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• Immunopathology))

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Immune response to infections

• Bidirectional relationship between Immune system
  and infectious agents
• Different layers
• - Innate
• - early Induced Response
• - Specific

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Innate Immunity
Innate immunity is responsible for the earliest
response by the body to potential
infection. Innate immunity precedes adaptive
immunity.
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Innate Immunity
The Epithelium is an Important First Line of
Defense.
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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 N-terminus
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.
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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 CR) Mannose
Receptor Glucan Receptor.
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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.
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Pattern Recognition Receptors (PRR)
Receptors with specificity for pathogen surfaces
recognize patterns of repeating structural
motifs. These receptors are designated
Pattern-Recognition Receptors (PRR). 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.
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Pattern Recognition Receptors (PRR)
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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.
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Innate Receptors can Signal the Presence of
Pathogens
.
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TLR Ligands
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Members of the TLR family
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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

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• 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

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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).
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The Immune Response to Extracellular Bacteria
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Extracellular Bacteria Commonly Associated with
Diseases
Species Diseases Mechanisms of
Pathogenicity Staphylococcus aureus Skin and
soft tissue infections Acute inflammation induced
by toxins lung abscess cell death from
pore-forming toxins toxic shock
syndrome Superantigen-induced cytokine
production food poisoning skin necrosis, shock,
diarrhea. Streptococcus pyogenes Pharyngitis Tox
in-induced acute inflammation (Group A) Skin
infections impetigo e.g. Streptolysin O damage
of cell membranes erysipelas,
cellulitis Anti-phagocytic actions of capsule
polysaccharides Scarlet Fever Streptococcus
pneumoniae Pneumonia Cell wall constituent-induced
acute inflammation meningitis Toxin
(pneumolysin, similar to streptolysin) Escherich
ia coli Urinary tract infections Toxins acts on
intestinal epithelium gastroenteritis Increased
chloride and water secretion septic
shock 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 Tetanu
s toxin binds to motor endplate at
neuromuscular junction Causes irreversible
muscle contraction Neisseria meningitis Meningit
is Potent endotoxin causing acute inflammation
and systemic disease Corynebacterium
diphtheriae Diphtheria Diphtheria toxin ADP
ribosylates elongation factor 2 Inhibits
protein synthesis
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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.

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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.

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Immune Responses to Extracellular Bacteria
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Immune Responses to Extracellular Bacteria
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Antibody Functions Against Extracellular Bacteria
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Antibody Functions Against Extracellular Bacteria
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Anti-Adhesin Antibodies Block Bacterial
Colonization
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Mechanisms of Extracellular Bacterial Immune
Evasion
Infection Process Host Defense Evasion
Mechanism Attachment to Host Cell Blockage of
attachment Secretion of proteases that by
secretory IgA molecules cleave secretory IgA
dimers (Neisseria, Hemophilus) Antigenic
variation in attachment structures (pili of N.
gonorrheae) Proliferation Phagocytosis Productio
n of surface structures (Antibody- and
Complement- (polysaccharide capsules, mediated
opsonization) M protein, fibrin
coat) Induction of apoptosis in
macrophages (Shigella) Complement-mediated
lysis Generalized resistance of
Gram-positive and localized inflammation bacteri
a to complement-mediated lysis Insertion of
MAC prevented by long side chain in cell wall
LPS Invasion of Host Cells Antibody-mediated Sec
retion of elastase inactivates C3a and
C5a agglutination Toxin-induced
damage Neutralization of toxin Secretion of
hyaluronidase by antibody (enhances
invasiveness) Survival in phagocytes Generation
of Reactive Oxygen Production of
catalase Intermediates by Staphylococcus
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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.
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The Immune Response to Intracellular Bacteria
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Hallmarks of Idealized Intracellular Bacterium
Hallmark 1

• Intracellular lifestyle is the distinguishing
  feature.
• Not all bacteria entering cells are
  intracellular transition through epithelial
  cells is a common invasion mechanism of both
  intracellular and extracellular bacterial
  pathogens.

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Hallmarks of Idealized Intracellular Bacterium
Hallmark 2

• T lymphocytes are the central mediators of
  protection against intracellular bacterial
  pathogens.
• T cells do not interact directly with pathogens.
• T cells interact with infected host cells and
  implement antibacterial mechanisms.

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Hallmarks of Idealized Intracellular Bacterium
Hallmark 3

• Infections with intracellular bacteria are
  accompanied by delayed-type hypersensitivity
  (DTH, Type IV hypersensitivity) reactions.
• Tissue reaction mediated by T cells and effected
  by macrophages.

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Hallmarks of Idealized Intracellular Bacterium
Hallmark 4

• Tissue reactions against intracellular bacteria
  are granulomatous.
• Protection and pathology are centered in these
  lesions.
• Rupture of granuloma promotes bacterial
  dissemination and formation of additional lesions.

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Hallmarks of Idealized Intracellular Bacterium
Hallmark 5

• Intracellular bacteria present little or no
  toxicity to the host cells themselves.
• Pathology is due primarily to the T cell-mediated
  immune response.

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Hallmarks of Idealized Intracellular Bacterium
Hallmark 6

• Intracellular bacteria coexist with their
  cellular habitat for a long period.
• There is a balance between persistent infection
  and protective immunity results in long
  incubation times and chronic diseases.

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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
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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
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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.
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Delayed-type Hypersensitivity (Type IV
Hypersensitivity)
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Delayed-type Hypersensitivity (Type IV
Hypersensitivity)
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Activation of Macrophages
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Functions of Activated Macrophages In
Anti-bacterial Immunity
Macrophage Response Role in Cell-mediated
Immunity
Production of reactive oxygen intermediates, Kill
ing of microbes in phagolysomes nitric oxide
increased lysosomal enzymes (effector function of
macrophages) Secretion of Cytokines TNF-a,
IL-1 leukocyte recruitment (TNF-a, IL-1,
IL-12) (Inflammation) IL-12 TH-1
differentiation, IFN-g production (induction of
response) Increased expression of Increased T
cell activation CD80, CD86 (amplification) Class
I, Class II MHC
These macrophage responses are induced by CD40
ligation to CD154 (CD40L) and T cell-derived
IFN-g in cell-mediated immunity similar
responses are induced by microbial products,
particularly LPS, and NK cell-derived IFN-g in
innate immunity.
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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 Phagosomelysosome
fusion Inhibition of phagosomelysosome
fusion Lysosomal enzymes 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)
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Intracellular Bacterial Evasion of Killing in
Phagocytes
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Evasion into the Cytoplasm
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Three Stages of the Immune Response to
Intracellular Bacteria
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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.

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Cytokines in Antibacterial Immunity
Cytokine Contribution to Major cellular source
Major function antibacterial protection in
bacterial infection in bacterial infection
Chemokines Likely Epithelial cell Leukocyte
recruitment and activation endothelial
cell macrophage IL-1 Important role
proven Macrophage Leukocyte recruitment and
stimulation IL-6 Essential role
proven Macrophage, T cell Leukocyte
recruitment T-cell differentiation TNF-a Esse
ntial role proven Macrophage Leukocyte
recruitment mast cell NK-cell
activation granuloma formation IFN-g
costimulation IFN-g Essential role proven Th 1
cell Macrophage activation NK
cell granuloma IL-12 Important role
proven Macrophage Th 1-cell, NK-cell
stimulation IL-18 Likely, not proven Macrophage T
h 1-cell stimulation IL-4 Exacerbation NK T
cell, Th2 cell Th 1-cell inhibition basophil
(?) Eosinophil (?) IL-10 Exacerbation Macroph
age Macrophage inhibition TGF-b Exacerbation
likely, not proven Macrophage Macrophage
inhibition
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Granuloma Formation

• Recirculating T-lymphocytes passing by the
  inflammatory lesion are recruited by
  pro-inflammatory 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 well-structured
  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.

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Granuloma Formation
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The Immune Response to Viral Infections
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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.

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Patterns of Viral Infection

• Viral infections can be divided into three
  general categories.

• Acute infection followed by viral clearance due
  to the host immune response.
• Acute infection followed by latent infection.
• Acute infection followed by persistent infection
  in which infectious virus is continuously shed.

(polio,
influenza, rotavirus, mumps, yellow fever, RSV,
etc.)
(herpesviruses, etc.)
(HIV, HBV, HCV, etc.)
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Patterns of Viral Infection
Cont.
1.
2.
3.
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Patterns of Viral Infection
Cont.

• What does this mean immunologically?
• Acute -
• Latent -
• Persistent -

• Immune response completely destroys the virus and
  long term memory prevents reinfection.

Immune response only destroys most of the
infectious virus (the virus hides and
periodically reactivates) and long term immunity
(mostly cell-mediated) must remain ever watchful.

• 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.

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Host Response to Viral Infection

• The immune response to viral infections can be
  broken down into two broad categories.

1. Innate
2. Adaptive
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Innate Immunity

• Cytokines
• Interferons (a, b, g)
• Others
• Cells
• NK cells
• Monocytes/Macrophages
• Complement

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Host Response to Viral Infection
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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.

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The Immune Response to Parasites
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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 highly evolved immune evasion
  mechanisms.
• As a group, parasitic diseases remain a
  significant global human health problem.

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The Role of T Lymphocyte Subsets in the Response
to Parasites

• CD4 T cells are divided into two distinct
  subsets Th1 cells synthesize predominantly IL-2
  and IFN-g, while Th2 synthesize predominantly
  IL-4, IL-5 and IL-10.
• The cytokines produced by the two subsets
  cross-inhibit each others development and
  function this leads to a polarization towards
  Th1 or Th2 responses in many infectious diseases.
• Because other cells, including CD8 T cells, NK
  cells and gd T cells also synthesize cytokines,
  immune responses are now classified as Type 1
  or Type 2 responses rather than Th1 or Th2
  responses.

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Leishmania
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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.

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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 iNOS-dependent mechanisms.

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Trypanosoma
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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.

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Plasmodium
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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.

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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
  parasite-directed effector response.

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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.

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