Transcript Understanding the Immune System

Understanding the
Immune System
Andrew E Thompson MD FRCPC
Fellow in Rheumatology
University of British Columbia
OBJECTIVES
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General overview of the immune
system
Introduction to the principal of
autoimmune disease
Two Types of Immunity
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Innate
– “possessed at birth, possessed as an
essential characteristic”
– Always present
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Adaptive
– “to make suitable to or fit to a specific
use or situation”
– Created and modified
Innate Immunity
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Protection by Skin and Mucous
Membranes
Phagocytic Cells
– Remove debris (garbage men)
– Macrophages, Neutrophils, Monocytes
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Natural Killer Cells
– Lymphocytes that kill virally infected cells and
tumours
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Complement System
– “complements antibody in the killing of bacteria”
– A group of >30 proteins found in the blood
Types of White Blood Cells
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There are 5 different types of WBCs
Neutrophils (60%)
– kill bacteria
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Eosinophils (2%)
– Allergic response
– Parasite killing
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Basophils (1%)
– Allergic reactions
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Monocytes (4%)
– Become macrophages
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Lymphocytes (33%)
– Direct the immune system
Lymphocytes
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Two types of lymphocytes
– T-Cells (Thymus derived)
Natural Killer Cells (Innate Immunity)
 CD4+ T-Cells (helper cells)
 CD8+ T-Cells (cytotoxic cells)
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– B-Cells (Bone Marrow derived)
Adaptive Immunity
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Two Components of Adaptive Immune
System
Humoral (humoral mediated immunity)
– B-Cells  Plasma Cells  Antibodies
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Cellular (cellular mediated immunity)
– CD8+ T-Cells  Direct Cellular Killing
– CD4+ T-Cells  Recruitment of other
immune cells (inflammatory response)
Immune Response
Antigen
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Antigen – “any substance when
introduced into the body stimulates
the production of an antibody”
– Bacteria, fungus, parasite
– Viral particles
– Other foreign material
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Pathogen – an Antigen which causes
disease
Immune Response
Antibodies
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Antibody – “a Y-shaped protein,
found on the surface of B-Cells or free
in the blood, that neutralize antigen by
binding specifically to it”
Also known as an Immunoglobulin
Antigen
Humoral Mediated
Immunity
Cellular Mediated
Immunity
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Via T-Cells
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CD8+ T-Cell
– Stimulated  Direct Killing
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CD4+ T-Cell
– Th1  Stimulated  Macrophage Activation
– Th2  Stimulated  B-Cell Activation
Cellular Mediated
Immunity
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Remember B-Cells have direct surface
receptors (immunoglobulins) for
antigen!
T-Cells do not possess these receptors
Instead, T-Cells need to have antigen
presented to them (like on a silver
platter)
Antigen is presented to T-Cells by …
Antigen Presenting Cells
Cellular Mediated
Immunity

TwoGeneral
Types of Antigen Presenting
Professional
Cells
(APCs)APC
APC
All Cells
B-Cells, Macrophages,
Dendritic Cells
Present antigen found inside
Present antigen found
the cell
outside the cell
Use an MHC class I
Use an MHC class II
molecule to present antigen molecule to present antigen
Interact with CD8+ T-Cells Interact with CD4+ T-Cells
 Cellular Killing
T-Cell Help
General APCs
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All cells in the body are always
“cleaning” themselves
When they find some “dirt” (viral
protein, normal cellular debris) 
Need to make sure it is not something
harmful
Attach the “dirt” to an MHC-I molecule
Present this “dirt” to a CD8+ T-Cell
General APCs &
+
CD8 T-Cells
Professional APCs
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Professional APCs have the ability to
take up (endocytosis) extracellular
proteins (self or foreign)
Break down this protein into peptides
and attach it to an MHC-II molecule
Present the peptide to a CD4+ T-Cell
Professional APCs
+
CD4 Th1-Cells
Professional APC
CD4+ Th2-Cells
Summary of Adaptive
Immunity
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Humoral
– Antibody Production – B-Cells
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Cellular
– CD8+ T-Cells  MHC-I  Cytotoxic
– CD4+ Th1-Cells  MHC-II  Activate
Macrophages
– CD4+ Th2-Cells  MHC-II  Activate
B-Cells to produce Antibody
What Prevents the Body
from Attacking Itself?
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Two Concepts
– Central Tolerance
– Peripheral Tolerance
Central Tolerance
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Occurs during lymphocyte (T & B Cells)
maturation in the primary lymphoid organs
(thymus & bone marrow)
The body presents immature lymphocytes
with self-antigen
Lymphocytes which react with high affinity
to this self-antigen are deleted (apoptosis)
Lymphocytes which react with low affinity
are positively selected to mature
Central Tolerance
Peripheral Tolerance
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During maturation, lymphocytes cannot be
presented with every self-antigen
– Some antigens are found in low concentrations
in specific locations
– New antigens are formed during life
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Therefore, lymphocytes come in contact
with new antigen
Particular importance to the cytokine
environment present when lymphocytes
encounter this new antigen
Rheumatoid Arthritis (RA)
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RA is thought to be T-Cell mediated
Most widely accepted hypothesis:
– Professional APC encounters some
“unknown” antigen
– It presents this “unknown” antigen to a
CD4 T-helper Cell
– In a genetically predisposed individual,
this starts an immune chain reaction
Cellular components of synovial inflammation
Click here to run the animation
Mechanisms in Rheumatology ©2001
Rheumatoid Arthritis
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Certain cytokines are important in
driving the inflammatory process in RA
Two important cytokines are
– Tumour Necrosis Factor – alpha (TNF-α)
– Interleukin-1 (IL-1)
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Rheumatologists have developed new
medications which target these
cytokines
Rheumatoid Arthritis
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Drugs which inhibit TNF-α
– Infliximab (Remicade®) – Chimeric
monoclonal antibody directed against
TNF-α
– Etanercept (Enbrel®) – Soluble receptor
which “floats” around and mops up any
TNF-α
Infliximab (Remicade®)
Infliximab: Mechanism of action
Click here to run the animation
Mechanisms in Rheumatology ©2001
Etanercept (Enbrel®)
Etanercept: Mechanism of action
Click here to run the animation
Mechanisms in Rheumatology ©2001
Ankylosing Spondylitis
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Up to 90% of white patients with AS
are positive for HLA-B27
HLA-B27 is an MHC Class I molecule
HLA-B27
Ankylosing Spondylitis
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Remember – MHC is part of the
adaptive immune system – so
everybody is different
Those people with HLA-B27 type of
MHC Class I are at higher risk for
developing AS
But Why?
Ankylosing Spondylitis
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The HLA-B27 molecule has a specific
binding groove
Only certain peptide fragments will fit
into this binding groove
Big Question: What peptide fragment
could be responsible for the initiation
of Ankylosing Spondylitis?
Summary
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Innate and Adaptive Immunity
B-Cells
– Act as Professional APCs for Th2-Cells
– Turn into plasma cells and synthesize
antibody
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T-Cells
– Natural Killer Cells – Innate Immunity
Summary
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CD8 T-Cells
– Interact with MHC Class I (any cell)
– Direct Cellular Killers
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CD4 T-Cells
– Interact with MHC Class II (professionals)
– Th1– Cellular activation - Macrophages
– Th2– B-Cells - Antibody