Brown University

BIOL 0530 Fall 2015

Principles of
Immunology

Lecture 4:

Innate
Immunity

Tuesday September 22nd, 2015

Richard Bungiro, Ph.D.
Richard_Bungiro@Brown.edu

Why Study Innate

Immunity?

To gain perspective on how

immune mechanisms have
evolved over time
To understand its role as a
first line of defense
To determine how it
interacts with and influences
the adaptive immune system
2

Kuby Chapter 5: Innate

Immunity
Anatomical Barriers to
Infection

Phagocytosis
Induced Cellular Innate
Responses
Inflammatory Responses
Natural Killer Cells
Regulation and Evasion
of Innate and
Inflammatory Responses
Interactions Between the
Innate and Adaptive
Immune Systems
Ubiquity of Innate
Immunity
3

Innate Immunity is
Ancient

With my mighty
tomato immune
system, one day
ILL RULE THE
WORLD!

Keep on
dreamin
buddy!

Innate
Immunity

Basic inborn resistance mechanisms that

require no prior experience
Critical first line of defense against
invading pathogens
Oldest mechanisms of immune defense some form of it is present in all
multicellular organisms, including
insects and plants
Made independently of B and T cells
Is not adaptive and does not improve
with experience (no memory)
6

Innate
Immunity

Acts within minutes to hours

Employs receptors with fixed specificity that

broadly recognize certain patterns shared
by various classes of microorganisms
Eliminates most pathogens encountered and
limits many others so that adaptive
immunity may be engaged
Activation generates signals that enhance
the adaptive immune response and
influences the nature of that adaptive
response
7

Innate Immunity Is the First Line of

In an immunocompetent
Defense

person, an infection is initially

contained by innate immunity
and then cleared from the body
by the adaptive immune
response (yellow line)

Some
infectio
ns

Adapted from Parham et al

Infection of the umbilical
cord stump in an infant
with severe neutrophil
deficiency

Lee et al., HK J Paediatr 15:289-

In a person lacking necessary

adaptive immune responses, an
infection is initially contained
by innate immunity but cannot
be cleared from the body
(green line)
- Note that certain infections can
be contained and eliminated by
innate immunity even in the
absence of adaptive responses
(dashed green line)

If a person were to lack certain

critical innate immune
responses, uncontrolled
infection (and probably death)

Skin and Epithelial Barriers to

Infection
(Kuby Figure 5-2)

Psoriasin is an
antimicrobial protein
produced by the skin that
selectively prevents
colonization by E. coli

From Glaser et al.,

Nature Immunology 2005

10

It Really
S.
E. coli
Works!
epidermis
Gram(-)
Gram(+)

inoculated
directly
on
on
fingertips fingertips
10 min
30 min
on
fingertips
20 min

NO GROWTH!

11

Mechanisms of
Innate Defense of
the Airways

12

Inflammation
Induced by tissue injury
May be acute or chronic
Hallmarks first characterized by Roman
physicians
Swelling (tumor)
Redness (rubor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Major events include
Vasodilation
Increased blood flow
Increased vascular permeability
Accumulation of fluid
Extravasation of leukocytes
Phagocytosis
Release of inflammatory mediators
13

The Inflammatory
Response

14

Inflammation May
Be Triggered By
Infection

Subject has an infected sebaceous gland of the

lower eyelid, commonly known as a stye. Note
swelling and redness in the affected eyelid (subject
also reported burning sensation and pain). These
are usually caused by Staphylococcus aureus

15

Inflammation Can Occur

Even In the Absence of
Infection

Swelling
occurred
within 30
minutes of
ankle
sprain

commons.wikimedia.org/
wiki/File:Sprained_ankle_3

16

Elimination of Bacteria by
Phagocytosis

Pattern
Recognition
Receptors bind
directly to
pathogens
Opsonin
Receptors bind to

17

The Macrophage: Natures Death

Star?
Take your
place
in my
phagosomes.
It is your
destiny.

I have a
bad feeling
about
this

18

Antimicrobial
Peptides

Isolated from humans, frogs, flies, & nematodes

Over 800 have been identified to date
Range in size from 6-59 amino acids, most are
positively charged
The human defensins are 29 to 35 amino acids long

Kill multiple species of bacteria, typically within

minutes by disrupting microbial membranes
In humans, defensins are produced by
neutrophils, certain cells of the intestine, and
epithelial cells of the pancreas and kidney
Could (in theory) be used as therapeutics
19

20

Severe
Fungal
Infection in a
Fruit Fly
Unable to
Produce the
Antifungal
Pep-tide
Drosomycin

(Kuby Figure 5-9)

21

Pattern Recognition
If a pathogen gains
entry, its Pathogen-Associated
Receptors
Molecular Patterns (PAMPs) interact with Pattern
Recognition Receptors (PRRs) of the host
PAMPs are not found in the host and are broad features
of pathogens that are essential for survival,
reproduction, etc.

Damage-Associated Molecular Patterns (DAMPs)

are released by dead/dying cells and damaged
tissues, allowing innate responses to occur even
in the absence of infection
Dendritic cells and macrophages employ PRRs to
bind DAMPs and PAMPs, leading to:

Increased phagocytic activity

Cytokine production
Antigen processing/presentation

22

The Complement
System Straddles
Innate and Adaptive
Immunity
May be
activated
(Kuby
Figure
5-7)by PAMPs

(e.g. LPS) or by antibodies

bound to pathogens

Activated complement lyses

pathogens and promotes
phagocytosis (opsonization)
Byproducts of complement
activation promote
inflammation and recruit
leukocytes
23

Pattern
Recognition:
A Cartoon
Example

!
K
C
U
D

A
T K!
O C
N U
D
Daffy and Donald each possess recognizable duck patterns24

Pattern
Recognition:
An Actual Example

Escherichia coli

Salmonella
typhimurium

25

Pattern Recognition
Receptors

26

Lipopolysaccharide (LPS) and Peptidoglycan

Are
Important Microbial Patterns Found in
Bacterial Cell Walls

27

Toll-like Receptors
(TLRs)

Related to the fruit fly signal

receptor protein Toll, which
is essential for development
Toll was also found to be
essential for protection of
flies from fungal infection
In 1997 Medzhitov and
Janeway identified a human
Toll-like receptor that was
implicated in immune
function
In 1998 Beutler et al. found
that mice resistant to lethal
LPS challenge have a
mutant form of TLR4
11 distinct TLRs have been
identified in humans to date

Kuby Figure 5-

28

Toll-like Receptors and Their Ligands (Kuby

Figure 3-11)

11 TLRS
in
humans
13 TLRS
in mice
222
TLRS in
sea
urchins!

Adaptive,
Shmadaptive!
Who needs it?

29

TLRs Recognize a Wide Range of Microbial

Patterns

30

Signaling
Downstream of
Toll-Like Receptors
Is Mediated by
Several Protein
Highlights:
Complexes
1)Binding of microbial
pattern by LRR domain
2)Assembly of adaptor
proteins on the
intracellular TIR
domain
3)Protein kinasemediated
phosphorylation
4)Initiation of enzyme
cascades
5)Activation of

31

32

CLRs
C-type Lectin
Receptors
Plasma membrane
receptors expressed on
various leukocytes
Recognize
carbohydrates

RLRs
Retinoic Acid-Inducible
Gene I-Like Receptors
Soluble PRRs found in
the cytosol of various
cells
Recognize viral RNAs

NLRs
Nucleotide Oligomerization Domain/Leucinerich Repeat-Containing
Receptors
33

Some NLRs Assemble

Into Large Complexes
Called
Inflammasomes, Which
Activate Enzymes That
Convert Procytokines
Into Active Forms

34

35

The Major Leukocytes of Innate

Immunity

36

Innate Immunity Helps to

Activate the Adaptive Immune
Response!
LPS

Cytokines:
IL-1, IL-6,
IL-12, TNF,
IFN- /

Peptidoglycan
dsRNA
Glycolipids
Mannans
Flagellins
Microbial
Patterns

Dendritic
Cell
(PRRs)

Costimulatory
Molecules:
B-7, CD40

T-B cell
conjugate

37

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