IMMUNOLOGY

Immunity to microbe
Infection procces involved sequence
interaction between the microbe and
the host :
- entry of microbe
- invasion & colonization
- evasion from the host immunity
- tissue injury or fuctional impairment

Immunity to microbe
1. Mediated by both natural and acquired
immunity
2. Stimulate distinct lyphocyt response
and effector mechanism
3. Influenced by their ability to evade or
resist
4. Tissue injury & disase may be caused
by the host response to mirobe and its
product

Extracelluler bacteria
- Replicating outside host cells :
- gram-positive pus-forming (Staphylococcus & Streptococcus)
- gram-hegative cocci (meningococcus & gonococcus)
- gram-negative bacilli (eanteric)
- gram positive bacilli (Clostridium)

Extracelluler bacteria cause disease by

1. Induce inflamation wich result
in tissue destruction
2. Produce toxins, wich have diverse
pathologic effect :
a. endotoxin ( bacterial cell wall)
b. exotoxin (actively secreted)

Natural immunity to extracelluler

bacteria
-Phagocytosis by neutrophil , monocyt
and tissue macrophages
-Activation complement system in the
absent of antibody
-Inflamation

or.vas. endoth.

Cytokine
Chemokine

monocyts

Bacreial LPS

Bacterial
elimination

Adhesion
neutrophil

Activatin
of
inflam.cell

Migration &
local acculatiom of inflammatory cells

Specific imm. resp.to extracelluler bact.

- Polysaccharides capsules & cell walls
(as T-independent -antigent) directly
stimulate B cells antibody
- Respons of CD4+T cells to bacterial proteins in association with Class II MHC
- Antibody & T cells perform several
function that serve to eliminate bacteria

APC

HLA-II

CD4+

bacteria
Various
cytokines
Antibody
response

IFN

Nacrophage
activation-->
phagocytosis
and Bacterial
killing

TNF

inflammation

Immune evasion by extracelluler bact.

- Mechanism utilized by bacteria to
evade spedific immunity
- Produce surface atigent that favor tissue
invasion and colonization

Immune Evasion by Extacelluler bacteria

Antigenic variation

- N.gonorrhoeae
- E. coli
- S.typhimurium

Inhibition of Compl.
activation

- Many bacteria

Resistence to phagocytosis

- Pneumococcus

Scavenging of reactive
oxygen intermediates

- Catalase positive
staphylococcus

Immune resp. to intracelluler bacteria

- Mycobacteria
- Listeria monocytogenes
- Legionella pneumophila
- Survive and replicate within host cells
- Resistent to degradation in macrophages
- Tend to cause chronic infection that
may last years

Natural immunity to intracelluler bacteria

- Phagocytosis
quite ineffective in controlling colonization and spread of this microorganism
- Activate NK cells --> IFN- --> activate
macrophage --> promote killing of
phagocytosed bacteria
- NK cells provide an early defense again
this microbe

Specific immune response

to intracelluler bactera
- CMI ( cell-mediated-immunity)
1. Killing of phagocytosed microbe as
result of macrophage activation by
T cells derived cytokines ( IFN-)
2. Lysis of infected cells by CD+ CTLs

IFN-

Resting
macrophaqge

Resting
macrophaqge

Phagocytosed
icrobe

CD4+

Phagocytosed
icrobe
Lysis of macrophage
and dead of bacteria

Klling of
phagocytosed
microbe

CD8

Immune Evasion by intracelluler

bacteria
Inhibition of phagolysosom
Formation

- M.tuberculosis
- Legionella pneumophilla

Scavenging of reactive oxygen

Intermediates

- M. leprae
(phenolic glycolipid)

Disruption of phagosome
membrane, escpae into
cytoplasm

- Listeria monocytogenes
(hemolysin protein)

Natural immunity to virus

1. Viral infection directly stimulate the
production of Interferon (IFN) -->
inhibit viral replication
2. NK cells lyse virally infected cells
IFN can also enhance ability of NK cell
to lyse infected target cells
3. Complement activation and phagocytosis serve eliminate extracelluler
viruses & from the circulation

Specific immune response to virus

- Is mediated by combination of humoral
and celluler immune mechanism
- Neutralizing and opsoning antibodies
- The principal specific immunity to virus
is lysis cells cells by CD8 CTLs

Immune Evasion by Viruses

1. Antigenic variation

- Influenza, rhinovirus,
HIV

2. Inhibition of Antigen processing

- inhibition of proteasome activity : - EBV, human CMV
- block in TAP transport

- HSV

- block MHC synthesis

- Adenovirus, CMV

- removal of MHC I from ER

- CMV

Phagocytic Cells
1. Professional phagocytes :
- PMN leukocytes
- Monocytes
- Macrophages
2. Paraprofessional
-Dendritic cells (DC) have selective
phagocyte activity
3. Non professional :
- fibroblast & ephithelial cells

Macrophage function
1. Detection of microbial invasion
Opsonic and nonopsonic receptor for
microbe and their product
2. Restriction of microbial spread
Phagocytosis
Granuloma formation
Intracelluler killing
3. Recruitment of immune cells
Cytokines & inflamatory mediators

4. Accessory cells in lymphocyte activ.

-Ag processing & and presentation
-Costimulatory molecules : ligand for
CD40 L, CD28 and CTLA4 (T cells)
-Cytokines
5. Effector cells in CMI
-Increase phagocytosis
-Increase intracelluler killing
-Clearence of apoptotic cells
6. Participation in humoral immunity

Properties of Macrophages
1. Membrane receptor
-Scavenger receptor
-C receptor
-Fc- eceptor
-Macrosialine
-Cytokines receptor
-CD14 (LPS receptor)
2. Production of cytokines
-IL-1

- TNF
- IL-12
- IL-10
- IL-4
- FGF
3. Antigent processing and presentation
4. Produce enzymes
- colagenase
- elastase
- lysozymes
- lysosomal enzymes

5. Production of bioactive lipid and

small radical
- Prostaglandin
- Platelet activatig factor
- reactive oxygen & nitrogen intermediate
.

Phagocytosis
1. Microbial recognition
- PRRs (pattern recognition reseptor
a. membrane bound
b. free in plasma
- Recognize wide variety of microbial
molecules
- As reeptors for binding & entry of
many intraclluler pathogens

2. Microbial uptake
- actin polymerization
- engulfment and internalization
3. Phagosomal maturtion
- depolymerization of actin
- fussion with endosome
- final step : fussion with lysosome
---> phagolysosome generating low
pH and containig degradative hylases

4. Microbial killing
Accomplished by :
- low pH of phagosom
- limitation of nutrien (iron)
- generation of reactive oxygen and
nitrogen intermediates
- Nramp-1 : removal of iron and divalen cation from phagosom
- phox ---> reactive oxygen intermed.
- inos ----> reactive nitrogen intermed.

Phox : phagocyte NADPH oxydase

phox

O2-

O2
NADPH

O2 H2O2

NADPH+
+ H2O
H2O2 + OH*
ClHOCl- + OH*
MPO

antibacterial

LPS
IL-1
TNF
IFN-

INOS

Deaminasi
oxydative
L-arginin

NO
+
H2O2

NO
+
Thiol groups

peroxynitrit

nitrosothiol

5. Production of soluble mediator

- signal & recruit other cells to the
side of infect.
. Stimulate adaptive immune resp.
6. Antigen presentation
- Histocompatibility molecule(HLA)
- HLA-I --> CD8 cells
- HLA-II --> CD4 cellsa
- Costimulatory molecules

Ag

IL-1
M

HLA-II

Th1
CD4

Th2

IL-4 , IL-12

HLA-I

BCGF, BCPF, BCDF

CD8
ADCC

IFN-

Ab

B
IL-2

NK

CD 4

microbe

phagosom

lysosom

golgi
phagolysosom

RE

Phox
Inos
Nram-1

CD 8

viral

golgi
proteasom

RE
TAP

T cells

CD40L

CD28

CTLA4

TCR

Ag-HLA
CD40

B7-1

APC

B7-2