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‫بسم هللا الرحمن الرحيم‬
‫موارد مربوط به بحث‪:‬‬
‫‪‬‬
‫كليات‬
‫‪‬‬
‫پاسخ ايمني دربرابرانواع ميكروارگانيسم ها‬
‫‪‬‬
‫گريز(‪ )Evasion‬ميكروارگانيسم ها ازپاسخ ايمني‬
‫‪‬‬
‫آسيب هاي ناش ي ازپاسخ ايمني به عوامل عفوني‬
‫)‪)Immunopathology‬‬
Immune response to infections

Bidirectional relationship between Immune
system and infectious agents
Different layers
- Innate
- early Induced Response
- Specific

Innate Immunity
Innate immunity is responsible for the earliest response by the
body to potential infection.
Innate immunity precedes adaptive immunity.
Innate Immunity
The Epithelium is an Important First Line of Defense.
Defensins
Killing of Salmonella by human
defensins secreted by Paneth
cells. The small intestine is lined by
finger-like absorptive villi interspersed
with crypts — narrow pits containing a
cluster of defensin-rich Paneth cells at
the bottom. The granules of Paneth
cells have high concentrations of
prodefensin 5, consisting of a propiece
segment (blue circles) joined to the Nterminus of mature human defensin 5
(red circles), together with Paneth cell
trypsin
(green
triangles).
After
Paneth-cell degranulation, induced by
the entry of bacteria into the intestinal
lumen, trypsin activates defensin 5 by
cleaving off its propiece. This process
might
function
to
protect
the
absorptive epithelium, as well as the
crypt, with its intestinal stem cells
that
generate
the
absorptive
enterocytes.
Pathogens are Recognized and
Killed by Phagocytes
Phagocytes bear different receptors
that recognize microbial
components and induce
phagocytosis. These include:
CD14 (LPS Receptor)
CD11b/CD18 (CR3 – C’R)
Mannose Receptor
Glucan Receptor.
Comparison of Innate and Specific Receptors
The innate immune system lacks the specificity of the adaptive (Specific) immune system.
However, the innate immune system can distinguish between self and non-self.
Pattern Recognition Receptors (PRR)
Receptors with specificity for pathogen surfaces recognize
patterns of repeating structural motifs.
These
receptors
Receptors (PRR).
are
designated
Pattern-Recognition
The mannan-binding lectin that initiates the MB-lectin pathway of
complement activation is an example of a PRR.
Pathogen recognition and discrimination from self is due to the
recognition of a particular of certain sugar residues, as well as
the spacing of these residues, which is found only on pathogens
and not on normal host cells.
Pattern Recognition Receptors (PRR)
Innate Receptors can Signal the
Presence of Pathogens
The binding of pathogens to phagocytes can trigger the
innate response, acting as a signal to the body.
This “Danger Signal” precedes the activation of the specific
immune response.
The initiation of the innate mechanisms is mediated by a
family of evolutionarily conserved, transmembrane receptors
that function exclusively as signaling receptors.
These receptors are known as the “Toll” receptors, because
they are related to the Toll receptor in the fruit fly, Drosophila.
In the fruit fly, the Toll receptor triggers the synthesis of
antifungal peptides in response to fungal infection.
A different member of the family is involved in the production
of antibacterial peptides.
Innate Receptors can Signal the
Presence of Pathogens
.
TLR Ligands
Members of the TLR family
Function of TLRs

recognition of microbial
components

Generation of defensive
responses to pathogens in the
organism:
signal transduction causes
transcriptional activation,
synthesis and secretion of
cytokines

Directs the adaptive immune
responses against antigens of
microbial origin
Activation of signal transduction pathways by TLRs
leads to induction of various genes that function in
host defence:




Inflammatory cytokines
Chemokines
Major histokompatibility complex
Costimulatory molecules
Additionally mammalian TLRs can induce effector
molecules that can destroy directly microbial
pathogens:
• Inducible nitric oxide synthase
• Antimicrobial peptides
Toll-like Receptors (TLR) Function in
Higher Organisms
A Toll-like receptor, TLR-4, signals the presence of bacterial LPS
in mammals. It requires the interaction with another protein, LPS
binding protein (LBP).
The Immune Response to
Extracellular Bacteria
Extracellular Bacteria Commonly
Associated with Diseases
Species
Diseases
Mechanisms of Pathogenicity
Staphylococcus aureus
Skin and soft tissue infections
lung abscess
toxic shock syndrome
food poisoning
Acute inflammation induced by toxins
cell death from pore-forming toxins
Superantigen-induced cytokine production
skin necrosis, shock, diarrhea.
Streptococcus pyogenes
(Group A)
Pharyngitis
Skin infections: impetigo
erysipelas, cellulitis
Scarlet Fever
Toxin-induced acute inflammation
e.g. Streptolysin O damage of cell membranes
Anti-phagocytic actions of capsule polysaccharides
Streptococcus pneumoniae
Pneumonia
meningitis
Cell wall constituent-induced acute inflammation
Toxin (pneumolysin, similar to streptolysin)
Escherichia coli
Urinary tract infections
gastroenteritis
septic shock
Toxins acts on intestinal epithelium
Increased chloride and water secretion
Endotoxin (LPS) stimulates cytokine synthesis
Vibrio cholerae
Diarrhea
Cholera toxin – ADP ribosylates G protein subunit
Leads to increased cAMP in intestinal epithelial cells
Results in chloride secretion and water loss
Clostridium tetani
Tetanus
Tetanus toxin binds to motor endplate
at neuromuscular junction
Causes irreversible muscle contraction
Neisseria meningitis
Meningitis
Potent endotoxin causing acute inflammation and
systemic disease
Corynebacterium diphtheriae
Diphtheria
Diphtheria toxin ADP ribosylates elongation factor – 2
Inhibits protein synthesis
Immune Responses to
Extracellular Bacteria
 Infection by extracellular bacteria induces production of humoral antibodies.
 Antibodies are secreted by plasma cells in the regional lymph nodes and the
submucosa of the respiratory and gastrointestinal tracts.
 Antibodies act in several ways:
 Prevention of bacterial attachment.
 Opsonization and removal of bacteria.
 Neutralization of toxins.
 Extracellular bacteria are pathogenic because they induce a localized
inflammatory response or through toxin formation.
 The toxins (endotoxins and exotoxins) can be cytotoxic.
 Toxins may act in other ways – diphtheria toxin blocks protein synthesis
through the ADP-ribosylation of the translation elongation factor EF-2.
 Endotoxins are components of bacterial cell walls.
 Exotoxins are secreted.
Immune Responses to
Extracellular Bacteria
 Antibody functions as an opsonin by binding to specific antigenic structures on
the bacterial cell wall or capsule.
 Complement component C3b, deposited on the bacterial cell surface, is an
additional opsonin.
 Opsonization increases phagocytosis and clearance of the bacterium.
 For certain Gram-negative bacteria (e.g., Neisseria species), the formation of the
membrane attack complex following complement activation can lead to direct
bacterial lysis.
 Antibody-mediated complement activation can induce the localized production
of inflammatory mediators that further amplify the inflammatory response.
 C3a, C4a and C5a act as anaphylotoxins, inducing local mast cell degranulation,
which results in vasodilation.
 Neutrophils, monocytes and lymphocytes are recruited to the site of
inflammation by C5a, and various chemokines.
Immune Responses to
Extracellular Bacteria
Immune Responses to
Extracellular Bacteria
Antibody Functions Against
Extracellular Bacteria
Antibody Functions Against
Extracellular Bacteria
Anti-Adhesin Antibodies Block
Bacterial Colonization
Mechanisms of Extracellular Bacterial
Immune Evasion
Infection Process
Host Defense
Evasion Mechanism
Attachment to Host Cell
Blockage of attachment
by secretory IgA molecules
Secretion of proteases that
cleave secretory IgA dimers
(Neisseria, Hemophilus)
Antigenic variation in attachment
structures (pili of N. gonorrheae)
Proliferation
Phagocytosis
(Antibody- and Complementmediated opsonization)
Production of surface structures
(polysaccharide capsules,
M protein, fibrin coat)
Induction of apoptosis in macrophages
(Shigella)
Complement-mediated lysis
and localized inflammation
Generalized resistance of Gram-positive
bacteria to complement-mediated lysis
Insertion of MAC prevented by long side
chain in cell wall LPS
Invasion of Host Cells
Antibody-mediated
agglutination
Secretion of elastase inactivates C3a and C5a
Toxin-induced damage
Neutralization of toxin
by antibody
Secretion of hyaluronidase
(enhances invasiveness)
Survival in phagocytes
Generation of Reactive Oxygen
Intermediates
Production of catalase
by Staphylococcus
Evasion Through Antigenic Variability
The different strains of S. pneumoniae have antigenically distinct capsular polysaccharides. The capsule
prevents effective phagocytosis until the bacterium is opsonized by specific antibody and complement,
allowing phagocytes to destroy it. Antibody to one type of S. pneumoniae does not cross-react with the
other types, so an individual immune to one type has no protective immunity to a subsequent infection
with a different type. An individual must generate a new adaptive immune response each time he or she is
infected with a different type of S. pneumoniae.
The Immune Response to
Intracellular Bacteria
Facultative Intracellular Bacteria
Pathogens That Do Not Depend on Intracellular Environment
For Survival
Mycobacterium tuberculosis
Mycobacterium leprae
Salmonella enterica
Brucella species
Legionella pneumophila
Listeria monocytogenes
Francisella tularensis
Obligate Intracellular Bacteria
Pathogens Depend Absolutely on Intracellular Environment
For Survival
Bacteria prefer non-phagocytic cells as host cells, including
epithelial and endothelial cells.
Rickettsia prowazekii
Rickettsia rickettsii
Rickettsia typhi
Rickettsia tsutsugamushi
Coxiella burnetii
Chlamydia trachomatis
Chlamydia psittaci
Chlamydia pneumoniae
Innate immunity Against L.monocytogenes
Innate immune activation by virulent Listeria monocytogenes is a multistep process.
a | Bacteria in the
bloodstream are bound by macrophages and internalized. In the macrophage vacuoles, bacteria secrete
listeriolysin O (LLO), which lyses the vacuolar membrane and activates nuclear factor-kB (NF-kB)-mediated
transcription of innate immune-response genes, such as CC-chemokine ligand 2 (CCL2). b | The CCL2 that is
produced then induces the recruitment of circulating monocytes that express CC-chemokine receptor 2 (CCR2).
c | Microbial products are released by infected macrophages, and these activate recruited monocytes through
Toll-like receptors (TLRs) in a MyD88 (myeloid differentiation primary-response protein 88)-dependent manner. d
| Monocytes differentiate into tumor-necrosis factor (TNF-a)- and inducible nitric-oxide (NO) synthase (iNOS)producing dendritic cells (TipDCs), which promote bacterial killing.
Delayed-type Hypersensitivity
(Type IV Hypersensitivity)
Delayed-type Hypersensitivity
(Type IV Hypersensitivity)
Activation of Macrophages
Functions of Activated Macrophages
In Anti-bacterial Immunity
Macrophage Response**
**
Role in Cell-mediated Immunity
Production of reactive oxygen intermediates,
nitric oxide; increased lysosomal enzymes
Killing of microbes in phagolysomes
(effector function of macrophages)
Secretion of Cytokines
(TNF-a, IL-1, IL-12)
TNF-a, IL-1: leukocyte recruitment
(Inflammation)
IL-12: TH-1 differentiation, IFN-g production
(induction of response)
Increased expression of:
CD80, CD86
Class I, Class II MHC
Increased T cell activation
(amplification)
These macrophage responses are induced by CD40 ligation to CD154 (CD40L) and T cellderived IFN-g in cell-mediated immunity; similar responses are induced by microbial
products, particularly LPS, and NK cell-derived IFN-g in innate immunity.
Intracellular Bacterial Evasion of
Killing in Phagocytes
Intracellular bacteria have evolved strategies to evade killing by the
mechanisms available to the phagocyte.
Macrophage effector capacity
Microbial evasion mechanism
Phagosome acidification
Phagosome neutralization
Phagosome–lysosome fusion
Lysosomal enzymes
Inhibition of phagosome–lysosome fusion
Resistance against enzymes
Intraphagolysosomal killing
Evasion into cytosol
Robust cell wall
C3b receptor-mediated uptake,
ROI
ROI detoxifiers, ROI scavengers
RNI
Unknown (ROI detoxifiers probably interfere with RNI)
Iron starvation
Microbial iron scavengers (e.g., siderophores)
Evasion into the Cytoplasm
Three Stages of the Immune Response
to Intracellular Bacteria
The Central Role of T Lymphocytes
 Acquisition of resistance against intracellular bacteria crucially depends on T-lymphocytes,
which, ideally, accomplish sterile bacterial eradication.
 When a “normal” immune status is provided, bacterial clearance is rapidly achieved in the
case of susceptible bacteria, such as L. monocytogenes.
 In the case of resistant pathogens, such as M. tuberculosis, clearance frequently remains
incomplete and is arrested at the stage of bacterial containment to, and growth control at,
distinct foci.
 Bacterial containment and eradication occur in granulomatous lesions.
 The longer the struggle between host and microbial pathogen continues, the more essential
the granuloma becomes.
 Granuloma formation and perpetuation are orchestrated by T-lymphocytes.
 The cross-talk in the granuloma between T-lymphocytes, MPs, and the other cells is
promoted by cytokines.
 T-lymphocytes are an unavoidable element of the pathogenesis of intracellular bacterial
infections.
 Expanding granulomas impair tissue functions by occupying space and affecting
surrounding cells.
Cytokines in Antibacterial Immunity
Cytokine
Chemokines
Contribution to
Major cellular source
antibacterial protection in bacterial infection
Major function
in bacterial infection
Likely
Epithelial cell
endothelial cell
macrophage
Leukocyte recruitment and activation
IL-1
IL-6
Important role proven
Essential role proven
Macrophage
Macrophage, T cell
Leukocyte recruitment and stimulation
Leukocyte recruitment
T-cell differentiation
TNF-a
Essential role proven
Macrophage
mast cell
Leukocyte recruitment
NK-cell activation
granuloma formation
IFN-g costimulation
IFN-g
Essential role proven
Th 1 cell
NK cell
Macrophage activation
granuloma
IL-12
Important role proven
Macrophage
Th 1-cell, NK-cell stimulation
IL-18
IL-4
Likely, not proven
Exacerbation
Macrophage
NK T cell, Th2 cell
basophil (?)
Eosinophil (?)
Th 1-cell stimulation
Th 1-cell inhibition
IL-10
Exacerbation
Macrophage
Macrophage inhibition
TGF-b
Exacerbation likely, not proven
Macrophage
Macrophage inhibition
Granuloma Formation
 Recirculating T-lymphocytes passing by the inflammatory lesion are recruited by proinflammatory cytokines and chemokines.
 Gradually, infiltrating cells become organized and form a granuloma predominantly
consisting of MPs.
 TNF-a and IFN-g appear to be of crucial importance for this event.
 ab T cells are the dominant T-lymphocyte population throughout all stages of
granuloma formation
 A significant proportion of gd T cells has been observed in the initial phase. These gd
T cells apparently play an important role in the organization of a tight and wellstructured granulomatous lesion.
 Granulomas are at the forefront of protection by restricting bacterial replication at, as
well as confining pathogens to, discrete foci. This is achieved by the following:
 Activated MPs capable of inhibiting bacterial growth
 Encapsulation promoted by fibrosis and calcification
 Necrosis leading to a reduced nutrient and oxygen supply
 Yet, frequently, microbial pathogens are not fully eradicated, and some organisms
survive in a dormant form. A labile balance between microbial persistence and
antibacterial defense develops that lasts for long periods.
Granuloma Formation
The Immune Response to
Viral Infections
Overview
Immunity to viral infections is a broad subject that touches
upon all aspects of cellular and humoral immune mechanisms.
 This reflects the strong selective pressure viruses have
exerted upon the evolutionary development of the immune
system.
 The immune system fights a ceaseless battle against
infectious agents and both of these forces have been shaped
by the constant conflict - microbe/immunology/survival.
 Viruses are by definition obligate intracellular parasites;
therefore effective immunity is often directed against the
infected cell rather than against the invading virus itself.
 The type of immune response most effective against a
particular virus is heavily dependent upon the life cycle of that
virus.

Patterns of Viral Infection

Viral infections can be divided into three general
categories.
1. Acute infection followed by viral clearance due to the
host immune response. (polio, influenza, rotavirus,
mumps, yellow fever, RSV, etc.)
2. Acute infection followed by latent infection.
(herpesviruses, etc.)
3. Acute infection followed by persistent infection in
which infectious virus is continuously shed.
(HIV, HBV, HCV, etc.)
Cont.
Patterns of Viral Infection
1.
2.
3.
Cont.
Patterns of Viral Infection

What does this mean immunologically?

Acute - Immune response completely destroys the virus
and long term memory prevents reinfection.

Latent - Immune response only destroys most of the
infectious virus (the virus hides and periodically
reactivates) and long term immunity (mostly cellmediated) must remain ever watchful.

Persistent - Immune response destroys most but not all of
the infected cells (no viral clearance and the
remaining infected cells continuously shed virus)
and long term immunity is ever vigilant but can
never completely remove the virus.
Host Response to Viral Infection

The immune response to
viral infections can be
broken down into two
broad categories.
1. Innate
2. Adaptive
Innate Immunity

Cytokines
Interferons (a, b, & g)
 Others


Cells
NK cells
 Monocytes/Macrophages


Complement
Host Response to Viral Infection
Cell-Mediated Effector Mechanisms

Bottom line: CD8+ T cells rock. They are the
predominant effector cell in the adaptive arm
of the immune system in defense of viral
infections.
The Immune
Response to
Parasites
Parasites and the Immune System
 Parasite – applies to all infectious agents.
 Usually understood to be protozoan and metazoan
pathogens
 Characterized by chronicity in host and metamorphosis
through multiple, usually antigenically distinct, life-cycle
stages.
 Most express
mechanisms.
highly
evolved
immune
evasion
 As a group, parasitic diseases remain a significant
global human health problem.
Leishmania
Protective Type 1 Responses
Protozoa
Leishmania major
 Prototype of a protective type 1 response is resistance to L.
major in resistant mice.
 L. major causes an early lesion of varying magnitude – in
resistant mice, the lesion resolves.
 Resolution of the lesion is due to the activation of
macrophages by IFN-g produced initially by NK cells, and
subsequently by Th1 CD4 T cells.
 CD4 T cells play a central role – class II MHC0/0 mice are unable
to control infection – b2m0/0 (class I MHC-deficient) mice heal
with equivalent kinetics to wild-type mice.
Protective Type 1 Responses
Protozoa
Leishmania major
 The ultimate effector molecule controlling L. major infection is
the production of nitric oxide (NO) and other reactive nitrogen
intermediates in response to macrophage activation by IFN-g.
 IFN-g is essential – neither IFN-g0/0 nor IFN-gR0/0 mice can control
parasite replication.
 Inhibition of iNOS also results in susceptibility – the use of
inhibitors after the lesion had resolved resulted in lesion
reactivation and parasite overgrowth – suggests that the
immune response does not result in complete removal of the
parasite, but instead suggests continued control by iNOSdependent mechanisms.
Trypanosoma
Protective Type 1 Responses
Protozoa
Trypanosoma cruzi
 T. cruzi is able to invade many different nucleated cell
types, forming a parasitophorous vacuole.
 Once inside the cell, the parasite leaves the vacuole and
enters the cytoplasm – entry into the cytoplasm makes
the T. cruzi antigens available to processing by the class
I MHC pathway.
 CD8+ T cells play a crucial role in controlling T. cruzi –
b2m0/0 and class I MHC0/0 mice are extremely susceptible
to infection.
 IFN-g synthesis rather than classical perforin- or
granzyme-mediated cytotoxicity is likely to be the major
protective mechanism.
Plasmodium
Protective Type 1 Responses
Protozoa
Plasmodium
 Malaria, caused by Plasmodia species, is undoubtedly the
most important parasitic disease of humans.
 Plasmodia have a complex life-cycle.
 Complex life-cycle involves two distinct cell types:
hepatocyte (expresses class I MHC) and the erythrocyte (no
MHC expression).
 Also involves several distinct extracellular forms of the
parasite.
 This implies that more than one form of immune response
is required to control infection.
Protective Type 1 Responses
Protozoa
Plasmodium
 Antibodies are effective against the sporozoite and
erythrocytic stages.
 Type 1 cytokines are effective against the intrahepatic
stage – the injection of IL-12 into mice 2 days prior to
infection with P. yoelli completely prevents infection.
 The effect of IL-12 in the mouse model, this was shown
to be due to the production of IFN-g by NK cells and the
upregulation in the liver of iNOS – NO is the assumed
effector mechanism against the intracellular parasite.
 Hepatocytes can express iNOS – presumably IFN-g
works directly on these cells to induce the parasitedirected effector response.
Protective Type 1 Responses
Protozoa
Plasmodium
 The injection of IL-12 into susceptible A/J mice, prior to
and following exposure to P. chabaudi-infected
erythrocytes results in decreased parasitemia and
increased survival – Th1 cells, IFN-g, TNF-a, and NO are
implicated in this process.