3. innate immunity i.pdf
TRANSCRIPT
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Innate Immunity
First step
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sistemul imun innascut
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Component of Innate Immunity
Innate Immune system
First line Second line1) Mechanical barriers A- cells2) Chemical & biochemical inhibitors 1- Natural killer
3) Normal flora 2- PhagocytesB- Soluble factors
C- Inflammatory barriers
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Figure 2-2 part 2 of 2
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Figure 2-2 part 1 of 2
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Anatomic Barriers
Skin, Mucous membranes, Cilia, Normal flora
Physiological Barriers
Temperature, Low pH, Chemical Mediators Lysozyme, Interferon, Complement, Collectin, TLR
Phagocytic/endocytic Barriers
Phagocytosis (tissue macrophages, neutrophils) Endocytosis
Inflammatory Barriers
redness, swelling, heat, pain
Innate Immunity(Nonspecific Immunity)
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Physical barriers
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First line1) Physic-Mechanical barriers:
A. Physical barriers:Intact skin
Mucous coat
Mucous secretion
B. Mechanical
Blinking reflex and tearsThe hair at the nares
Coughing and sneezing reflex
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First line
2) Chemical & biochemical inhibitors- Sweet and sebaceous secretion- Hydrolytic enzymes in saliva- HCl of the stomach- Proteolytic enzyme in small intestine- Lysozyme in tears- Acidic pH in the adult vagina
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First line
2) Chemical & biochemical inhibitors- Sweet and sebaceous secretion
- Hydrolytic enzymes in saliva- HCl of the stomach- Proteolytic enzyme in small intestine
- Lysozyme in tears- Acidic pH in the adult vagina
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Component of Innate Immunity
Innate Immune system
First line Second line1) Mechanical barriers A- cells2) Chemical & biochemical inhibitors 1- Natural killer
3) Normal flora 2- PhagocytesB- Soluble factors
C- Inflammatory barriers
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Anatomic Barriers
Skin, Mucous membranes, Cilia, Normal flora
Physiological Barriers
Temperature, Low pH, Chemical Mediators Lysozyme, Interferon, Complement, Collectin, TLR
Phagocytic/endocytic Barriers
Phagocytosis (tissue macrophages, neutrophils)
Endocytosis
Inflammatory Barriers
redness, swelling, heat, pain
Innate Immunity(Nonspecific Immunity)
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Hematopoiesis
I. Cells
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Second lineA) cells
1- Natural killer (NK)Definition: Large granular lymphocytes
Innate cytotoxic lymphocytes
Source : Bon marrow precursorsLocation : 10% or 15% of lymphocytes in peripheral blood
1% or 2% of lymphocytes in spleen Function :A. Cytotoxic for:
Tumor cellsViral infected cellsBacterial, fungal,
parasitic infection
B. Responsible for (ADCC) :antibody dependent mediatedcytotoxicity cell
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Hematopoiesis
I. Cells
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Second line
2- PhagocytesSpecialized cells for capture, Ingestion
and destruction of invadingmicroorganisms
Polymorphoniclear leucocytes(neutrophils)granulocytes circulate in blood Mononuclear cells(macrophages)
a. - Monocytes in bloodb. - Histocytes in connective tissuesc. - Fixed reticuloendothelial cells in
liver spleen, lymph
nods, bon marrow
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Role of Neutrophil
Second line: Phagocytes
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MACROFAGEs areMONOCITES which left thecirculation & established intissues
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Macrophage Monocytes in blood & Macrophages in the tissues Enlarge & increase lysosomes ; lysozyme, hydrolytic enzymes
Second line: Phagocytes
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Role of Macrophage
Second line: Phagocytes
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Toll-like receptors &Host-Pathogen Interaction
ONeill, Luke A.J. Immunitys Early -Warning System. Scientific American, Jan (2005), 38 -45.
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Cells of Innate Immunity recognize
Pathogen-associated molecularpatterns known as (PAMPs)
Damage-associated molecularpatterns known as (DAMPs)
Stressed induced proteins: HSP
Crystals: monosodium urateNuclear proteins: high mobilitygroup box-1 protein
S d li
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Second lineB- Soluble factors
1- Acute phase protein (Plasma protein, CRP=Creactive protein, Fibrin.)
2- Complement (proteins in serum, body fluids)2- Interferons (Proteins against viral infections)3- Properdin (Complement activation)4- Beta lysine (Antibacterial protein from Platelets)
5- Lactoferrrin,Transferrin (Iron binding protein)6- Lactoperoxidase (Saliva & Milk)7- Lysozyme (Hydrolyze cell wall)
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Pattern Recognition Receptors (PRRs)
Toll-like receptorsSoluble receptors: Mannose binding lectin (MBL) C-reactive protein Serum amyloid P
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Functions of PRRs: Opsonization, Activation of complement and Activation of coagulation cascades, Phagocytosis, Activation of pro-inflammatory signaling pathways
Pattern Recognition Receptors (PRRs)
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Nuesslein-Volhard: DrosophilaToll
Identified a protein shecalled Toll meaning
weird
Helps the Drosophilaembryo to differentiateits top from its bottom(Neural tubedevelopment)
1985 1991 20011996 1997 1998 1999 20001988 1989
http://www.nature.com/genomics/papers/drosophila.html
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Gay: Toll andInner Part of Human IL-1R is Similar
1985 1991 20011996 1997 1998 1999 20001988 1989
Searching for proteinssimilar to Toll
Shows cytoplasmic domain
of Toll related to that of hIL-1R
Identity extends for 135 aa Didnt make sense
Why does a protein involved in human inflammationlook like one involved in fly neural tube development?
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TLRRecognize1. PAMPs
1. Chemicalstructure
2. Localization3. Origine
2. DAMPs
1. HSP2. HMGB1
TLR C ll T Di t ib ti
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TLR Cell Type DistributionReceptor Cell Type
TLR1 Ubiquitous
TLR2 DCs, PMLs, and monocytes
TLR3* DC and NK cells, upregulated on epithelial andendothelial cells
TLR4 Macrophages, PMLs, DCs, ECs, but not onlymphocytes
TLR5 Monocytes, immature DCs, epithelial, NK, and Tcells
TLR6 High expression in B cells, lower on monocytes andNK cells
TLR7 B cells, plasmacytoid percursor DCs
TLR8 Monocytes, low in NK cells and T cells
TLR9 Plasmacytoid percursor DCs, B cells,macrophages, PMLs, NK cells, and microglial cells
TLR10 B cells, plasmacytoid precursor DCs
TLR11 Not Determined
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Converging Pathways
Effects of signaling are cell specific NF- B activation is the end result of TLR-signaling
Beutler, Nature 2004
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1. TLRdimers2. adaptor proteins
(MyD88)/ TRIF)3. Activation of
transcriptin factors(NfKB, IRFs)
4. +Genes CC, CK,
CAMs/IFN Acute inflammationAntiviral state
Adptoris I: MyD88=Myeloid differentiation factor 88); TRIF (TIR domain containing adaptorinducing IFN )IRF (interferon response factor)
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