Basic Immunology and Multiple Sclerosis
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Basic Immunology and Multiple Sclerosis






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    Basic Immunology and Multiple Sclerosis Basic Immunology and Multiple Sclerosis Presentation Transcript

    • Basic Immunology and Multiple Sclerosis Ben Thrower M. D. Shepherd MS Institute Atlanta, GA
    • Why Immunology? • MS is an autoimmune disease. • Existing and future therapies work by modulating or suppressing the immune system.
    • References 1. Abbas AK, Lichtman AH. Basic Immunology: Functions and Disorders of the Immune System. W.B. Saunders Company. 2001. 2. Sospedra M, Martin R. Annu. Rev. Immunol. 2005; 23: 683-747.
    • Immunology is like an onion …..
    • ….. not because it’s stinky and makes you want to cry…..
    • ….. but because there are lots of layers.
    • Overview of the Immune System Immune System Adaptive Innate (Specific) (Nonspecific) o line of defense 2 1o line of defense Protects/re-exposure Cellular Humoral Cellular Humoral Components Components Components Components
    • Function of the Immune System (Self/Non-self Discrimination) • To protect from pathogens • Intracellular (e.g. viruses and some bacteria and parasites) • Extracellular (e.g. most bacteria, fungi and parasites) • To eliminate modified or altered self
    • Effects of the Immune System • Beneficial: • Protection from invaders • Elimination of altered self • Detrimental: • Discomfort and collateral damage (inflammation) • Damage to self (hypersensitivity or autoimmunity)
    • Innate (Nonspecific) Immunity
    • Innate Host Defenses Against Infection • Anatomical barriers – Mechanical factors – Chemical factors – Biological factors • Humoral components – Complement – Coagulation system – Cytokines • Cellular components – Neutrophils – Monocytes and macrophages – NK cells – Eosinophils
    • The Adaptive Immune System • Cell-mediated Immunity (Cytotoxicity) • T cells • CD4+ (Th1 & Th2) • CD8+ • Humoral Immunity (Antibody production) • B Cells
    • Comparison of Innate and Adaptive Immunity Innate Immunity Adaptive Immunity • No time lag • A lag period • Not antigen specific • Antigen specific • No memory • Development of memory
    • Cells of the Immune System Immune System Myeloid Cells Lymphoid Cells Granulocytic Monocytic T cells B cells NK cells Neutrophils Macrophages Helper cells Basophils Kupffer cells Suppressor cells Plasma cells Eosinophils Dendritic cells Cytotoxic cells
    • Immune Interactions • Cell Receptors
    • Immune Interactions • Cell Receptors Endothelial Lining
    • Immune Interactions • Cytokines – Powerful chemical substances that allow for interactions between cells of the immune system.
    • Immune Interactions • Chemokines – Chemicals used by one immune cell to attract another cell to an area of inflammation.
    • Cells of the Immune System • Lymphocytes 1) B cells, T cells, Natural killer (NK) cells. 2) Have receptors for specific antigens. 3) Key mediators of adaptive immunity. 4) Nomenclature based upon surface proteins called CD (cluster of determination).
    • Cells of the Immune System • Antigen-presenting cells (APC) 1) Dendritic cells, macrophages, B cells, microglia (CNS). 2) Capture of antigen for display to lymphocytes.
    • Cytokines • Mediators involved in cellular immunity, including hormone-like glycoproteins released by activated T cells and macrophages. • Some are co-stimulators of T cells and T cell proliferation.
    • T-cells CD8 T cell APC Naïve T cell CD4 T cell
    • CD4 T Helper Cells • Activation of macrophages • Activation, proliferation and differentiation of T and B lymphocytes
    • CD4+ T Helper Cells MHC II – Major Histocompatibility Complex* CD4 APC TCR CD8 Immature CD4+/CD8+ T Cell * MHC = HLA (Human Lymphocyte Antigen)
    • CD4+ T Helper Cells CD4 TCR CD8 Mature CD4+ Cell
    • CD4 / APC Receptors CD4 TCR Class II MHC CD3 CD28 B7-1/B7-2 (CD80/CD86) LFA-1 ICAM -1 VLA-4 CD4 T Helper Cell APC
    • The “Immunological Synapse” • The interaction between the TCR and MHC molecules is not strong • Accessory molecules stabilize the interaction – CD4/Class II MHC or CD8/Class I MHC – CD2/LFA-3 – LFA-1/ICAM-1
    • The “Immunological Synapse” • Specificity for antigen resides solely in the TCR • The accessory molecules are invariant • Expression is increased in response to cytokines
    • The “Immunological Synapse” • Engagement of TCR and Ag/MHC is one signal needed for activation of T cells • Second signal comes from costimulatory molecules – CD28 on T cells interacting with B7-1 (CD80) or B7-2 (CD86) – Others • Costimulatory molecules are invariant
    • CD4 / APC Receptors CD4 Costimulatory TCR Class II MHC Receptor CD3 CD28 B7-1/ B7-2 LFA-1 ICAM -1 VLA-4 CD4 T Helper Cell APC
    • CD4 / APC Receptors CD4 Adhesion TCR Class II MHC Receptors CD3 CD28 B7-1/ B7-2 LFA-1 ICAM -1 VLA-4 CD4 T Helper Cell APC
    • Costimulation is Necessary for T Cell Activation • Engagement of TCR and Ag/MHC in the absence of co- stimulation can lead to anergy • Engagement of co-stimulatory molecules in the absence of TCR engagement results in no response • Activation only occurs when both TCR and co-stimulatory molecules are engaged with their respective ligands • Downregulation occurs if CTLA- 4 interacts with B7 – CTLA-4 sends an inhibitory signal
    • Key Steps in T cell Activation • APC must process and present peptides to T cells • T cells must receive a costimulatory signal – Usually from CD28/B7 • Accessory adhesion molecules help to stabilize binding of T cell and APC – CD4/MHC-class II or CD8/MHC class I – LFA-1/ICAM-1 – CD2/LFA-3 • Signal from cell surface is transmitted to nucleus – Second messengers • Cytokines produced to help drive cell division – IL-2 and others
    • CD4 Subsets CD4 T cell CD4 CD4 Th1 cell CD4 Th17 cell Th2 cell
    • Naïve CD4 T cells differentiate into TH1 and TH2 cells Naïve CD4 T cell Th1 Th2 Anti- Pro-inflammatory inflammatory Cytokines • IL-2 Cytokines • Il-12 Reciprocal Inhibition • IL-4 • IL-5 • IFN-γ • Il-10 • TNF • IL-13 • TGF-β (TH3) B cell Macrophage Yong, W
    • CD4 Th17 Cells • Recently described subset of CD4 cells. • Cytokines produced = IL-17 and TNF- alpha. • Stimulated by IL-23 cytokine. Bettelli E, Carrier Y, Gao W, et al. Nature 2006; 441(7090):235-238.
    • T-cells CD8 T cell APC Naïve T cell CD4 T cell
    • CD8 T Cells • Cytotoxic CD8 cells are the only T cells capable of killing other cells by direct contact. • CD8 cells may also serve a regulatory or suppressive role.
    • CD8+ T Cells MHC I – Major Histocompatibility Complex* CD4 APC TCR CD8 Immature CD4+/CD8+ T Cell * MHC = HLA (Human Lymphocyte Antigen)
    • CD8+ T Cells TC Cytotoxic CD4 TCR CD8 TS Suppressor Mature CD8+ Cell
    • CD8 / APC Receptors CD8 TCR Class I MHC CD3 CD28 B7-1/ B7-2 LFA-1 ICAM -1 VLA-4 CD8 T Cell APC
    • Cytotoxic T Cell (Tc) • TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells • They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized • Their targets include: – Virus-infected cells – Cells with intracellular bacteria or parasites – Cancer cells – Foreign cells from blood transfusions or transplants
    • Mechanisms of Tc Action • In some cases, TC cells: – Bind to the target cell and release perforin into its membrane • In the presence of Ca2+ perforin causes cell lysis by creating transmembrane pores • Other TC cells induce cell death by: – Secreting lymphotoxin, which fragments the target cell’s DNA – Secreting gamma interferon, which stimulates phagocytosis by macrophages
    • B Cells • B cells may mature into antibody producing plasma cells. • B cells may function as APC’s.
    • B Cell – CD4 Th Interactions CD40 CD 40 Ligand CD4 Th B Cell TCR Cell MHCII CD28 B7 Cytokine Receptor
    • B Cell Proliferation CD4 Activation and Differentiation CD40 CD 40 Ligand CD4 Th B Cell TCR Cell MHCII CD28 B7
    • Antibodies • Also called immunoglobulins – Constitute the gamma globulin portion of blood proteins – Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen – Are capable of binding specifically with that antigen • There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE
    • Natural Killer (NK) Cells • Bind to and kill antibody-coated cells. • Called “natural killers” because they do not have to recognize antigen first.
    • Immunological tolerance • Definition: – Specific immune unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen) • Significance: – All individuals should be tolerant of their own antigens (self-tolerance); breakdown -->autoimmunity – The induction of tolerance could be exploited to treat autoimmune diseases – Mechanisms of tolerance must first be understood
    • Mechanisms of unresponsiveness to self antigens • Central tolerance – Immature self-reactive T lymphocytes that recognize self antigens in the thymus undergo negative selection (deletion). • Peripheral tolerance – Mature self-reactive T lymphocytes that escape central tolerance and recognize self antigens in peripheral tissues can be inactivated (anergy), killed (deletion) or regulated (suppressed). • “Clonal ignorance” – Mature self-reactive lymphocytes do not respond to self antigens in non-inflamed settings.
    • Multiple Sclerosis What went wrong?
    • Key Steps in the MS Process 1. A breakdown in the ability to distinguish self from non-self. 2. Upregulation of myelin reactive CD4 Th1 cells. 3. Increased permeability of the BBB. 4. The role of B cells and CD8 cells.
    • Requirements for the development of an autoimmune disease Nature Immunology (9): 759-761 (2001)
    • HLA Type and MS Risk • Many autoimmune diseases in humans are linked to particular HLA alleles. • HLA DR2 and DR4 haplotypes are associated with an increased risk for MS.
    • Environmental Factors • Many pathogens have been proposed to have a role in the pathogenesis of MS. • HHV-6, EBV, Chlamydia pneumonia
    • Molecular Mimicry • The pathogen contains similar peptide sequences to peptides found in myelin (MBP, MAG, MOG others). • The pathogen may have similar three- dimensional structures that promote cross- reactive immunity.
    • Immune Dysfunction in MS • Myelin autoreactive CD4 cells may have less of a need for co-stimulation to become activated in a person with MS. • Downregulation of CD4 cells via CTLA-4 may be impaired in MS.
    • Innate and Adaptive Immune Responses TLR (Toll Like Autoreactive Cytokines Receptor) CD4/CD8 Pathogen Innate Immune Cell
    • Naïve CD4 T cells differentiate into TH1 and TH2 cells Naïve T cell Th1 Th2 Anti- Pro-inflammatory inflammatory Cytokines • IL-2 Cytokines • Il-12 Reciprocal Inhibition • IL-4 • IL-5 • IFN-γ • Il-10 • TNF • IL-13 • TGF-β (TH3) B cell Macrophage Yong, W
    • Th1 / Th2 Imbalance Th1 Th2 Normal
    • Th1 / Th2 Imbalance MS
    • Increased BBB Permeability • Some chemokine levels are increased, leading to increased adhesion and attraction of autoreactive T cells into the CNS. • Increased production of matrix metalloproteinase leads to increased BBB permeability.
    • The Role of B Cells in MS • Increased immunoglobulin (Ig) production in the CSF, but not the serum. • CSF Ig in MS shows an oligoclonal distribution, i.e. a limited number of B cell clones contribute to the Ig production.
    • How Do B Cells and Ab Contribute to the Pathogenesis in MS? • B cells may serve as APC’s for autoreactive T cells. • B cells provide costimulation for autoreactive T cells. • B cells may help recruit autoreactive T cells into the CNS. • B cells produce myelin-specific autoantibodies that destroy myelin.
    • The Role of CD8 Cells in MS • Cells in the CNS express MHC I much more so than MHC II. • Myelin-reactive CD8 cells are more common than myelin-reactive CD4 cells in MS brain tissue. • Myelin-reactive CD8 cells secrete chemokines for myelin-reactive CD4 cells.
    • Thanks!