Transcript The Immune System - University of Arizona

The Immune
System
Douglas Larson
Sarver Heart Center
Room 6152
626-0944
[email protected]
Course Format
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Mondays
– basic concepts
Wednesdays – applied concepts
Fridays
– problem based learning
Exams
– 50% multiple choice and
50% essay
Final
– NIH grant take-home
grant
Today’s Outline
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Innate and Adaptive immune systems
Major Histocompatibility Complex (MHC)
Human Leukocyte Antigen (HLA)
Antigen Presentation
Cytokines
Th1 versus Th2
Effector functions
Question
• What are the 2 major arms of
the immune system?
The Immune System
Adaptive and Innate Immunity
• The adaptive immune response confers
lifelong protective immunity to re-infection
with the same pathogen.
• The innate immunity, which many
microorganisms could be engulfed and
digested by phagocytic cells
Innate vs. Adaptive
Innate
Cytotoxicity
Phagocytosis
stem
Adaptive
CD4+
stem
CD8+
Macrophage
B-cell
Cytotoxicity
Cytolysis
Cytolysis
Sequence of Immune Response
Innate Immune System
Immediate response
No memory
No specific recognition
ADAPTIVE IMMUNE
SYSTEM
T-lymphocytes
T-cytotoxic
B-lymphocytes
Plasma cells
Cytoyoxic
Antibodies
Response takes 7 to 10 days
Adaptive Immune System
Adaptive
Immune
Response
T-Cells and Antigen Presenting
Cells
Major Histocompatibility Complex
(MHC)
• There are two major classes of MHC
molecules associated with T-cell
function, namely:
MHC Class I
MHC Class II.
Major Histocompatibility Complex
• The major function of the molecules
encoded by the Mhc is to facilitate
the display of unique molecular
fragments on the surface of cells in
an arrangement that permits their
recognition by immune effectors such
as T-lymphocytes.
Major Histocompatibility Complex
HUMAN LEUKOCYTE ANTIGEN (HLA)
HUMAN LEUKOCYTE ANTIGEN
(HLA)
• The HLA is related to MCH Class I
and II expression
• HLA is related to risk for
autoimmune diseases and allograft
transplantation survival.
HLA - Autoimmunity
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Rheumatoid Arthritis
Multiple Sclerosis
Myasthenia gravis
Ankylosing spondylitis
Diabetis (Type I)
DR4
DR2
B8
B27
DR3, 4
Antigen Presenting Cells
Antigen Presenting Cell
• Macrophages,
• Vascular endothelial cells,
• B-cells, and
• Dendritic cells (Heart)
• Express the major histocompatibility
complex (MHC) molecules and can
present antigen to the T-cells.
Major Histcompatibility Complex
MHC - Antigens
• An antigen (Ag) is a specific
molecule that is recognized by an
Ab or T-cell Receptor (TcR).
The soluble Mediators of T-cell
Immunity
Soluble Mediators of
Immunity
• Cytokines secreted signaling
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molecules
The nomenclature and functions of
well-defined T-cell cytokines.
Each cytokine has multiple activities
on different cell types. The mixture
of cytokines secreted by a given cell
type produces many effects through
what is called a ‘cytokine network’.
CYTOKINES
• Interleukins
• Colony Stimulating
• Interferons
• Chemokines
• Growth Factors
Factors
Macrophage - Cytokines
• Macrophages process and present antigen,
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produce chemokines and cytokines such as
interleukin (IL)-1b, IL-6, IL-12, IL-18,
tumor necrosis factor (TNF)-a, and IL-10,
and phagocytose apoptotic and necrotic
cells.
Acting directly or under the influence of
other immune cells, macrophages capture
extra- and intracellular pathogens,
eliminate invaders, and deliver them to
appropriate subcompartments of lymphoid
organs
Macrophage -Cytokines
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other cell types:
microglial cell of the brain,
alveolar macrophages,
Kupffer cells of the liver,
Synovial cells of joints,
Mesangial cells of the kidney,
and vascular endothelial cell of blood
vessels
Macrophage
 Phagocytes
 Can prime T-cells
 10 –18 m
 Well developed golgi complex
 Express MHC Class II.
 Secrete IL-1b, IL-6, TNF-a, and INFs
 Express CD14, CD64, CD35, CD11a,b,c,
MFR(mannosyl-fucosly receptors)
Serve as a major antigen presenting
cell
Macrophage - Cytokines
• Pro-inflammatory
•IL-1b
•TNF-a
•IL-6
• These
cytokines
are secreted as an early
response to an immune stimulus.
Pro-inflammatory
Cytokines
Tumor Necrosis Factor
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Tumor necrosis factor (TNF) was originally
described as a factor responsible for
lipopolysaccharide (LPS)-induced
hemorrhagic necrosis of tumors in animals.
TNF was later independently identified as
“cachectin,” a factor responsible for
wasting of animals during parasitic
infections and patients with heart disease
and cancer.
Tumor Necrosis Factor
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Produced as a pro-hormone of 233 amino
acids, TNF-a is anchored in the cell
membrane and then processed to a 157
residue mature protein by cleavage of a 76
residue signal peptide.
In response to a wide variety of infectious
or inflammatory stimuli (e.g.,LPS, viruses,
fungal or parasitic antigens, IL-1b, TNF-a),
both transcription and translation of TNF
precursor is increased, and large amounts
of mature protein are rapidly released into
the circulation.
Tumor Necrosis Factor
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The soluble form of TNF, consisting of
157 amino acids, is derived from the
transmembrane precursor by proteolytic
cleavage. The specific metalloproteinase
responsible for this process (TNF
converting enzyme or TACE) is an 824amino acid transmembrane protein whose
catalytic portion is part of the
extracellular domain.
Tumor Necrosis Factor
• The cellular effects of TNF-a are
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highly pleiotropic.
At low concentrations,TNF-a effects
paracrine or autocrine regulation of
leukocytes and endothelial cells and,
thus, serves as an important
regulator of the inflammatory
response.
Pro-inflammatory Cytokines
IL-6
• Mobilizes acute phase proteins
• Mannose binding protein
• C-reactive protein
• opsonin
• act like C1q
IL-6 activation of CRP
• Acute Phase Proteins C-reactive
Proteins
 Innate immune function
 Binds to molecular groups on bacteria
and fungi
 Facilitates opsonization
 Activates C'
CRP -Acute Phase Proteins
IL-6 and CHF
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IL-6 has been implicated in pathogenesis
of CHF.
• IL-6 is elevated with CHF and
associated with NYHA classification.
• IL-6 also has been implicated in
osteoporosis that develops with CHF
• Elevated IL-6 is associated this a poor
prognosis.
Roig J Am Coll Cardiol 82;688-90:1998
CYTOKINES
• Interleukins
• IL-1a, IL-1b, IL-2, IL-3, IL-4,
IL-5, IL-6, IL-7, IL-9, IL-10,
IL-11, IL-12, IL-13,
IL-14, IL-15
IL-2
• IL-2 is produced by CD4+ TH and
CD8+ cells. It is the most potent
of growth factors and activators.
• The IL-2r consists
of two chains,
each of which can bind IL-2 with
low affinity, and following
stimulation the high affinity
receptor is expressed with up to
50,000/cell.
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The low/High-affinity IL-2
receptor (CD25)
IL-2 Modulation by
Immunosuppressants
IL-2 Gene Expression
IL-2r 2nd Messenger
Lymphocyte
• T lymphocytes or T cells
• Helper T cells (CD4+), which
activate other T-cells, B-cells
and macrophages
• Cytotoxic T cells (CD8+), which
kill cells infected with viruses and
fungi, tumors, and transplanted
tissues.
CD4 - Th1 and Th2 cells
• T-helper (CD4) cells are defined by
cytokine profile secretion
• Th1 cells help the immune responses
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of CD8+ and macrophages function.
Th2 cells help the activation of Bcells toward antibody formation.
Lymphocyte
• T-helper: CD4+
• TH1 secretes IL-2, IFNg, and TNFb
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which promote T-cytotoxic (TC)
TH2 secretes IL-4, IL-5, IL-6, and
IL-10 which promote B cell
CYTOKINES
Tc
IL-2
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B
IL-4
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IFNg
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Th2
Th1
IL-10
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IL-12
IL-4
Th0
T-cell Cytotoxicity
CD8 - Cytotoxic T-cell
• Once naive T cells have completed
their development in the thymus,
they enter the bloodstream, from
which they migrate through the
peripheral lymphoid organs – and
attach to the High endothelial
venules (HEV).
CD8 - Cytotoxic T-cell
• Activated
effector T cells, armed
effector T cells, are triggered to
perform their effector functions
immediately upon contact with cells
bearing the peptide:MHC complex
for which they are specific.
T-cytotoxic:
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CD8
Effector arm of the immune response
Soluble mediators:
• Perforins,
• Serine esterase,
• Endonuclease
• Tumor Necrosis Factor (TNF),
• Interferon a,b,g (INF a,b,g)
• Activation via Class I MHC
and TCR
Cytotoxic T-Cell
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(CD-8 )
• Viruses infect all cells
• When replicating intracellularly, they
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are unaffected by antibodies and
macrophages
Virally infected cells are eliminated
by cytotoxic T-cells.
To prevent destruction of healthy
cells their activity must be tightly
controlled.
Necrosis vs. Apoptosis
• Necrosis: is the death of cells or
tissues due to chemical or physical
injury.
• Necrosis leaves extensive cellular
debris that needs to be removed by
phagocytes, while apoptosis does
not.
Necrosis vs. Apoptosis
• Apoptosis, or programmed cell
death, is a form of cell death in
which the cell activates an internal
death program.
• It is characterized by nuclear DNA
degradation, nuclear degeneration
and condensation, and the
phagocytosis of cellular residuals.
Induction of apoptosis
Natural killer cells (NK)
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Derived from bone marrow
15% of lymphoid pool
No T-cell receptor (TCR)
Respond to non-MHC expressing cells
Inhibited by MHC Class I expression
Respond to IL-2
Able to kill certain tumors, virusinfected cells, and IgG coated Targets.
Release IL-1b, GM-CSF, and IFN-g
Natural killer cells (NK)
T-Cell Immunology
Notes
Class notes and Powerpoints will be
posted on a WEB site.
• Goto http://perfusion.arizona.edu
• Course PHCL 582
• Username: phcl582
• Password: s06ua582