3. Innate Immunity

8/10/2019 3. Innate Immunity

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Imunologie

Aparare Ne-specifica

Celule


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General Introduction

Primitive pattern recognition receptors (PPRR)are conserved across evolution

They recognize common motifs on pathogen

Innate immune system is triggered as soon asphysical and chemical barriers are penetrated bypathogens

Why do you think it is Innate immune systemthat kicks in first?


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GENERAL FEATURES

Complement activation

Phagocytosis

Cell-mediated cytotoxicity

Cytokines and chemokines also contribute

to the enhancement of innate immunity


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Role of complement system

opsonization by phagocyte

(fig.2-1) Alternative pathway Spontaneous hydrolysis of C3 protein to

produce C3b

C3b deposits on microbial surface and activates

cascade

Various proteins are generated

C3b on the bacteria recognizes CR1 receptorson phagocytes and the opsonization takes place


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Alternative pathway: MAC

Generation of membrane attack complex

(MAC)

Insertion of MAC into bacterial cell

membrane induces lysis of the cells or

bacteria


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Alternative pathway: C5a,

C4a, and C3a

Some proteins are anaphylatoxins(C5a,C4a, C3a)

They bind to cognate receptors on mast cells

and basophils which have receptors for

anaphylatoxins

Induction of degranulation takes place

Release of histamine and inflammatorymediators

(This is a sign why we feel sick. So what do we

do about it? We take antihistamine such as

Advil)


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PHAGOCYTOSIS

Neutrophils

Macrophages


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Phagocytic cells

Neutrophils mature in bone marrow

Small % is stored in bone marrow

Majority released into circulation Number of inflammatory cytokines

enhance release of neutrophils from bone

marrow *cytokines enhance activity of Innate and

Adaptive Immunity


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Recruitment of phagocytes

into infected tissues Neutrophils and monocytes are attracted to site

of infection by chemotactic moleculesandchemokines

They marginatealong and attach to lumenalsurface

Secrete enzymes that break basementmembrane

Diapedesistakes place (squeezing through theendothelial wall)

Monocytes differentiate into macrophages intissues

fig. 2-2


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Direct recognition of

pathogens Occurs via primitive receptors (PPRR)

Receptors on cell recognize bacterium

directly

Phagocytosis takes place


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Indirect recognition of

pathogens Uses cell surface receptors

Recognize molecules bound to pathogen

cell surface

Molecules that attached to pathogen are

called opsonins


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Complement activation

opsonins Bacterium carries C3b (opsonin)

It is recognized by CR1 receptor which is

present on phagocyte


mus t have receptor !


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B-cell activation opsonins

Bacteria has IgG(opsonin)

It is recognized by FcRreceptor on

phagocyte


mus t have receptor!

*IgG is synthesized by B-cells, specificallyby plasma cell


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PHAGOSOME

Phagocytic vacuole

Contains lysosomal enzymes, reactive

oxygen intermediates, reactive nitrogen

intermediates


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NADPH oxidase and reactive

oxygen intermediates Increase in oxygen consumption due to

phagocytosis

Activation of NADPH oxidase

Uses oxygen

Generates superoxide anion (ROI)

Fig. 2-6(you will be tested on this concept)


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Nitric oxide and reactive

nitrogen intermediates NO is a lipid and water soluble gas which is

cytotoxic to microbes

Releases RNIs

Important for elimination of pathogens resistantto ROIs

In phagocytes, synthesis of NO requiresinduction of nitric oxide synthase (got to know

thisenzyme) Catalyzes conversion of L-arginine to L-citruline

and NO in presence of oxygen


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Regulation of nitric oxide

synthase 2 signals needed for NO synthase activation:

1) Induction of NOS occurs in response to phagocytosisof Mycobacter ia, leishmania,or tumor necrosis factor

2) cytokine INFsignal

Downregulation occurs in response to cytokines IL-10,IL-4, and transforming growth factor beta (TGF ), whichare Th2 cytokines

TGFis the most effective inhibitor of NO synthesis

Th1 cells are responsible for these signals (intracellularbacteria)

(there is an antagonistic activity of Th1 and Th2 cells)


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Chronic granulomatous

disease Inherited immunodeficiency disorder

Individuals are susceptible to normally nonpathogenicand pathogenic organisms

Characterized by absence or decreased NADPH oxidase

activity in neutrophils In phagosome NADPH oxidase complex assembly is

diminished or absent

Degradation of microbe is diminished

Must rely on phagolysosome and lysosomal enzymes Nitrozole tetrazolium (NBT) test is used to diagnose

CGD

NBT is a yellow dye that becomes insoluble and turnspurple in presence of NADPH oxidase activity


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CGD

Thus, CGD inhibits NADPH oxidase complexassembly

That leads to inability to form superoxide,

hydrogen peroxide, hydroxyl radicals, hydroxylanions

The phagosome takes a different rout herethrough lysosomal enzymes: lactoferrin,

lysozyme, defensins

Fig. 2.8-very important figure


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NATURAL KILLER CELLS

Destruct host cells in order to eliminate virus

Express receptors that recognize viral proteins

embedded in cell membrane

NK cells also express killer inhibitoryreceptors(KIRs), whose ligand is class I MHC

molecule

Upon interaction with class I MHC, NK cellreceives a signal that inhibits killing of cell

expressing class I MHC


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Receptor-mediated

cytotoxicity Virus invades cell

Viral proteins expressed on cell surface

NK cell receptor binds to viral protein

Polarization of granules

Granules release perforin (this proteinpunches or perforates holes in

membrane of NK cells and CD8 cells) Cells osmotic lysis


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Any

cell

Virus

Viral envelope proteins

on the cell surface

Antibodies are generated that

recognize viral envelope proteins

NK cell

FcR

Release of perforin

from granules

Osmotic lysis

NK receptor

Release of perforin

from granules

Osmotic lysis


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Antibody-mediated cellular

cytotoxicity (ADCC) Virus invades cell

Viral proteins expressed on cell surface

Antibodies generated that recognize viral

envelope proteins FcR receptors on NK cells recognize antibody

bound to viral proteins

Polarization of granules from NK cells

Release of perforin Cells osmotic lysis

*B-cell has to be activated to produce antibody


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Eosinophils

Derived from bone marrow

Exist both in circulation and tissues

Major role in immunity to parasites (helminths)

Requires antibodies (IgE) which binds to helminth

Recognition is indirect

Have FcRthat recognizes Fc region of IgE

Triggers degranulation of eosinophils

Release of major basic protein(MBP) and eosinophil

cationic protein(ECP)

IL-5 is a peptide secreted by T-cells and is a precursor ofeosinophils


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Schema experimentala de cultivare a celulelor stem. Celulele stromale ale maduvei osoase formeaza o matrice pe

care celulele hematopoietice prolifereaza. Celulele singulare pot fi apoi trasnferate pe un gel semisolid de agar

pentru a le oferi posibilitatea sa creasca in colonii.

Celule din maduva osoasa in cultura de lunga durata.


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Macrofagele sunt de 5-10 ori mai mari decat monocitele,

contin mai multe organite celulare, in special lisosomi.


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Pseudopode lungi, care ajung in contact cu bacteria, un prim pas sprefagocitoza.

Fagocitoza si procesarea antigenelor exogene. Materialul digerat esteexocitat; unele peptide sunt prezentate de catre MHC II.


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Limfocit normal (in timus)


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Timocite in apoptoza


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Timocit normal


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Timocit in apoptoza.


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3. Innate Immunity

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