chapter 10 innate immunity

Chapter 10

Innate Immunity

• Innate immunity is the first line of defense against infections.

• Innate immunity exist before encountering with microbes and are rapidly activated by microbes before the development of adaptive immune responses.

• Innate immunity is present in all multicellular organisms, including plants and insects.

Introduction of innate immunity

Characteristics:• Set up at birth

• Non–specific and early

• Heredity

• Racial or species difference

• No immune memory

Characteristics of Innate and Adaptive ImmunityCharacteristics of Innate and Adaptive Immunity

No Immunologic

memory

Antigen independent

No time lag

No antigen specific

Antigen dependent

A lag period

Antigen specific

Development

of memory

Innate Immunity Adaptive Immunity

Components of Innate and Adaptive ImmunityComponents of Innate and Adaptive Immunity

Innate Immunity Adaptive Immunity

skin, gut Villi, lung cilia,etc

many protein andnon-protein secretions

phagocytes, NK cell, B1, γδT, APC

physical barriers

soluble factors

cells

none

Immunoglobulins(antibody)

T , B lymphocytesAPC

Contents

Part Components of innate Ⅰ immune systemPart Cells participating in Ⅱ innate immunityPart Recognition features of theⅢ innate immune systemPart Functions of innate immunity Ⅳ

Part Components of innate Ⅰimmune system

Ⅰ.Barriers

Ⅱ.Humoral factors

Ⅲ. Cells

Part Components of innate immune systemⅠ

Ⅰ. Barriers:• Mechanical defense: skin & mucous membrane• Anatomic barrier:

blood – brain barrier blood – placenta barrier blood – thymus barrier• Biotic barrier: normal flora

• Chemical defense (lysozyme, acid)

Part Components of innate immune systemⅠ

Ⅱ.Humoral factors: Complement Cytokine---macrophage, neutrophil, NK cell Lysozyme

Ⅲ. Cells: Mononuclear phagocyte, NK cell, Neutrophils, Dendritic cells ， Eosinophil, Basophil, Mast cell， γδT cell, B1 cell, Microfold cell

ICC

Part Cells participating in innate immunityⅡ

Natural killer cells (NK)Mononulear phagocytesNeutrophilsDendritic cellsOther cells participating in innate immunity

Ⅰ. Natural killer(NK)cells

1. Source: Bone marrow,exist mainly in peripheral blood(5-7%) and spleen.

Part Cells participating in innate immunityⅡ

2. Characteristics of NK cells2. Characteristics of NK cells

Also called large granular

lymphocytes (LGL)

Kill various infected and malignant

cells spontaneously, without

stimulation of antigen and MHC

restriction

Identified by the presence of

CD56,CD16 (FcR )Ⅲ Activated by IL-12 and produce IFN

-γ

Also called large granular

lymphocytes (LGL)

Kill various infected and malignant

cells spontaneously, without

stimulation of antigen and MHC

restriction

Identified by the presence of

CD56,CD16 (FcR )Ⅲ Activated by IL-12 and produce IFN

-γ

3. Recognition mechanism of NK cells

• FcγRⅢ: recognize antibody covered cell

------ADCC

• Killer activating receptor and killer inhibitory receptor

ADCC

Receptors associated with killer activation and killer inhibition on NK cells

• NK receptors bind with class MHC moleculesⅠ

• NK receptors bind with non class MHC moleculesⅠ

(1) NK Receptors bind with class molecules:Ⅰ -KIR(killer immunoglobin-like receptors):• Number of immunoglobin-like domain:KIR2D/KIR3D• Cytoplastic region: longer---KIR2DL/KIR3DL(ITIM), inhibitory receptor shorter---KIR2DS/KIR3DS, non-covalent combination with DAP-12(ITAM), activating receptor

-KLR(killer lectin-like receptor): • Heterodimer of CD94 & NKG2 (C type lectin) CD94: short cytoplastic region, no signal transmission NKG2A: ITIM in cytoplastic region --------CD94/NKG2A, inhibitory receptor NKG2C: no signal transmission, bind with DAP-12(ITAM) --------CD94/NKG2C, activating receptor

ITIM ： immunoreceptor tyrosine-based Inhibitory motif

ITAM ： immunoreceptor tyrosine-based activation motif

(2) NK receptors bind with non class MHC moleculesⅠ --NKG2D: Express mainly on the surface of NK and γδT

No signal transmission

Non-covalent binding with DAP-10(ITAM)

MHC class chain-related molecules A/B(MIC A/B)Ⅰ

--Natural cytotoxic receptor(NCR): NKp46,NKp30,NKp44

IgSF

Express on the surface of NK cells

Bind with other molecules(ITAM)

Kill target cells when KIR/KLR lose their function

Receptors associated with killer activation and killer inhibition on NK cells

Killer activatory receptor Killer inhibitory receptor

KIR: KIR2DS,KIR3DS

KLR: CD94/NKG2C

NKG2D

NKp46

NKp30

NKp44

NCR

KIR2DL,KIR3DL

CD94/NKG2A

Bind class I HLA

molecules

Function

Bind non-class I HLA

molecules

Figure 3-23

These are important molecules for presentation of peptides to CD8 T cells

These are important NK inhibitory ligands（ CD94/NKG2A/B/C ）

Normal condition(Class HLA molecules are Ⅰexpressed normally):

Effect of Inhibitory recepter > Activatory recepter------Killing effect of NK cell is inhibited

Abnormal condition(Class HLA molecules are Ⅰexpressed abnormally) :

NK cells lose ability of distinguishing self from non-self------NK cells kill target cells （ NKG2D and NCR)

NK cells is tolerant to self-antigen:Only virus infected cells and tumor cells could be

killed by NK cells, not the normal tissue cells.

Virus infected cells or tumor cells MHC-I

inhibitory signal Killed by NK cells。

4. Effector of NK cells•Secretion of cytokines,e.g. IFN-γ, to a activates

macrophages

•Cytotoxicity:

-ADCC-mediated by FcγR (CD16)Ⅲ

-Granules like CTLs:

Perforin: creates pores in target cell membranes

Granzymes : enzymes which enter through perforin pores and induce apoptosis of target cells.

-FasL/Fas pathway

-TNF-α/TNFR- pathwayⅠ

Target cell

NK cell

Contact tightly

TNFR-I

TNF- α

ADCC

5. Functions of NK cells

Participate in anti-tumor and anti-virus immunity

Participate in immunological regulation

Ⅱ. Mononuclear phagocytes

Part Cells participating in innate immunityⅡ

monocytes and macrophages

Phagocytes are the Most Important Cells

Phagocytes are the Most Important Cells

George Bernard Shaw wrote:

“There is at bottom only one

genuine treatment for all

diseases,…to stimulate the

phagocytes. Drugs are a

delusion. …(when) the

phagocytes are stimulated; they

devour the disease…”

macrophageTissues

Blood

MacrophagesMacrophages

Phagocytose & kill intracellularly

Characteristic nucleus and

identified by CD14

Act as APC

Activated by cytokines

Kill malignant and altered self

targets

Adherent of plastic and glass

surfaces

Phagocytose & kill intracellularly

Characteristic nucleus and

identified by CD14

Act as APC

Activated by cytokines

Kill malignant and altered self

targets

Adherent of plastic and glass

surfaces

Receptors on Macrophages:

Fcγ receptors

Complement receptors

IFN-g receptor

Chemokine receptors

Mannose receptor

Toll-like receptors(TLRs)

Scavenger receptors(SRs)

LPS receptor(CD14)

Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells.

1. Recognizing and excluding pathogens

Recognizing

Ingestion

Digestion

Exclusion

recognizing

digestion ingestionexclusion

(1) Recognition Mechanism

Pattern recognition receptor(PRR): The receptor on macrophage which can recognize and

bind specific molecular structure on some pathogens , injured or apoptotic cells.

The receptor associated with antigen-recognition of macrophage

Pattern recognition receptor (PRR) or non-opsonic

receptor

------Mannose receptor(MR)

Scavenger receptor(SR)

Toll like receptor(TLR)

Opsonic receptor

------FcγR and C3bR/C4bR

IgG FcR

ScavengerR

CR

Initiation of Phagocytosis

Pathways of Intracellular KillingPathways of Intracellular Killing

m yloperoxidase-independent m yeloperoxidase-dependent

oxygen-depenedent oxygen-independent

In trace llu la r K illing

m yloperoxidase-independent m yeloperoxidase-dependent

oxygen-depenedent oxygen-independent

In trace llu la r K illing

(2) Ingesting and digesting the pathogen

Oxygen-dependent system:

---Reactive oxygen intermediates, ROIs :

O2-, OH-, H2O2, 1O2

---Reactive nitrogen intermediates, RNIs:

NOOxygen-independent system:

---Low pH(3.5-4) , Lysozyme, Defensin

(3) Excluding the pathogen

2. Functions of macrophage

① Recognizing and excluding pathogens and died cells; Killing target cells(tumor cells and virus-infected cells)

② Participating in and stimulating inflammation

③ Participating in immunological regulation

④ Processing and presenting antigen, initiating adaptive immune response

Ⅲ. Neutrophil

Part Cells participating in innate immunityⅡ

NeutrophilsNeutrophils

Phagocytosis, intracellular killing, inflammation and tissue damage

Characteristic nucleus, cytoplasm

Granules and CD66 membrane marker

FcγR and CR

Ⅳ. Other cells• Dendritic cells

• Mast cells and eosinophils

• Microfold cells

• NKT cells

• γδ T cells

• B1 cells

Part Cells participating in innate immunityⅡ

Part Features of innate immune Ⅲrecognition

• Molecular patterns(pathogen associated molecular pattern, PAMP): dsRNA,CpG DNA,LPS.

• Pattern recognition receptors （ PRR） : the receptors that bind these conserved structures.

PAMP :1.Structures that are characteristic of microbial

pathogens and are not present on mammalian cells.

2.Microbial products that are often essential for survival of the microbes.

The receptors of the innate immune system( PRRs) are encoded in the germline.

• Very conserved

• Limited diversity

PRRs including:

Scavenger receptor, SR

Mannose receptor ， MR

Toll-like receptor, TLR

Part Role of innate immunityⅣ

1. Defense against microbes• The early local reaction of innate immunity is the

inflammatory response, in which leukocytes are recruited to the site of infection and activated to eradicate the infection.

• Inflammation produces a variety of systemic changes in the host that enhance the ability of the innate immune system to eradicate infection and, in sever infections, can contribute to systemic tissue injury or death.

Progression of Immunity

At least three cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products: Macrophages, Mast Cells, and Langerhan’s cells (a skin dendritic cell)

Figure 8.5

2. Stimulating adaptive immune responses

• Provides signals that function in concert with antigen to stimulate the proliferation and differentiation of antigen-specific T and B lymphocytes.

• Works as effector cells or molecules

Important functions of innate immunity:

• Innate immunity is the initial response to microbes

• The effector mechanisms of innate immunity are often used to eliminate microbes even in adaptive immune responses

• Innate immunity to microbes stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes.

Components Principle FunctionsBarriersPhysical barriers Prevent entryChemical barriers Microbial killingBiotic barriers Competition of microbial

Circulating and Tissue Effector CellsNeutrophils Early phagocytosis and killing of microbesMacrophages Efficient phagocytosis and killing of microbes: cytokinesNK cells Lysis of infected cells, activation of macrophagesEosinophils Nasty toxic cells designed to kill helminths (worms)Mast Cells Release of inflammatory granules

Circulating ProteinsC Killing of microbes, opsonization of microbes, activation leukocytesMannose-binding protein Opsonization of microbes and activation of CC-reactive protein Opsonization of microbes and activation of CLysozyme Bacterial cell wall lysis

CytokinesTNF, IL-1, 6, 18 InflammationIFN a, b Resistence to viral infectionIFN g Macrophage activationIL-12 IFNg production by NK cellsIL-15 Proliferation of NK cells, memory T cellsIL-10, TGF b Control of Inflammation