Introduction to Innate Immunity

Ando van der Velden

[email protected]

HBM640
Molecular Mechanisms of Microbial Pathogenesis
 OVERVIEW

• INTRODUCTION OF BASIC PRINCIPLES IN INNATE IMMUNITY

• INNATE IMMUNITY: THE FIRST LINES OF DEFENSE

– Anatomic barriers and initial chemical defenses
– The complement system and innate immunity

• THE INDUCED RESPONSES OF INNATE IMMUNITY

– Pattern recognition by cells of the innate immune system
– Induced innate responses to infection
 INTRODUCTION OF BASIC PRINCIPLES IN INNATE IMMUNITY

• Commensal organisms cause little host damage while pathogens damage

host tissues by a variety of mechanisms

• Protection against pathogens relies on several levels of defense

 INTRODUCTION OF BASIC PRINCIPLES IN INNATE IMMUNITY

• The immune system is activated by inflammatory inducers that indicate

the presence of pathogens or tissue damage
• Sensor cells express pattern recognition receptors that provide an initial
discrimination between self and nonself

• Sensor cells include many types of innate immune cells

• Sensor cells induce an inflammatory response by producing secreted

proteins called cytokines and chemokines that act in a manner similar to
hormones to convey important signals to other immune cells
 INTRODUCTION OF BASIC PRINCIPLES IN INNATE IMMUNITY

• The triggering of innate sensors on various cells not only activates these
cells’ individual effector functions, but also stimulates the release of pro-
inflammatory cytokines and chemokines that act together to recruit more
phagocytic cells to the site of infection

• Cytokines and chemokines released by tissue phagocytes can induce

more systemic effects, including fever and the production of acute
response proteins (e.g., mannose-binding lectin, C-reactive protein,
fibrinogen), which add to a general state of augmented innate immunity

• Cytokines can also mobilize antigen presenting cells that induce the
adaptive immune response

• Impaired innate immunity results in increased susceptibility to infection

 INTRODUCTION OF BASIC PRINCIPLES IN INNATE IMMUNITY

• The myeloid lineage comprises most of the cells of the innate immune
system
 INNATE IMMUNITY: THE FIRST LINES OF DEFENSE

• Anatomic barriers and initial chemical defenses

• The complement system and innate immunity

 Anatomic barriers and initial chemical defenses

• Infectious diseases are caused by diverse living agents (pathogens) that

replicate in their hosts

• Pathogens can be found in various compartments of the body, where they

must be combated by different host defense mechanisms
 Anatomic barriers and initial chemical defenses

• Pathogens must overcome innate host defenses to establish a focus of

infection

• Pathogens can damage tissues in a variety of different ways

 Anatomic barriers and initial chemical defenses

• Epithelial surfaces of the body provide the first barrier against infection

• Many barriers prevent pathogens from crossing epithelia and colonizing

tissues

• Epithelia form specialized physical and chemical barriers that provide

innate defenses in different locations
 Anatomic barriers and initial chemical defenses

• Epithelial cells are held together by tight junctions, which form a seal
against the external environment
• The internal epithelia (i.e., goblet cells) secrete mucus, a sticky solution of
proteins (mucins) that form a protective layer on the epithelial surface
• Epithelial cells (e.g., Paneth cells) and phagocytes produce several kinds of
antimicrobial proteins
– Enzymes (e.g., lysosyme, secretory phospholipase A2) that attack chemical features
specific to bacterial cell walls
– Antimicrobial peptides (e.g., defensins, cathelicidins, histatins) that disrupt the cell
membranes of microbes
– Bactericidal lectins of the RegIII family of carbohydrate binding proteins that form pores
in microbial cell membranes (e.g., RegIIIγ)
 The complement system and innate immunity

• When a pathogen breaches the host’s epithelial barriers and initial

antimicrobial defenses, it next encounters the complement system
• Complement is a collection of soluble proteins present in blood and other
body fluids that protects against pathogens in extracellular spaces

The complement system proceeds in three distinct phases in the

elimination of microbes: Proteins that can distinguish self from
microbial surfaces (yellow) activate a proteolytic amplification cascade
that ends in the formation of the critical enzymatic activity of C3
convertase (green box). This activity is the gateway to three effector
arms of complement that produce inflammation (purple), enhance
phagocytosis (blue), and lyse microbial membranes (pink)
 The complement system and innate immunity

• Complement is a system of soluble pattern recognition receptors and

effector molecules that detect and destroy microorganisms
 THE INDUCED RESPONSES OF INNATE IMMUNITY

• Pattern recognition by cells of the innate immune system

• Induced innate responses to infection

 Pattern recognition by cells of the innate immune system

• After entering tissues, many microbes are recognized, ingested, and killed
by phagocytes
Neutrophil extracellular
traps (NETs) can trap
bacteria and fungi
 Pattern recognition by cells of the innate immune system

• Cells of the innate immune system detect microbes or the cellular damage
they cause

• Cells of the innate immune system express receptor systems that

recognize microbes and induce rapid defenses as well as delayed cellular
responses

• These pattern-recognition receptors (PRRs) function as the primary

sensors for conserved pathogen-associated molecular patterns (PAMPs)

• Activation of PRRs induces expression of a variety of genes, including

those for molecules that have essential roles in immediate defense and in
directing the course of adaptive immunity
 Pattern recognition by cells of the innate immune system

• PRRs can be classified into four main groups on the basis of their cellular
localization and function

– Free receptors in the serum (e.g., complement, mannose-binding lectin)

– Membrane-bound phagocytic receptors (e.g., complement, Fc, scavenger and lectin-like

receptors, β-glucan receptor Dectin-1)

– Membrane-bound signaling receptors (e.g., G-protein-coupled receptor fMLF, Toll-like

receptors)

– Cytoplasmic signaling receptors (e.g., NOD proteins, NOD-like receptors, RIG-I, cGAS)
 Pattern recognition by cells of the innate immune system

• Toll-like receptors (TLRs) are membrane-bound PRRs that detect extracellular PAMPs
 Pattern recognition by cells of the innate immune system

• TLRs interact with adaptors to activate transcription factors that induce the expression of pro-
inflammatory cytokines and type I interferons
 Pattern recognition by cells of the innate immune system

• NOD and NOD-like receptors are cytoplasmic PRRs that detect bacterial PAMPs and cellular
stress or damage
• NLRs signal through the inflammasome, which generates pro-inflammatory cytokines and
induces pyroptosis, a form of cell death

 The inflammasome is a large, pro-inflammatory multi-protein complex that upon production of an active caspase
protein in the complex processes cytokine proproteins into active cytokines
 Pattern recognition by cells of the innate immune system

• RIG-I and RIG-I-like receptors (RLRs) are

cytoplasmic PRRs that detect viral RNA
and activate the MAVS signaling pathway

• AIM2 and cGAS are cytoplasmic PRRs that

detect cytosolic DNA and activate the
STING pathway

• Both the MAVS pathway and the STING

pathway induce production of type I
interferons
 Induced innate responses to infection

• An important effect of the interaction between microbes and tissue

macrophages is the activation of macrophages and other immune cells to
release cytokines and chemokines

– Cytokines are secreted proteins that affect the behavior of cells, particularly immune
cells, whereas chemokines are chemoattractant cytokines that stimulate the migration
and activation of cells, especially phagocytes and lymphocytes

• Collectively, cytokines and chemokines induce a state of inflammation in

the tissue, attract neutrophils and monocytes to the site of infection, and
allow plasma proteins to enter the tissue from the blood

• All of the major phagocytes of the innate immune system – neutrophils,

macrophages and dendritic cells, can be stimulated to release cytokines
 Induced innate responses to infection

• Cytokines (e.g., GM-CSF, IL-1β, TNF-α, IFN-γ) are released by various types
of cells in the body, usually in response to an activating stimulus

• Cytokines induce responses (e.g., cell growth, differentiation, activation)

through binding to specific receptors and can act in an autocrine,
paracrine, or endocrine manner

• Cytokines and their receptors fall into distinct families of structurally

related proteins
 Induced innate responses to infection

• Many cytokine receptors signal using the JAK-STAT pathway to induce gene
transcription
 Induced innate responses to infection

• Chemokines are released by a wide variety of cell types and act on the
leukocyte as it rolls along endothelial cells at sites of inflammation

• Chemokines direct the migration of the leukocyte along a gradient of

chemokine molecules bound to the extracellular matrix and the surfaces
of endothelial cells – this gradient increases in concentration toward the
site of infection

• Chemokines mainly fall into two related but distinct groups

– CC chemokines (e.g., CCL2) promote the migration of monocytes, lymphocytes, and
other cell types
– CXC chemokines (e.g., CXCL8) promote the migration of neutrophils
– Complement fragments can also act as chemoattractants for neutrophils
 Induced innate responses to infection

• Important cytokines and chemokines secreted by macrophages and

dendritic cells in response to bacterial products include IL-1β, TNF-α, IL-6,
CXCL8, and IL-12
 Induced innate responses to infection

• Chemokines require the action of vasoactive mediators that bring

leukocytes close to the blood vessel wall and cytokines such as TNF-a to
induce the necessary adhesion molecules on endothelial cells
• Cell adhesion molecules control interactions between leukocytes and
endothelial cells during an inflammatory response
 Induced innate responses to infection

• Neutrophils make up the first wave of leukocytes that cross the blood
vessel wall to enter an inflamed tissue (extravasation/diapedesis)
 Induced innate responses to infection

• Several types of innate lymphoid cells (ILCs) also provide protection in

early infection

• ILCs develop in the bone marrow from the same common lymphocyte
progenitor that gives rise to B and T cells, but lack specific antigen
receptors

• ILCs function in innate immunity as effector cells that amplify the signals
delivered by innate recognition

• ILCs are stimulated by cytokines produced by other cells that have been
activated by innate sensors of microbial infection or cellular damage
 Induced innate responses to infection

• NK cells are ILCs that are activated by macrophage-derived cytokines and

type I interferons

• NK cells express activating and inhibitory receptors to distinguish between

healthy and infected cells

• Stimulation of activating receptors can lead to the release of cytokines

(e.g., IFN-γ) and the killing of the stimulating cell through the release of
cytotoxic granules
 SUMMARY

• The response to an initial

infection occurs in distinct phases
(i.e., the innate phase, the early
induced innate immune
response, and the adaptive
immune response)

• Innate immune responses can

select from several effector
modules to protect against
different types of pathogens and
direct the course of the adaptive
immune response later in
infection