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