Introduction to the
Immune System
Stephen Canfield
Asst. Prof. Medicine
Allergy/Immunology
Prologue:
The Immune System in Health
Defense against invading organisms
Surveillance against malignancy
Orchestrator of tissue repair
Patrol against senescence
Interface with metabolic processes
Body temperature
Fe3+ balance
Body mass
Prologue:
The Immune System in Disease
Too little - immune deficiency
Too much - attack on self
Too long - tissue remodeling
Too vigilent - hypersensitivity
Too effective - graft rejection
Prologue:
Tips on Challenges You Will Face
Details, details, details - new vocabulary
Rules are built on experimental observation
Every rule has an exception
The system is a network of many players
Zoom in to study a player, but remember...
Pan around to see how it fits in big picture
The elegance is in the orchestra, not one player
Understanding is evolving
New concepts and new players added every year
Plight of the Hapless Pathogen
Epidermis,
Mucous Membranes
Serum,
Lymph
Innate
Pre-existing Hostile Milieu
Pre-positioned guards ready to engulf
Dermal
and
submucosal
tissues
Adaptive
Sentries ready to sound the alarm
Reconnaissance specialists
Return invader fingerprints to the central
immune system
Peripheral
tissues
Immune Brain
Uses recon data to build the perfect responder
Remembers the invader for future rapid response
2o Lymphoid
Organs
2o Lymphoid Organs:
LN, Spleen
Mucosa-Associated Lymphoid
Tissue
Innate Immune System
Soluble
Complement Cascade
Cellular
Phagocytes
Natural Killers
Array of sensors for danger
Recognize pathogen-associated molecular
patterns (PAMPs) - shared by many pathogens
LPS
CpG DNA
Mannose
Flagellin
dsRNA
Rapid activation - no prior contact needed
The Complement System
The pre-existing hostile milieu
Set of ~25 highly abundant serum proteins
Forms a proteolytic cascade at the cell surface
Generation of
cell-bound fragments
Release of
soluble fragments
Lysis of pathogen cell
or
Tagging of pathogen
for phagocytosis:
opsonization
Recruit phagocytes
Cells of the Innate System
Phagocytes
Macrophages
Neutrophils (aka: polymorphonuclear leukocytes)
Dendritic Cells
Natural Killers (NK) Cells
Hematopoietic Lineage
Macrophages
Tissue-resident sentinels
& refuse collectors
Arrayed with sensors:
- PAMP receptors
- Complement Rs
- Antibody Rs
Reorganize cytoskeleton
in response to these inputs:
Seek & Engulf
Sompayrac: How the Immune System Works, 3rd Edition. Copyright 2008 by Blackwell Publishing, Inc.
M as Refuse Manager
Used with permission, Cells Alive.com
Neutrophils
Most abundant blood leukocyte
- 3 million/day exit bone marrow
- production with infection
Exit blood tissue when called
Chemotax along gradients:
- pathogen components
- complement fragments
- macrophage signals
Engulf and kill
Survive hours to days - major component of pus
Lichtman, et al: Review of Immunology, Copyright 2005 by Elsevier, Inc.
Neutrophil Chemotaxis
Used with permission, Cells Alive.com
Macrophage/Neutrophil Killing
Phago-lysosome contents
Phagocyte Oxidase oxygen radicals
Inducible NO Synthase nitric oxide
Acid pH
Proteases
Janeway, et al: Immunobiology, 6th Edition. Copyright 2005 by Garland Science.
Dendritic Cells
Phagocyte with a dual career - reconnaissance specialist
Starts out a tissue-resident sentinel
Constant pinocytosis - small bites
sampling surroundings
Pathogen contact career change
Picks up stakes - migrates from tissue
to local lymph node
Literally presents pathogen
fragments to cells of the adaptive
system
Bridge between the innate and
adaptive responses
Lichtman, et al: Review of Immunology, Copyright 2005 by Elsevier, Inc.
Soluble Intercellular Signals
Cytokines - secretory proteins that mediate
immune cell development & inflammatory
reactions
Bind to specific receptors on signal-receiving cells
Influence the state of activation, effector
functions, or lineage of the recipient cell
Interleukins - cytokines that generally function to
communicate between leukocytes
Chemokines - small cytokines that function in
leukocyte chemotaxis: hence chemo- +
-kine
Innate Call for Help
PAMP recognition M activation ALARM
Secrete interleukin-1 (IL-1)
Secrete tumor necrosis factor (TNF-)
Two critical innate immune system cytokines:
Activate nearby neutrophils
Alter local vascular endothelium
recruit more neutrophils
Signal DCs to mature - initiate migration
Signal hypothalamus to body temperature
Is that all there is?
Yes, for 99% of the animal kingdom
But if youre a jawed vertebrate... theres more!
Adaptive Immune System: B & T Lymphocytes
Learn from pathogen contact: effectiveness
Discern fine molecular differences:
Addition of a phosphate group to an amino acid
side chain in a polypeptide
The target of these lymphocytes is termed an antigen
(abbreviated Ag)
How the Adaptive System Learns
Each cell develops with a unique Ag receptor
Generated randomly
Gen. by genomic DNA rearrangement
Extremely diverse: ~100 billion possible Rs
Naive lymphocytes patrol 2o lymphoid organs
Most never find Ag survive ~3 weeks
Lucky few: Ag encounter activation and
proliferation clonal expansion
B Lymphocytes
Develop in the bone marrow
Each new B cell makes a unique antigen receptor (BCR)
This BCR is also called surface immunoglobulin (Ig),
or antibody
Ag binding by BCR clonal expansion
Some daughter cells become plasma cells: immunoglobulin
secreting factories
Others become memory B cells: long-lived, capable of rapid
response on re-encounter of antigen
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Immunoglobulins
A
Binntig
din en
g
en
tig ing
n
A ind
B
VH
Tetramer
VL
2 H chains + 2 L chains
CH1
Complementarity
Determining
Regions (CDRs)
CL
Interchain disulfides
CH2
Variable End - CDRs
Huge diversity
CH3
Constant End
Fc Region:
Complement Initiation
Fc Receptor Binding
Determines Ig Class:
IgM, IgD, IgG, IgA, IgE
and effector functions
Immunoglobulin-Antigen Binding
Ag
VH
Ag
VH
VL
VL
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T Lymphocytes
Hematopoietic origin (marrow) but most of
their development occurs in the thymus
Like B cells, T cells:
Utilize a surface Ag receptor (TCR)
Extreme diversity of Ag binding
Ag receptor triggering is required to initiate
clonal expansion
Ag experienced cells produce a long-lived
memory population
T Lymphocytes
Unlike B cells, T cells:
Never secrete their Ag receptor
Cannot bind free antigen molecules - only
peptides of 8-25 amino acids
Require that Ag be presented to them on a
special billboard:
Major Histocompatibility Molecule
Abbas, et al: Basic Immunology, 3rd Edition. Copyright 2008 by Saunders, an imprint of Elsevier,
Inc.
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Major Histocompatibility Molecules
Two Classes: I and II
Highly polymorphic
Vary greatly from one
individual to the next
Identified as the basis for
organ rejection between
genetically non-identical
individuals
Also termed Human
Leukocyte Antigens (HLA)
Reproduced with permission CartoonStock.com
MHC Class I
antigen
peptide
Expression:
All nucleated cells
Structure:
-chain + 2 microglobulin
Antigenic peptides:
Derived from cells
cytoplasm (generally from
proteins made within the
cell)
Viral Peptides
MHC I
Cytoplasm
Nucleus
Adapted from Janeway, et al: Immunobiology, 6th Edition. Copyright 2005 by Garland Science.
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MHC Class II
Expression:
Antigen presenting cells
(APCs)
Examples - macrophages,
dendritic cells, B cells
Structure
and chains
MHC II
Antigenic peptides
Lysosome
Derived from the cells
endocytic compartment
(generally from proteins
external to the cell)
Nucleus
H+
Adapted from Janeway, et al: Immunobiology, 6th Edition. Copyright 2005 by Garland Science.
Peptide/MHC Class I
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T Cell Career Paths
CD4+ T cells
Most commonly termed
helper T cells (THs)
IFN-
TH
Recognize Ag peptide
presented by MHC Class
II
Provide essential
activation signals to B
Cells, CD8+ T cells, and
phagocytes
IL-4
TH
Cytokine
CD40L
Contact
soluble - cytokines
surface molecules - CD40LJaneway, et al: Immunobiology, 6th Edition. Copyright 2005 by Garland Science.
CD40
T Cell Career Paths
CD8+ T cells
Most commonly termed
cytotoxic T cells (CTLs)
Recognize Ag peptide
presented by MHC Class I
Kill target cells expressing
abnormal cytoplasmic
proteins
Infected by intracellular
pathogen - eg, virus
Tumor cells
Killing
puncture cell membrane
Induce programmed cell
death or apoptosis
Janeway, et al: Immunobiology, 6th Edition. Copyright 2005 by Garland Science.
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Natural Killer (NK) Cells
Lymphocyte without BCR or TCR - innate
like
Dont require prior contact or clonal expansion
Receptors recognize distressed cells:
Virally infected
DNA damaged
Transformed (malignant)
Also recognize cells opsonized by Ig
Kill, using a mechanism similar to CTLs
Innate vs. Adaptive Immunity
Innate
Adaptive
On first
contact
Immediate response
5-10 days for clonal
expansion
Receptor
Specificity
Broad classes of
molecules
Highly specific for a
single structure
Ligands
Microbial origin
Potentially any
protein, lipid, or carbo
Memory
None
Long-lived
Recurrent
contact
Same response as
previously
Rapid response
tailored to pathogen
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Adaptive Immune System
Clonal Recognition, Molecular Specificity
T Cells
Helper
B Cells
Cytotoxic
Directors
Killers
Antibody Producers
Innate Immunity - First Responders
Recognize Ancient Pathogen Assoc. Molecular Patterns
Cell Wall Components Bacterial DNA
Viral RNA
Complement
Lyse Opsonize
M
Kill
Phagocytes
Neutrophils Dendritic Cells
Wall Off
Recruit Adaptive Arm
Integument (Skin, Mucous Membranes) - Passive
Summary
1.
We are protected from dissolution at the hands of microbes by an army of specialists
each of which provides an essential piece of a complex defense.
2.
The innate arm, the most ancient, is the first to respond. Its cells utilize evolutionarily
conserved pathogen characteristics to recognize danger and act rapidly to tag, engulf,
lyse, or wall off the invader.
3.
The innate system recruits the more highly evolved adaptive system through specialized
reconnaissance experts termed dendritic cells (DCs). These cells engulf bacteria and
virally infected cells, digest the pathogen proteins, and present peptides from these
proteins to naive CD4+ T cells, resulting in their activation and clonal expansion.
4.
The adaptive system utilizes a unique gene rearrangement technique to generate
awesome diversity and subtlety in antigen recognition: the lymphocyte repertoire.
5.
a) CD4+ T cells provide cytokine and contact-dependent help to B cells, resulting in a
highly specific, high-affinity antibody response.
b) CD4+ T cell help and immunoglobulins in turn provide signals to the innate system,
greatly facilitating phagocytosis and killing.
6.
T cell direction, required for the optimal immune response, is completely dependent
on the peptides presented. Highly polymorphic MHC genes, and co-dominant
expression of multiple MHC molecules helps ensure that every individual can make a
response to some part of every pathogen.
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