Innate vs. Acquired Immunity- conceptual and practical difference

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Lecture 1 Introduction to the Principles of
Immunity

• Innate vs. Acquired Immunity- conceptual and
  practical difference
• The vertebrate invention of acquired immunity
• How does innate immunity work? (Chapters 1 and 8)
• Cells
• Recognition receptors
• Mediators

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The Triumph of Death - Pieter Brueghel the Elder
ca. 1562
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Why the immune system?

• What is its function?
• How widely is it present in nature?
• Why does it affect so many aspects of life?
• How can we alter it for improved quality of life?

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How does the Immune System (IS) affect your life?
Autoimmune diseases Graves'/hyperthyroidism,
Type I diabetes, pernicious anemia, rheumatoid
arthritis, thyroiditis, and vitiligo The
incidence of 24 autoimmune diseases is 1/31
Americans. Women are at 2.7x greater risk Clin
Immunol Immunopathol 1997 Sep84(3)223-43
Cancer Evidence in the past year indicates that
the immune system does indeed function in tumor
surveillance
Hypersensitivity Diseases Allergy-Incidence rise
from 6-20 in the past two decades Asthma-Inciden
ce rise from 3-8 of the total population in the
past two decades -The hygiene hypothesis- Heart
Disease-The blood vascular system is an integral
part of the immune system. It instructs
leukocytes to migrate from the blood to a site of
infection. New evidence supports that idea that
coronary heart disease results from chronic
arterial inflammation
Infectious Diseases Almost any deficiency in
immunity--you die
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Big bugs have little bugsUpon their backs to
bite emLittle bugs have littler bugsAnd so on
ad infinitum -Ogden Nash, I think
Immune Evolution

• Colonization of large organisms by smaller
  organisms or viruses is the inverse food chain
• Large complex organisms present a source of
  energy and a habitat for smaller organisms and
  viruses via colonization
• Colonization and defense against colonization is
  a fundamental principle in biology
• The immune system is principally and most
  importantly evolved to sculpt colonization to
  benefit the host

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Dance of the Eons

• Virtually every organism faces pressure from
  viral or microbial colonization and so has
  evolved strategies to control colonization
• Likewise, every parasitic organism or piece of
  selfish DNA has evolved a strategy to mitigate
  the effects of immunity
• This eternal waltz of parasites and their hosts
  surely began with the origin of life

• Corollaries
• Just as predator species improve the fitness of
  their prey, colonial agents select for fitness in
  their hosts
• Just as a host cannot be too permissive for a
  parasitic agent, the parasitic agent cannot be
  too effective in killing a host
• The more effective the immune system, the more
  complicated and evolved the parasite
• Perhaps we should view the host-parasite
  interaction as a constantly escalating war or an
  uneasy (metastable) truce

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One view of animal phylogeny
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Biological Inventionof Acquired Immunity
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Innate vs. Adaptive Immunity
Figure 1.5
Memory
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Innate Immunity

• All animals have an innate immune system
• Innate immunity is manifest in many cells of the
  body. The basis is the recognition of molecular
  patterns, that occur in microbes but not animals
  (e. g., unmethylated DNA sequences, dsRNA, cell
  wall components, etc)
• This is the bedrock of immunity in all
  organisms--even bacteria have defense mechanisms
  against bacterial viruses

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Innate Immunity, cont

• An apparent limitation is that parasitic agents
  have a generation time orders of magnitude less
  than that of their hosts
• A second limitation is that there is only limited
  amplification of the response
• A third limitation is that there is no memory

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Adaptive Immunity

• Recognizes any biochemical determinant
• Provides a mechanism for immune recognition that
  can evolve as rapidly as the parasite (clonal
  selection)
• There is rapid amplification of a response
• There is memory

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• To a given organism, other species can represent
  a source of energy and nutrition
• Food Chain- Large animals eat smaller animals
  (simplified)
• Inverse Food Chain Colonization - Small animals
  (or microbes and viruses) colonize larger animals
  that, in turn, provide an environment for
  replication
• All living organisms have a form of immunity to
  defend against colonization from bacteria to
  blue whales to giant sequoia, there are a myriad
  of mechanisms that have evolved to prevent
  colonization

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Innate vs. Acquired Immunity
The innate immune system of a species detects
molecular patterns found in other (parasitic)
organisms, but not in the species itself.
Detection sets up a response that can kill the
parasite. The limitation of the innate immune
system is that parasitic microbes have a much
shorter generation time than higher animals, and
therefore variants can arise to circumvent the
recognition or response. The acquired immune
system learns the molecular self and anything
else is potentially a target for response. The
ability to respond to new molecular determinants
is on a time-scale similar to the generation time
of microbes.
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Components Principle Functions Barriers Epithelial
layers Prevent entry Defensins and
Cryptidins Microbial killing Circulating and
Tissue Effector Cells Neutrophils Early
phagocytosis and killing of microbes Mast
Cells Release of inflammatory granules Macrophages
Efficient phagocytosis and killing of microbes
cytokines Eosinophils Nasty toxic cells designed
to kill helminths (worms) NK cells Lysis of
infected cells, activation of macrophages Circulat
ing Proteins Complement (C) Killing of microbes,
opsonization of microbes, actvn
leukocytes Mannose-binding protein Opsonization
of microbes and activation of C C-reactive
protein Opsonization of microbes and activation
of C Lysozyme Bacterial cell wall
lysis Cytokines TNF, IL-1, 6,
18 Inflammation IFN a, b Resistence to viral
infection IFN g Macrophage activation IL-12 IFNg
production by NK cells IL-15 Proliferation of NK
cells, memory T cells IL-10, TGF b Control of
Inflammation
Components of Innate Immunity
Adapted from Abbas (Saunders)
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Figure 8.6
Defensins (epithelium)
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Figure 1.4
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Figure 8.9
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Figure 8.1
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Salmonella infection with and without adaptive
immunity
Mice deficient for innate immunity (macrophage)
WT
T lymphocyte deficient
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What is the basis for innate immunity, and how
does is relate to vertebrates? Drosophila
melanogaster mutants were found that were
susceptible to fungal and bacterial infections.
Immunity in Drosophila (Innate) Toll mutant
lacks defense against fungal infections 18
Wheeler lacks defense against bacteria This led
to the discovery of a family of receptors known
as the Toll-related receptors (TLR) present in
vertebrates
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Innate Immunity Pattern Recognition
Molecular Pattern of Microbe Source Pattern Recognition Receptor Principle Innate Immune Response
dsRNA Replicating viruses ds-RNA activated kinase TLR3 IFNa,b
LPS Gram-negative bacteria LBP/CD14/TLR4 Macrophage activation
N-formylmethionyl peptides Bacterial proteins NFM receptors Neutrophil and macrophage act.
Mannose-rich glycans Microbial glycoproteins MF mannose recptr Plasma mannose lectin Phagocytosis Opsonization, C activation
Phosphorylcholine and related Microbial membranes Plasma c-reactive protein Opsonization, C activation
CpG (PuPuCpGPyPy) Bacteria ? TLR9/DNAPK Macrophage activation
Other teichoic acid,
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Genes to Cells 6 (9), 733-742 Kiyoshi Takeda and
Shizuo Akira (2001)
Activation of the transcription factor NFkB
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Toll family of receptors
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Toll-like receptors TLR1-10

• Recognition alone or in combinations of
• LPS (gram-negative cell wall component)
• Lipopeptides and peptidoglycan (gram positive
  cell wall components
• Yeast particles

TIR Domain
Activation of NFkB transcription factor and thus
induction of cytokines and other genes that are
anti-microbial
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Interface between the innate and adaptive immune
systems
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Unified Immunity Concept

• Innate Immunity
• molecular pattern recognition
• inflammation (alarm and danger)
• mobilization of many immune components including
  presentation of foreign agents to the lymphoid
  system

• Adaptive Immunity
• clonal recognition of foreign agents by T and B
  cells followed by selective expansion (production
  of antibodies, cytokines, and chemokines)

• mechanisms exclusive to adaptive immunity

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Progression of Immunity
Figure 8.5
At least two cell types reside within or beneath
the epithelium and induce inflammation in
response to trauma or microbial products
Macrophages and Mast Cells
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Figure 1.6ij
Alveolar macrophages (lung) Histiocytes
(connective tissue) Kupffer cells (liver)
Mesangial cells (kidney) Microglial cells
(brain) Tissue macrophage
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Figure 1.13
Receptors on Macrophages LPS receptor-CD14 Toll-l
ike receptors Fc receptors Mannose
receptor Complement receptors IFNg
receptor Chemokine receptors
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Figure 1.6gh
Function in disease, not entirely
understood Contains high affinity receptors for
IgE, and preformed granules that contain
inflammatory mediators including histamine
heparin TNFa chondroitin sulfate neutral
proteases and other. Mast cells can also
secrete cytokines to induce inflammation
chemokines to induce infiltration by monocytes,
and neutrophils, leukotriences to induce muscle
contraction and increase vascular
permeability Mast cells are capable of inducing
an inflammatory cascade
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Mast cells are also found in the tissues
Figure 1.14
TNF
Mast cells can release histamines which induce
inflammation
Neutrophils and monocytes are recruited
Redness, swelling (erythema, edema)
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Figure 1.6ef
Express some of the same receptors found on
macrophages
High affinity FceRI receptor. Effective against
worm infections. Granules contain
mediators-smooth muscle contraction and worm
toxicity
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Figure 8.8
LPS receptor CD14 toll-like receptor-4 CR3,4
Complement (C) receptors (C3b) Scavenger
receptor sialic acid-bearing protein Mannose
receptor Binds mannose on bacteria, activates
C Glycan receptor Polysaccharides IN ADDITION
TLRs
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Lymphocytes are entirely involved with acquired
immunity. The come in two types T lymphocytes (T
cells) that differentiate in the thymus and B
lymphocytes or B cells that differentiate in the
bone marrow. B cells can further differentiate
after antigen-activation to plasma cells that
produce antibodies
Figure 1.6ab
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Nature Killer Cells play several interesting
roles in the immune system. One is to monitor
cells for identification. If a cell doesnt
reveal its identity papers, it is killed. Youll
see this later in the course.
Dendritic cells are the most important antigen
presenting cells (APCs) in the immune system
Figure 1.6cd
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Figure 8.10

The most important inflammatory cytokine (at
least in this course)
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Figure 8.14
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Complement facilitates phagocytosis
Figure 1.15