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
Phagocytosis takes place
mus t have receptor !
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B-cell activation opsonins
Bacteria has IgG(opsonin)
It is recognized by FcRreceptor on
phagocyte
Phagocytosis takes place
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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