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Innate Immunity (III)

Soluble Molecules

NK Cells
First line of defense against:
Tumor cells Virally-infected cells Other intracellular pathogens
NK Cell

Tumor Cell

Implicated in:
Transplant rejection Autoimmunity Spontaneous abortions
Christina Trambas, Cancer Council of Tasmania, http://www.ciml.univ-mrs.fr/fr/science/lab-eric-vivier/pour-specialistes

Functions of NK

1. Direct Cytotoxicity:
Target cell lysis
a. by perforines & granzymes b. By Ab dependent cellular cytotoxicity (ADCC)

Functions of NK (II)

2. NK secrete IFNs:
Enhance the activation of M Anti-viral activity

Discovery of Interferons
Isaacs and Lindenmann (1957) Found a substance that interfered with viral replication and was therefore named interferon Nagano and Kojima also independently discovered this soluble antiviral protein

What are Interferons?


Naturally occurring family of proteins & glycoprotein each with slightly different physiological effects Genes (chr 9/12*) that synthesize IFN are activated when a host cell is invaded by a virus IFNs are secreted by cells of immune system : NK, lymphocytes eukaryotic cells in response to viral infections,

tumors

Interferon Family Main functions


stimulates the healthy cells which are living neighbor an infected cell to activate genes for an antiviral protein blocks viral reproduction in the neighboring cell activate macrophages and mobilize NKs

General Action of Interferons


When a tissue cell is infected by a virus, it releases interferon. Interferon will diffuse to the surrounding cells. When it binds to receptors on the surface of those adjacent cells, they begin the production of a protein that prevents the synthesis of viral proteins.
This prevents the spread of the virus throughout the body.
Three types of interferons: alpha, beta and gamma.

Type I Interferons
Alpha: produced by leukocytes Beta: produced by fibroblasts
Largest group of interferons

Receptors: interferon cell receptors type 1:


stimulus for expression: viral infection different binding affinities

similar biological effects

Roles
Used to mobilize our 1st line of defense against invading organisms

Anti-viral effects of interferon a/b

Type II Interferon (gamma)


Gamma: produced by
TH1, CTLs NK B cells and professional antigenpresenting- cells
stimuli

for Gamma production:


activation

immune

Inflammatory state*
Bind

to type 2 receptors

Innate Immune System


First line
Natural Barriers:

Second line
Componentes: I. Cells: NK, Phagocytes II. Soluble molecules III. Mechanisms

I.

Physical II. Chemical III. Biological

Soluble molecules
recognition opsonization distruction cellular lysis

+phagocytosis

+ inflammation

Soluble molecules
recognition
1. Natural Ab (limitated

distruction
1. Interferons
(anti-viral proteins ) (Membranar Attack Complex)

2. Pentraxines
3. Collectins 4. Ficolines

specificity)

(C Reactive Protein, serum amiloid P)

2. Complement
3. Beta lysine

(MBL, pulmonar surfactants)


(plasma proteins)

4. Lactoperoxydase 5. Lysosim
(saliva & milk )

(antibacterial proteins)

(anti-bacterial enzyme))

Recognition Soluble Molecules


Natural Abs:
Produced by some subsets of LB limited number of specificities without overt exposure to foreign Ags Are present in plasma before the infection Recognize common non-self molecules Recognize microbial structures Structure: pentameric proteins Members:

Pentraxines:

CRP: plasma conc low (N) 1000 fold during infection (phase acute reactant)

Short PTX: Reactive C protein, serum amyloid P Long PTX: PTX3

Recognition Soluble Molecules


3. Collectines: Family Members: Structure:
MBL (manose-binding lectin) SP-A & SP-D (pulmonar surfactants

collagen-like tail bound to lectinic calcium-dependent (C-type) sequence Role: recognize Man, Fru residuu

4. Ficolins: structure : Role:

Similar to collectins N-acetylglucosamin & acid lipotheicoicG+ bacteria


recognize

Dupa Abas at al. 2012 Elsevier/Saunders

Soluble molecules
recognition
1. Natural Ab (limitated

distruction
1. Interferons
(anti-viral proteins ) (Membranar Attack Complex)

2. Pentraxines
3. Collectins 4. Ficolines

specificity)

(C Reactive Protein, serum amiloid P)

2. Complement
3. Beta lysine

(MBL, pulmonar surfactants)


(plasma proteins)

4. Lactoperoxydase 5. Lysosim
(saliva & milk )

(antibacterial proteins)

(anti-bacterial enzyme))

Complement (C) Definition


Definition: Group of 30 different heat labile proteins, component of normal plasma When activated, they can enhance aspects of innate immunity & some of the biological effects of Abs
exist normally in an inactive form (zymogen).

their activity was said to complement antibacterial activity of antibodies

C Protein Sources
Nomenclature:
are designated by letter C followed by a number (C1-C9) fragments obtained by cleavege a/b** Factors: B, D, P, H, I

Source:

Hepatocytes Tissue macrophages Epithelial cells of the GI Blood monocytes

The effector functions of complement can be activated through 3 major pathways


The Classical Pathway Lectin Pathway

The Alternative Pathway

Innate Immune Activation of Complement Pathway: 2 modes of initiation

Alternative Pathway of Complement Activation


Triggered by
LPS Cell Walls of some bacteria and yeasts Cobra venom

Components of Alternative Pathway of Complement


Proteins C3 structure Heterodimer : 180kDa : terminal C: thiol esther domain TED2S : terminal N: bound C5 Conc (g/dL) function 1000-1200 Non-enzymatic Activated C3a: stimulate inflammation C3b: opsonin; component of C3 convertase

Factor B (zymogen)
Factor D (active protease FactorP /properdin

Monomer: 93 kDA 1 chain AA


Monomer 25 kDA

200
1-2

Bb=Ser protease: active form of C3 & C5 convertase


Plasmal Ser-protease Cleavage factor B

Monomers 56KDa (max 4 subunits)

25

Stabilize C3 convertase (C3bBb)

Dupa Abas at al. 2012 Elsevier/Saunders

Alternative Pathway of Complement Activation

Dupa Abas at al. 2012 Elsevier/Saunders

Final Stages of C cascade

Abas at al. 2012 Elsevier/Saunders

3 Main Consequences of Complement Activation


Opsonization of Pathogens: C3b Acute Inflammation: C3a, C5a Killing of Pathogens: pore formation

Functions of C system (a)

Dupa Abas at al. 2012 Elsevier/Saunders

Functions of C system (b)

Functions of C system (b)

Dupa Abas at al. 2012 Elsevier/Saunders

Regulation of Complement Activation


Regulators of Complement Activation

Decay Accelerating Factor, Membrane Cofactor 1, Complement Receptor 1, C1 Inhibitor etc. Inhibit formation of C3 convertase Breakdown and inactivate C3 and C5 convertase Inhibit formation of MAC

Regulation of Complement Activation

Dupa Abas at al. 2012 Elsevier/Saunders

Regulatory Protein placed on the surface of host cell prevent/dissociate formation of Bb complex Decay Accelerating Factor/ Complement Receptor 1, Membrane Cofactor 1

Inhibition of activation of C
Plasma Factors:
H Factor: bound C3b & C3bBb complex Catalyze the activity of I factor I Factor (inhibitory): protease cleavage bound C3b inactiv C3b

Dupa Thao Doan 2008; LWW

The end

Interferon Family
Interferons are a family of related Lymphocytes secrete gamma () interferon, but most other WBCs secrete alpha () interferon Fibroblasts secrete beta () interferon Interferons also activate macrophages and mobilize NKs FDA-approved alpha IFN is used:
As an antiviral drug against hepatitis C virus To treat genital warts caused by the herpes virus
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4 a. Interferon (IFN)
Interferon molecules leave the infected cell and enter neighboring cells
Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein)
PKR nonspecifically blocks viral reproduction in the neighboring cell

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The exact mechanism of type I interferons are not fully understood, but this is an idea of what happens:
Alpha and beta bind to heterodimeric receptor on cell surface. Alpha receptor is made up of at least 2 polypeptide chains: IFNa-R1 and IFNa-R2 IFNa-R1 is involved in signal transduction IFNa-R2 is the ligand-binding chain that also plays a role in signal transduction Ligation induces oligomerisation and initiation of the signal transduction pathway This results in phosphorylation of signal transductors and activators of transcription proteins, which translocate to the nucleous as a trimeric complex, ISGF-3. ISGF-3 activates transcription of interferon stimulated genes, with many biological effects.

Interferon Gamma Receptor


Composed of two ligand binding IFNg-R1 chains associated with two signal transducing IFNg-R2 chains The IFNg-R2 chain is generally the limiting factor in IFNg responsiveness, as the IFNg-R1 chain is usually in excess. The IFNg-R1 intracellular domain contains binding spots for the Jak 1, latent cytosolic factor, signal transducer and activator of transcription (Stat1) IFNg only associates with IFNg-R2 when the IFNgR1 chain is present.