ɣ Promote Cell-mediated immunity Humoral immunity
- 32. 32 CYTOKINES Cytosolic "endogenous" Vesicular "exogenous" Examples • Viruses • Intracellular bacteria e.g.T.B. • Extracellular bacteria and their products when internalized Degraded in • Cytoplasm • Vesicles Peptides bind to • MHC I molecules • MHC II molecules Presented to • CD8 T cells • CD4 T cells Result • Cytotoxic killing of presenting cell by CD8 T cell • Secretion of cytokines by CD4 T cells, giving help to macrophages, B cells and others
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- 36. 36 Epitopes Heterophil antigens HETEROPHIL ANTIBODIES CROSS REACTIVITY
- 37. 37 Super antigen
- 38. MHC 38 • MHC antigens are a group of molecules expressed on cell surface membranes. • They are also called HLA because they were first discovered on the surface of Human Leucocytes. • MHC genes are divided into 3 major classes; class I, II and class III
- 39. MHC 39 • Class I • There are three class I loci (HLA-A, B and C). Each locus is highly polymorphic i.e. a single HLA locus contains one of many possible alleles( Alleles: variants of a single genetic locus) • The various possible alleles are given consecutive numbers, e.g. HLA- A1, HLA-A2, etc.
- 40. MHC 40 • Class II • Molecules are encoded by three principal loci (HLA-DP, -DQ and - DR), which also show polymorphism. • MHC molecules have a much more limited cellular distribution. • They are mainly found on the surface of (APCs). • Class III • The class III genes code for a number of complement components and are grouped together in a region between HLA-D and HLA-B.
- 42. TOLERANCE 42 • Tolerance = the absence of specific immune response against some antigens in an otherwise fully immunocompetent person. • It includes: autotolerance and aquired (induced) tolerance. Autotolerance: • It is a tolerance to self antigens that is acquired early in life, probably in utero. • Failure of autotolerance may result in autoimmune disease.
- 43. Mechanisms of Autotolerance 43 1. Central tolerance • During development in the primary lymphoid organs, B and T lymphocytes go through a phase in which contact with antigen leads to their death or permanent inactivation. • Such antigens are most likely to be self-antigens. The elimination of immature self-reactive lymphocytes during their maturation is called negative selection (clonal deletion). 2. Peripheral tolerance
- 44. AUTOIMMUNITY 44 • It is an adaptive immune response to self-antigens. Normally, this is prevented by autotolerance. • Breakdown in autotolerance leads to production of autoantibodies and/or self-reactive T cells which may cause autoimmune diseases.
- 45. Mechanisms of Autoimmune Diseases 45 Cross reactivity Breakdown in the immune network which may occur as a result of: • Interference with the mechanisms which normally suppress surviving self- reactive T cells. • Polyclonal activation of lymphocytes: Certain agents (e.g. viruses or bacteria) are capable of non-specifically stimulating many clones of lymphocytes, including self-reactive clones. • Over production of IL-2 by Th1 cells.
- 47. Immunopathogenesis of multiple sclerosis 47 Genetics EnvironmentalAutoimmunity
- 48. The Virus Hypothesis Viruses thought to be associated with MS 48 • Measles, rubella, mumps. • Herpes viruses, including epstein barr virus (EBV), herpes simplex virus (HSV) 1 and 2. • Varicella zoster virus. • HHV6.
- 49. How Do Autoreactive T Cells Become Activated 49 Molecular mimicry: • Antigenic epitopes of an infectious agent mimic a self protein epitope. Superantigens: • Bind to Class II MHC and specific TCR V segments and may occur during the course of a bacterial or viral infection.
- 50. Frequency Of Autoreactive T Cells 50 • T Cells recognizing MBP and PLP are present in normal individuals. • No difference in the frequency of these cells between MS patients and normal individuals.
- 51. Clonal expansion and persistence of autoreactive T cells 51 1) Engagement of T cell receptor by crossreactive microbial antigen CD282) B7 APC 3) IL-12 THP auto- reactive TH1 auto- reactive TH1 auto- reactive TH1 auto- reactive TH1 auto- reactive
- 54. Immunopathogenesis of M.S. 54 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 55. Immunopathogenesis of M.S. 55 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 56. Immunopathogenesis of M.S. 56 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 57. B.B.B. 57
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- 60. Matrix metalloproteinases 60 • MMPs are endopeptidases that serve as effectors of cell migration, cytotoxicity, inflammation and tissue remodeling via degradation of ECM components. • MMPs can be secreted by activated T cells and macrophages. • In the normal CNS, the expression of MMP-2, -7 and -9 by astrocytes and microglia is thought to control physiological processes such as cell migration, differentiation and survival via ECM remodelling. • Higher levels of TIMP-1(a negative regulator of MMPs) are found in astrocytes surrounding perivascular infiltrated areas and microglial nodules. • In acute and chronic MS lesions, astrocytes express moderate levels of MMP-2-, -3 and -9. • Unlike astrocytes, microglia seem to be contributing to the inflammatory process by upregulating the expression of pro-inflammatory MMPs that in conjunction with those produced by infiltrating leukocytes further destabilize the BBB.
- 61. Activated Autoreactive T cells expressing VLA-4 adhere to endothelium via interactions with VCAM and enter into the tissue 61 Peripheral Immune System 1) Engagement of T cell receptor by crossreactive microbial antigen CD282) B7 3) IL-12 THP auto- reactive TH1 auto- reactive VLA-4 VCAM TH1 auto- reactive TH1 auto- reactive Inflammed Tissue
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- 64. 64 Structure of chemokine classes
- 65. Chemokines and Chemokine Receptor 65 • the CC chemokine ligands CCL3, CCL4 and CCL5, and the receptors CCR2, CCR3 and CCR5 were found to be elevated in CNS tissue recovered from MS patients. • Levels of the CC chemokine CCL2 and the CXC chemokine CXCL10 were found to vary inversely in the cerebrospinal fluid of patients with acute MS: CCL2 levels were much lower than controls, whereas CXCL10 chemokines were markedly increased. • CCR5 — one of the receptors for CCL3, CCL4 and CCL5 — is a key receptor in T-cell trafficking into the CNS.
- 66. Immunopathogenesis of M.S. 66 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 67. Immunopathogenesis of M.S. 67 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
- 68. Activated autoråeactive T cells enter into tissue, recognize self antigen presented by local APC with costimulation and induce inflammation 68 Tissue Damage IL-2 IFN- TNF- CD154 CD40 IL-12 tissue APC autoantigens CD28 B7 TH 1 auto- reactive Peripheral Immune System 1) Engagement of T cell receptor by crossreactive microbial antigen CD282) B7 3) IL-12 TH P auto-reactive
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- 70. Immunopathogenesis of M.S. 70 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
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- 72. 72 More Than a Demyelinating Disease
- 73. Immunopathogenesis of M.S. 73 Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage RemyelinationAxonal loss
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- 76. Myelin 76
- 77. Myelin
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- 80. 80 Inflammation and Neurodegeneration in MS Disease Stage Dominant Component Main Clinical Outcome MRI Early INFLAMMATION Edema Demyelination (axonal loss, brain atrophy) Relapses Gd enhancement Late NEURODEGENERATION Severe axonal injury Permanent tissue loss Disability Black Holes Gd enhancement Brain Atrophy Filippi et al., EJN 2001, 8:291-297
- 81. 81 More Than a Demyelinating Disease Time (Years) DiseaseParameter INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY NEURODEGENERATIONNEURODEGENERATION PROGRESSIONPROGRESSION RelapsesRelapses cMRIcMRI WMLsWMLs FLAIRFLAIR T1 Gd+T1 Gd+ FLAIRFLAIR Rx effectRx effect Poor Rx effectPoor Rx effect No NewNo New WMLsWMLs
- 82. B Cells in MS 82 • Function as antigen presenting cells (APC) and contribute to T cell activation. • Produce effector cytokines that may modulate the local immune environment. • Function at the innate-adaptive interface. • Play a role in formation and maintenance of new lymphoid foci, including at ectopic sites such as the inflamed CNS.
- 83. 83 B cell directed therapies
- 84. DMT 84
- 85. Existing & Emerging MS therapies Modified from P. Vermersch Phase I Phase II Phase III Marketed Interferons Antiproliferative agents Cytolytic mAbs Symptomatic TxVaccine, tolerization Lymphocyte trafficking Immune regulation Other Idebenone BIIB033 Fingolimod Firategrast Siponimod ONO-4641 CS-0777 ELND-002 Tysabri Daclizumab Laquinimod BG12 NI-0801 AZD5904 GRC4039 CCX-140 AIN457 Cladribine NerispirdineOfatumumab Belimumab Ampyra Ocrelizumab Sativex Alemtuzumab Copaxone IPX-056 RPI-78M LY-2127399 Novantrone Rebif Betaferon Pixantrone Peg IFN (BIIB017) ATX-MS-1467 PI2301 RTL1000 Copaxone generics x2 Azathioprine Teriflunomide LV Copaxone Avonex = Oral administration = Injectable Extavia Ponesimod
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- 87. 87 Mechanism of action of DMD (IFN)
- 88. 88 Mechanism of action of DMD (GA)
- 89. 89 Mechanism of action of DMD (Natalizumab)
- 90. 90 Mechanism of action of DMD (Natalizumab)
- 91. 91 Mechanism of action of DMD (Fingolimod)
- 92. 92 Mechanism of action of DMD (Fingolimod)
- 93. THANK YOU