g.2014-immuno~ (7.innate immunity-wjy)

Innate immunity

Innate (non-specific) immunityImmune barriersImmune moleculesIntrinsic cells

Macrophage(MΦ); Natural Killer(NKRecognition mechanisms

Pattern recognition receptors (PRR) Pathogen associated molecular pattern (PAMP

Key ContentsKey Contents

Immune organs

Immune cells

Immune molecules

Primary lymphoid organsSecondary lymphoid organs

Lymphocytes: T, B, NK cells NeutrophilsMonocytes/Macrophages Antigen-presenting cells

Antibody , Complement,Cytokines, MHC, CD.

The immune system protects us from attack by infectious agents.

Immune system

primary lymphoid organs thymus–T cell maturation bone marrow – B cell maturation Bursa of Fabricius secondary lymphoid organs lymph nodes spleen mucosal-associated lymphoid tissue (MALT)

Poultry/Birds

Major lymphoid organs and tissue

The body has two types of immunity: the innate immunitythe adaptive immunity

Innate immunity refers to any inborn resistance that is already present the first time a pathogen is encountered; it doesn’t require prior exposure and is not modified significantly by repeated exposures to the pathogen over the life of an individual.

the first defense line of against infection.

is the initial response by the body to eliminate microbes and prevent infection.

Innate Immunity

CharacteristicsCharacteristics

Present from birthPresent from birthHereditableHereditableThe first line of defenseThe first line of defenseNon-specificNon-specificNo immune memoryNo immune memoryBe the basisBe the basis

of specific immunityof specific immunity

Composing of Innate immunity: Immune barriers Intrinsic cells Immune molecules

Components of Innate Immunity

Mechanical ChemicalBiological

Immune barriers

Immune molecules

Complement CytokineDefensinsLysozymeacute-phase

proteins

Mo/M 、 DC 、 NK、T 、 NKT 、 B1

Intrinsic cells

Composing of Innate Immunity

skin-mucous membrane

epithelial cells joined by tight junctions;movement of mucus by cilia;

1.Mechanical barrier

Ⅰ Ⅰ Immune barriers

fatty acids in sweat

skin

movement of mucus by cilia

mucous membrane

BloodBlood--brain barrier (BBB)brain barrier (BBB)◆BBB is a barrier that

separates the circulating blood from the brain extracellular fluid in the CNS. ◆BBB is formed by brain endothelial cells, and astrocytes contribute to strocytes contribute to the differentiation of BBB.the differentiation of BBB.

◆Tight junctions restrict Tight junctions restrict paracellular movement of paracellular movement of substances across the BBB. substances across the BBB.

◆ BBB prevents the invasion BBB prevents the invasion of pathogens into the brainof pathogens into the brain

BloodBlood--placenta barrier(BPB)placenta barrier(BPB) ◆ In the placenta, the fetal In the placenta, the fetal blood is separated from the blood is separated from the mother’s blood by BPB. mother’s blood by BPB. ◆ BPB is consist of decidua BPB is consist of decidua basalis and trophoblast cellsbasalis and trophoblast cells

◆BPB allows slow passage of BPB allows slow passage of gases, ions and small gases, ions and small molecules but restricts molecules but restricts movement of larger movement of larger molecules.molecules.

◆BPB prevents the invasion of BPB prevents the invasion of pathogens into the fetuspathogens into the fetus

基蜕膜

Lactic acid and fatty acid in sweat: inhibit the growth of bacteria.

Lysozyme, phospholypase A in secretions (saliva, tears, milk)

break down the cell wall of bacteria.Low pH (gastric acid) and pepsin in stomach:

prevents growth of bacteria.

2.Chemical barrier

The normal flora on the skin and in the gastrointestinal tract

prevent the colonization of pathogens – by secreting toxic substances – by competing nutrition with pathogens– by blocking the attachment of pathogens.

3.Biological barrier

Antimicrobial factors in saliva (lysozyme)

Normal floraMucus,ciliaremoval of inhaled bacteria

Acid in stomach(low pH)

Normal flora

Lysozyme in tears, other secretions

Skin-physical barrier, fatty acids, sweat,normal flora

Normal flora can prevent the colonization and growth of pathogens

What happens when the physical and chemical barriers are breached? defense

mechanisms?

Complement: *Cytokines: Interferons *Antimicrobial Peptides : >400 kinds

Defensins: cationic peptide, insert into bacterial membranes and form pores, allowing solutes to leak out.Antimicrobial Enzymes:

Lysozymes: basic protein, break down the cell wall (peptidoglycan) of G+ bacteria.

Ⅱ Immune molecules

Functions of Complement

*

The roles of Interferons

*

Ⅲ Ⅲ Intrinsic cells

﹡Immune cells: All kinds of cell associated with immune response, including phagocytes,

lymphocytes, mast cells, antigen presenting

cells (APC) as well as their precusor cells. Immune cells derive mainly from undiffe- ﹡

rentiated ‘self-renewing’ hemopoietic stem cells (HSCs) through a process of differentiation.

1. Mo /M

2. Granulocytes:

neutrophils 、 basophils 、 eosinophils

3. Dendritic cells

4. NK and NKT cells

5. B1 、 T cell 、 mast cell

* Innate immunocytes

monocytes/macrophages

Pseudopodium['sju:də'pəʊdɪəm]

Monocyte /Macrophage

1. Relatively large (12-20 um);

2. Kidney-shaped nucleus;

3. Abundant cytoplasm and cytoplasmic lysosomes

1. Derived from bone marrow

2. 3-8% of leukocytes3. Monocytes stay in

periphel blood for 12-24 h and then leave the circulation and reside within almost all of the organs----Macrophages

Monocyte/Macrophage

Cells of the mononuclear phagocyte systemLocation Cells Blood Monocytes Skin Langerhans’ cells

Liver Kupffer cells Lung Alveolar macrophages Spleen, lymph nodes Sinus macrophages Brain Microglia

Bone Osteoclasts

1. PRRs (pattern-recognition receptors) 1) MR (mannose receptors) 2) SR (scavenger receptors) 3) TLR (Toll like receptors)

PAMP: The ligand of PRRs (pathogen associated molecular patterns)2. IgG FcR (FcγR) 、 C3bR3. MHC I/MHC II molecules; B7 4. CKR: IFN-rR, M-CSFR,GM-CSFR, MCP-1R MCP-1(monocyte chemotactic protein 1)

1. The main surface receptors

Monocyte/Macrophage

2. Biological Functions(1)(1) Kill and eliminate the microorganisms: * Kill and eliminate the microorganisms: * * phagocytosis * opsonization* phagocytosis * opsonization(2)(2) Kill tumor and virus-infected cell; Kill tumor and virus-infected cell; (3)(3) Process and present Ag; * Process and present Ag; *(4)(4) Mediate/promote inflammatory response; * Mediate/promote inflammatory response; * IL-1, IL-6, TNF-a; IL-8, MCP-1 IL-1, IL-6, TNF-a; IL-8, MCP-1 (5)(5) Modulate immune response. Modulate immune response. IL-1 and IFN-r promote the APC to express MHC and IL-1 and IFN-r promote the APC to express MHC and

activate T and B cells; TNF-a promotes the activation, activate T and B cells; TNF-a promotes the activation, proliferation and differentiation of CTL; IL-10 can proliferation and differentiation of CTL; IL-10 can inhibit the activation of Mo/Mac.inhibit the activation of Mo/Mac.

An activated macrophage phagocytosing bacteria upon contact

Monocyte/Macrophage

Phagocytosis, processing and presenting Ag

Monocytes /MØ have numerous lysosomes in their cytoplasm

Human phagocytes that arrive quickly at the site of a bacterial infection and whoseprimary function is to eat and killbacteria.

Opsonization is the process of making microbes easier to phagocytose, more palatable to the phagocytes. Opsonins, IgG antibody and complement coating on the microbes aid attachment of the microbes to the phagocyte and trigger activation of phagocytosis.

Ab

bacteria

M

lysosome

*

*

Monocyte/Macrophage

*

Natural Killer CellsNatural Killer Cells

* Large granular lymphocyte, *Derived from bone marrow, * Contain cytotoxic substances, * Surface markers TCR-, mIg-, CD56﹢CD16﹢

Natural killer cells in the blood

1. Surface receptors KIR (killer-inhibitory receptor) ： CD94/NKG2A KAR (killer-activating receptor): NKp30, 44, 46; CD94/NKG2C; CKR CD16: FcγR —— ADCC2. Target cells Tumor cells, virus-infected cells.

Natural Killer Cells

3. Functions

⑴ ADCC *

⑵ Killing target cells *

*Perforin/Granzymes pathway

*Fas/FasL pathway

*TNF-/TNFR-1 pathway

⑶ Immunoregulation

IFN- 、 TNF-

activated NKs FcR Antibody IgG

Target cell Target cellTarget cell

ADCC (antibody dependent cell-mediated cytotoxicity)NK cells could be activated by the Ag-Ab (IgG) complexes through binding to its CD16 FcR, and then trigger killing activity and induce apoptosis of target cells.

NK apoptosis

*

*

Why NK cells don’t kill normal cells ???

Neutrophil

1. Derived from bone marrow

2. 60-70% of leukocytes

3. Short life: 2-3 days

4. Receptors: IgG FcR 、 C3bR

5. Biological functions:

Engulf and kill microorganisms;

Opsonization

Other innate-like lymphocytesOther innate-like lymphocytes

B-1 CellsB-1 Cells

* CD5+mIgM+B cells

* Produces IgM in 48 h

Main functions of Intrinsic cellsMain functions of Intrinsic cells

Cellular responseCellular responsePhagocytes and phagocytosis Phagocytes and phagocytosis * phagocytosis * opsonization* phagocytosis * opsonizationNatural killer (NK)Natural killer (NK) *ADCC * natural killing target*ADCC * natural killing targetInflammatory reaction Inflammatory reaction

Inflammatory reaction

Mast cells releasing histamine and Mast cells releasing histamine and prostaglandin cause local vessel dilation, prostaglandin cause local vessel dilation,

increased capillary permeability, resulting in:increased capillary permeability, resulting in: edemaedema (swelling) due to fluids seeping from (swelling) due to fluids seeping from

capillaries.capillaries.Phagocytes move out of vessels, release toxic Phagocytes move out of vessels, release toxic chemicals and enzymes that destroy chemicals and enzymes that destroy everything in the area, including the everything in the area, including the neutrophils themselves. neutrophils themselves.

Membrane PRRsMembrane PRRs MR (Mannose R)MR (Mannose R) TLR (Toll-like R)TLR (Toll-like R) SR (Scavenger R)SR (Scavenger R)Secreted PRRsSecreted PRRs MBLMBL 、、 CRPCRP 、、 LBP (LPS binding LBP (LPS binding

protein)protein)

IV Recognition mechanisms of PRRs

1. Patterns Recognition Receptors 1. Patterns Recognition Receptors (PRR)(PRR)

PRRs: The receptors on intrinsic cells which can recognize and bind specific molecular structure on some pathogens, injured or apoptotic cells. Most of immune cells involved in

innate immunity can express PRR. PRR recognizes microbes by PAMPs.

(1) Toll-like receptor (TLR)(1) Toll-like receptor (TLR) ﹡ ﹡name from a related protein called name from a related protein called

Toll.Toll. ﹡ ﹡Intrinsic cells can detect and

respond to infection by recognizing conserved motifs (LPS, flagellin(LPS, flagellin ， ， et et al.) al.) of microbes using TLRs and initiate protective response.initiate protective response.

Toll-like receptors in human

cytoplasm

(2) Mannose binding lectin (MBL)(2) Mannose binding lectin (MBL) ﹡ ﹡liver-derived liver-derived serum proteinserum protein ﹡ ﹡bind mannose on the surface of bind mannose on the surface of pathogenpathogen ﹡ ﹡the pathogens are captured and the pathogens are captured and destroyed by phagocytes through destroyed by phagocytes through opsonization and complement.opsonization and complement.

2. Pathogen Associated Molecular 2. Pathogen Associated Molecular Patterns (PAMPs)Patterns (PAMPs)

PAMPsPAMPs are some high-conserved macromolecules are some high-conserved macromolecules uniquely expressed by pathogens, which can be uniquely expressed by pathogens, which can be recognized by the innate immune system.recognized by the innate immune system.Structures of microbial pathogensStructures of microbial pathogens

Peptidoglycan (G+), Teichoic acid (G+), Peptidoglycan (G+), Teichoic acid (G+), LPS (G-), Mannose, Bacterial DNA / RNALPS (G-), Mannose, Bacterial DNA / RNA

Not present on mammalian cellsNot present on mammalian cellsSo the Innate immune system can distinguishSo the Innate immune system can distinguish

self (mammalian) from non-self (pathogen).self (mammalian) from non-self (pathogen).

Ⅴ Featuers of Innate Immunity

1. Action phages of innate immunity

PRR recognizes pathogen expressing PAMP,

and apoptotic cellsFcR and C3bR

recognizes pathogen combined with IgG or C3bKAR on the surface of NK cells

recognizes tumor and virus-infected cells

2. Features of Innate immunity

(1) Features of recognition

Rapid responseNonspecificNo differentiation and replication of immune cellsNo memory

(2) Features of innate response

3. Relationship of innate immunity and adaptive immunity

Is the first line of defense against infectionsInitiate adaptive immune responseAffect the types of adaptive immune responseRegulate adaptive immune response