basic immunology and multiple sclerosis
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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
Innate(Nonspecific)
1o line of defense
Adaptive(Specific)
2o line of defenseProtects/re-exposure
CellularComponents
HumoralComponents
CellularComponents
HumoralComponents
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
• Beneficial:
• Protection from invaders
• Elimination of altered self
• Detrimental:
• Discomfort and collateral damage
(inflammation)
• Damage to self (hypersensitivity or autoimmunity)
Effects of the Immune System
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
Innate Immunity Adaptive Immunity
Comparison of Innate and Adaptive Immunity
• No memory
• No time lag
• Not antigen specific
• A lag period
• Antigen specific
• Developmentof memory
Cells of the Immune System
Immune System
Myeloid Cells Lymphoid Cells
Granulocytic Monocytic T cells B cells
NeutrophilsBasophils
Eosinophils
MacrophagesKupffer cells
Dendritic cells
Helper cellsSuppressor cellsCytotoxic cells
Plasma cells
NK 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.
• 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.
Cytokines
T-cells
APC NaïveT cell
CD8T cell
CD4T cell
CD4 T Helper Cells
• Activation of macrophages• Activation, proliferation and differentiation
of T and B lymphocytes
CD4+ T Helper Cells
CD4
CD8
TCR
MHC II – Major Histocompatibility Complex*
Immature CD4+/CD8+ T Cell
APC
* MHC = HLA (Human Lymphocyte Antigen)
CD4+ T Helper Cells
CD4
CD8
TCR
Mature CD4+ Cell
CD4 / APC Receptors
CD4 T Helper Cell APC
CD4
TCR
CD3
CD28
LFA-1VLA-4
Class II MHC
B7-1/B7-2 (CD80/CD86)
ICAM -1
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 T Helper Cell APC
CD4
TCR
CD3
CD28
LFA-1VLA-4
Class II MHC
B7-1/ B7-2
ICAM -1
Costimulatory Receptor
CD4 / APC Receptors
CD4 T Helper Cell APC
CD4
TCR
CD3
CD28
LFA-1VLA-4
Class II MHC
B7-1/ B7-2
ICAM -1
Adhesion Receptors
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
CD4T cell
CD4Th1 cell CD4
Th2 cell
CD4Th17 cell
Naïve CD4 T cells differentiate into TH1 and TH2 cells
Th1 Th2
T cell
NaïveCD4
Macrophage
Pro-inflammatory Cytokines
• IL-2• Il-12• IFN-γ• TNF
Anti-inflammatoryCytokines
• IL-4• IL-5• Il-10• IL-13• TGF-β (TH3)
B cell
Reciprocal Inhibition
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
APC NaïveT cell
CD8T cell
CD4T 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
CD4
CD8
TCR
MHC I – Major Histocompatibility Complex*
Immature CD4+/CD8+ T Cell
APC
* MHC = HLA (Human Lymphocyte Antigen)
CD8+ T Cells
CD4
CD8
TCR
Mature CD8+ Cell
TC
Cytotoxic
TS
Suppressor
CD8 / APC Receptors
CD8 T Cell APC
CD8
TCR
CD3
CD28
LFA-1VLA-4
Class I MHC
B7-1/ B7-2
ICAM -1
• 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
Cytotoxic T Cell (Tc)
• 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
Mechanisms of Tc Action
B Cells
• B cells may mature into antibody producing plasma cells.
• B cells may function as APC’s.
B Cell – CD4 Th Interactions
B Cell
CD40
MHCII
B7
Cytokine Receptor
CD4 Th Cell
CD 40 Ligand
TCR
CD28
B Cell
CD40
MHCII
B7
CD4 Th Cell
CD 40 Ligand
TCR
CD28
B Cell Proliferation and Differentiation
CD4 Activation
• 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
Antibodies
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 Th1cells.
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
Innate Immune Cell
TLR (Toll Like Receptor)
Pathogen
Cytokines Autoreactive
CD4/CD8
Naïve CD4 T cells differentiate into TH1 and TH2 cells
Th1 Th2
T cell
Naïve
Macrophage
Pro-inflammatory Cytokines
• IL-2• Il-12• IFN-γ• TNF
Anti-inflammatoryCytokines
• IL-4• IL-5• Il-10• IL-13• TGF-β (TH3)
B cell
Reciprocal Inhibition
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!