3. Innate Immunity I.pdf

7/28/2019 3. Innate Immunity I.pdf

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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



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Role of Macrophage



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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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