Evaluation and importance of innate & adaptive immunity Dr. ihsan edan abdulkareem alsaimary

Evaluation and diagnostic importance of innate
and adaptive immunity
Prof.dr. Ihsan edan alsaimary




Protection from foreign macromolecules or invading
organisms (viruses, bacteria, protozoa or even larger
parasites).
Tumor immunity
Against our own aberrant cells.
Autoimmunity
immune responses against our own proteins.
The Immune System


 INNATE IMMUNITY:

Defense mechanisms used by the host immediately after
encountering a foreign ligand
Composed of hereditary components that provide an
immediate "first-line" of defense to continuously protect
against pathogens.
ADAPTIVE (ACQUIRED) IMMUNITY:
The body can develop a specific immunity Humoral or
cell-mediated to target particular pathogens.
This response takes days to develop, and so is not
effective at preventing an initial invasion, but it will
normally prevent any subsequent infection, and also
aids in clearing up longer-lasting infections.
Immune system

INNATE: Two Intrinsic
Defense
Systems
 Non specific and consists of:
A. EXTERNAL (SURFACE) DEFENSES -FIRST LINE OF
DEFENSE:
prevent entry of microorganisms
(1) Skin
(2) Mucosa
And their secretions


B. INTERNAL DEFENSES -SECOND LINE OF DEFENSE:
(1) Biochemical factors e.g. C, cytokines
(2) Cells, phagocytes, and other cells
Inhibit spread of invaders throughout the body
Inflammation is its hallmark and most important mechanism

1. Complement
2. Toll-Like Receptors (TLR)
3. Antimicrobial peptides
4. Cytokines
5. Macrophages
6. Neutrophils
7. Eosinophils
8. Basophils, mast cells
9. Natural killer cells (NK cells)
10. Inflammation
Internal Defenses (Second Line of
Defense) Mediated through


 Activated by three pathways:
1) Classical pathway: stimulated by antigen antibody
complex.
2) Alternative pathway: stimulated by polysaccharides
of microbial cell walls.
3) Lectin pathway: by the binding of the microbial
carbohydrates with mannose binding lectin (MBL).
1. The Complement system


 On the organism:
Pathogen associated molecular patterns (PAMPS),
 On the effector cells:
Pattern recognition receptors
(PRR).
Identification Of The Invader
2. Toll-like receptors (TLR)


 Toll-like receptors (TLRs) are transmembrane
proteins that serve as a key part of the innate
immune system considered pattern recognition
receptors (PRRs), binding to pathogen-associated
molecular patterns (PAMPs). Their function is the
recognition of pathogens and the activation of
immune responses directed against those pathogens.
2. Toll-like receptors (TLR)

PAMPS recognized by the innate immune system:
Cell wall constituents or microbial nucleic acids
1. Lipopolysaccharide (LPS) from the gram -ve cell wall.
2. Peptidoglycan found abundantly in the gram-positive cell wall and to a
lesser degree in the gram-negative cell wall .
3. Lipoteichoic acids in the gram +ve bacterial cell walls
4. Lipoarabinomannum (LAM) in mycobacterial wall
5. Mannose-rich glycans (common in microbial glycoproteins and
glycolipids but rare in those of humans).
6. Flagellin found in bacterial flagella.
7. Pilin from bacterial pili.
8. Bacterial and viral nucleic acid. Bacterial and viral genomes contain a
high frequency of unmethylated cytosine-guanine dinucleotide
sequences (a cytosine lacking a methyl or CH3 group and located
adjacent to a guanine). Mammalian DNA has a low frequency of
cytosine-guanine dinucleotides and most are methylated.
9. Double-stranded RNA unique to most viruses.
10. Lipoteichoic acids, glycolipids, and zymosan from yeast cell walls.
PAMPS


To recognize microbial molecules,
various body defense cells have on
their surface a variety of receptors
called
Pattern-recognition Receptors
capable of binding specifically to
PAMPS
Pattern-recognition Receptors (PRR)


 Found on the surface of phagocytes and
promote the attachment of microorganisms
to phagocytes and their subsequent
engulfment and destruction.
ENDOCYTIC PRR


 Binding of microbial molecules to the
receptor promotes the synthesis and
secretion of intracellular regulatory
molecules such as cytokines that is crucial
to initiating innate immunity and adaptive
immunity.
1. Toll-like receptors
2. CD14.
3. NOD (nucleotide-binding oligomerization
domain proteins)
Signaling PRR




Secreted pattern-recognition receptors. These
bind to microbial cell walls and enable them to
be recognized by the complement pathways
and phagocytes.
E.g. mannose-binding lectin is synthesized by
the liver and released into the bloodstream. MBL
recognizes carbohydrate patterns, found on the
surface of a large number of pathogenic micro-
organisms, including bacteria, viruses, protozoa
and fungi.
Secreted PRR

Classes of PRRs
 four different classes of PRR
families have been identified :
 Toll-like receptors(TLRs)
 C-type lectin receptors (CLRs)
 RIG-I-like receptors (RLRs)
 NOD-like receptors (NLRs).


 TLRs belong to the IL-1 receptor family.
 Linked to a signaling pathway that involves the
IL-1 receptor-associated kinase-4 (IRAK-4) 
transcription NF-κB .
 Upon binding of the extracellular ligand
recognition domain to PAMPs, changes in the
intracellular domain result in initiation of
signaling events leading to
 Inflammatory responses and/or
 Release of antimicrobial agents.
2. Toll like receptors (TLR(


TLRs are found both on the surface and within the
phagolysosomes of phagocytes.

ROLE IN INNATE IMMUNITY
1.The binding of a microbial molecule to its TLR
transmits a signal to the cell's nucleus inducing the
expression of genes coding for the synthesis of
cytokines. Many of the TLRs, especially those that bind
to BACTERIAL AND FUNGAL cell wall components
stimulate IL -1, TNF-alpha, and IL-8. triggering innate
immune defenses such as inflammation, fever, and
phagocytosis in order to provide an immediate
response against the invading microorganism.
2.Most of the TLRs that bind to VIRAL components
trigger the synthesis of interferons via activation of
interferon regulatory factor 3 (IRF-3) that block viral
replication within infected host cells..


TLR Responding to Lipopolysaccharide (LPS)
from the Gram-Negative Cell Wall

TLRstrigger various secondary signals needed for
- Humoral immunity (the production of antibodies).
- Cell-mediated immunity (the production of cytotoxic T-
lymphocytes and additional cytokines).
Dendritic cells express several types of TLRs. Upon activation
of these receptors by microbial components, the dendritic cells
mature and migrate to the lymph nodes, where they present
pathogen-derived antigens to
naive T cells differentiate into TH-1, TH-2 or T-reg
TLRs thereby bridge the gap between the innate and adaptive
immune systems
Without innate immune responses there could be no adaptive
immunity.
ROLE IN ADAPTIVE IMMUNITY


1. Human β-defensin hBD 1-4 attract immature dendritic
cells and memory T cells via the chemokine receptor
(CCR)-6
2. Antileukoproteases (ALP)
3. Dramcidin (DCD)-1 (SWEAT GLANDS)
4. Lysosyme
5. Psoriasin (SEBOCYTES) prevents E. coli infection
6. RNase7 (ribonucleotidase)
7. LL-37 A.K.A Cathelicidin antimicrobial peptide
(CAMP)/hCAP18 (UROGENITAL TRACT) mediates
dendritic cell activation in psoriasis
3. Antimicrobial peptides (AMPs)

3. Antimicrobial peptides (AMPs)

FAMILIES OF CYTOKINES:
1.Interleukins (ILs): (interaction bet. leukocytes), Cytokines produced by
leukocytes and exert effects preferentially on other WBCs.
2.Interferons )IFNs): interfere with viral replication.
3.Tumor necrosis factor (TNF(
4.CSFs (Colony stimulating factors) induce differentiation and
proliferation of hematopoietic progenitor cells.
5.Chemokines: Cytokines that have chemoattractant activity, and
they play a crucial role in leukocyte migration.
6.Inflammatory chemokines: Chemokines that recruit leukocytes.
7.Lymphoid chemokines: Chemokines that regulate trafficking within
lymphoid tissues.
4. Cytokines

CYTOKINES OF THE INNATE IMMUNE SYSTEM
Mainly cytokines with
1.Inflammatory capacity (e.g. IL-1, IL-6, IL-18, tumor necrosis factor-α
[TNF-α], inflammatory chemokines)
2.Antiviral capacity (e.g. IFN-α, IFN-β(.
CYTOKINES OF THE ADAPTIVE IMMUNITY:
Dependent on cytokineswith
Immunomodulatory capacities (e.g. IL-2, IL-4, IL-12, IL-13, IL-17, IL-
22, IL-23, IFN-γ(.
However, since most of these mediators exhibit multiple and
sometimes overlapping activities, a strict separation into
inflammatory and immunomodulatory cytokines is not possible.
4. Cytokines








Phagocytic cells derived from blood-borne monocytes.
Expresses PRR to identify organisms.
Receptors for antibodies and complement that enhances
phagocytosis.
Destroy the organisms by toxic intracellular molecules as:
superoxide anions, hydroxyl radicals, nitrous oxide,
lysozyme.
Antigen presenting capacity present processed antigens to
T and B cells. (much less than Langerhans cells)
Releases G-CSF, & GM-CSF that stimulate the division
and release of neutrophils from the bone marrow.
5. Macrophages




They enter the blood stream to enter the site of infection
through the complex effect of proinflammatory mediators, G-
CSF, GM-CSF, adhesion molecules chemoattractants and
chemokines
Phagocytosis is enhanced by coating the organism by
antibodies and complement that bind to their receptors on the
neutrophils
 kills the organisms within phagolysosomes by:
a) Oxygen dependent mechanisms (e.g. H2O2 and hydroxyl
radicals)
b) Oxygen independent mechanisms (e.g. lysozyme).
6. Neutrophils


 Major function protective against parasites.
 Weak phagocytic activity.
 Important in allergic reactions.
 IgE antibodies coat the parasite  eosinophils bind to IgE
antibodies and become activated  Release toxic substances
to the parasite as:
Major basic protein
Eosinophilic cationic protein,
Eosinophil peroxidase
Eosinophil-derived neurotoxin,
which can kill parasites, together with prostaglandins,
leukotrienes and various cytokines
7. Eosinophils





Basophil in the blood and mast cell in the tissues have
similar functional and morphologic characteristics.
Both express high-affinity receptors for IgE (FcεRI)
Two populations of mast cells
1. Mucosal mast cells: contain only trypsin,
2. Connective tissue mast: cells contain both trypsin an
chymotrypsin
 Mast cells are involved in TLR-mediated responses against
Gram-negative bacteria.
8. Basophils & mast cells


When a specific antigen binds to mast cell-bound IgE, the
FcεRI becomes activated, which leads to degranulation and
release of preformed mediators, including:
1. Histamine
2. Serotonin.
3. Prostaglandins
4. Leukotrienes (B4, C4, D4 and E4),
5. Platelet activating factor
 They enhance
i. vascular permeability
ii. bronchoconstriction
iii. induction of an inflammatory response


Thus both play an important role in immediate allergic
reaction, urticaria and angioedema.
Only cutaneous mast cells express receptors for the
anaphylatoxin C5 a so when activated by binding antigen
specific antibodies only a local reaction occur in the skin, but
8. Basophils & mast cells





• It’s major task to identify and eliminate virally
infected or malignant cells.
• Pattern recognition receptors (TLR 3,9)
• NK cells can recognize their targets in two
ways:
1. Adhere and kill target cells coated with IgG as they carry
receptors for it (antibody dependent cellular cytotoxicity
ADCC).
2. Activation of killer activating receptors that recognize
the abnormal cells and kills them by secreting perforin
and injecting granzyme that kills the cells by inducing
apoptosis.
9. Natural killer cells


10. Inflammation
 The inflammatory response is triggered whenever
body tissues are injured, infected or irritated.



physical barrier against the spread of infection
Prevents the spread of damaging agents to nearby
tissues
Disposes of cell debris and pathogens
Sets the stage for repair processes promote healing of
any damaged tissue following the clearance of
pathogens
 The 5 cardinal signs of acute inflammation are
redness, heat, swelling, tenderness and pain

3
7
Chapter 21, Immune
System
The adaptive immune system is antigen-specific,
systemic, and has memory
It has two separate but overlapping arms
Humoral, or antibody-mediated (B Cell) immunity
Cellular, or cell-mediated (T Cell) immunity
Adaptive Immune Defenses

3
8
Chapter 21, Immune
System
Important functional properties:
Immunogenicity – the ability to stimulate
proliferation of specific lymphocytes and antibody
production
Reactivity – the ability to react with the products of
the activated lymphocytes and the antibodies
released in response to them
Complete antigens include foreign protein, nucleic
acid, some lipids, and large polysaccharides
Complete Antigens

3
9
Chapter 21, Immune
System
Small molecules, such as peptides, nucleotides, and
many hormones,
not immunogenic (does not stimulate a response)
reactive when attached to protein carriers
If they link up with the body’s proteins, the adaptive
immune system may recognize them as foreign and
mount a harmful attack (allergy)
Haptens are found in poison ivy, dander, some
detergents, and cosmetics
Haptens (Incomplete Antigens)

have little or no immunogenicity 38
Chapter 21, Immune
System
Only certain parts of an entire antigen are
immunogenic
Antibodies and activated lymphocytes bind to these
antigenic determinants
Most naturally occurring antigens have numerous
antigenic determinants that:
Mobilize several different lymphocyte populations
Form different kinds of antibodies against it
Large, chemically simple molecules (e.g., plastics)
Antigenic Determinants

4
1
Chapter 21, Immune
System
Our cells are dotted with protein molecules (self-
antigens) that are not antigenic to us but are strongly
antigenic to others (reason for transplant rejection)
One type of these, MHC proteins, mark a cell as self
The two classes of MHC proteins are:
Class I MHC proteins – found on virtually all body
cells
Class II MHC proteins – found on certain cells in
the immune response
Self-Antigens: MHC Proteins

4
2
Chapter 21, Immune
System
Two types of lymphocytes
B lymphocytes – oversee humoral immunity
T lymphocytes – non-antibody-producing cells that
constitute the cell-mediated arm of immunity
Antigen-presenting cells (APCs):
Do not respond to specific antigens
Play essential auxiliary roles in immunity
Cells of the Adaptive Immune System

4
3
Chapter 21, Immune
System
T cells mature in the thymus under negative and
positive selection pressures
Negative selection – eliminates T cells that are
strongly anti-self
Positive selection – selects T cells with a weak
response to self-antigens, which thus become both
immunocompetent and self-tolerant
T Cells

4
4
Chapter 21, Immune
System
B cells become immunocompetent and self-tolerant
in bone marrow
Some self-reactive B cells are inactivated (anergy)
while others are killed
Other B cells undergo receptor editing in which
there is a rearrangement of their receptors
B Cells

4
5
Chapter 21, Immune
System
Major roles in immunity are:
To engulf foreign particles
To present fragments of antigens on their own
surfaces, to be recognized by T cells
Major APCs are dendritic cells (DCs), macrophages,
and activated B cells
The major initiators of adaptive immunity are DCs,
which actively migrate to the lymph nodes and
secondary lymphoid organs and present antigens to
T and B cells
Antigen-Presenting Cells (APCs)

4
6
Chapter 21, Immune
System
Secrete soluble proteins that activate T cells
Activated T cells in turn release chemicals that:
Rev up the maturation and mobilization of DCs
Prod macrophages to become activated
macrophages, which are insatiable phagocytes that
secrete bactericidal chemicals
Macrophages and Dendritic Cells

4
7
Chapter 21, Immune
System
Antigen challenge – first encounter between an
antigen and a naive immunocompetent cell
Takes place in the spleen or other lymphoid organ
If the lymphocyte is a B cell:
The challenging antigen provokes a humoral
immune response
Antibodies are produced against the challenger
Humoral Immunity Response

Chapter 21, Immune System 53
Clonal Selection
Figure 21.9

4
9
Chapter 21, Immune
System
Primary immune response – cellular differentiation
and proliferation, which occurs on the first exposure
to a specific antigen
Lag period: 3 to 6 days after antigen challenge
Peak levels of plasma antibody are achieved in 10
days
Antibody levels then decline
Immunological Memory

5
0
Chapter 21, Immune
System
Secondary immune response – re-exposure to the
same antigen
Sensitized memory cells respond within hours
Antibody levels peak in 2 to 3 days at much higher
levels than in the primary response
Antibodies bind with greater affinity, and their
levels in the blood can remain high for weeks to
months
Immunological Memory

5
1
Chapter 21, Immune
System
Differs from active immunity in the antibody source
and the degree of protection
B cells are not challenged by antigens
Immunological memory does not occur
Protection ends when antigens naturally degrade in
the body
Naturally acquired – from the mother to her fetus via
the placenta
Artificially acquired – from the injection of serum,
such as gamma globulin
Passive Humoral Immunity

Chapter 21, Immune System
Types of Acquired Immunity
Fig6u1re21.11

5
3
Chapter 21, Immune
System
Commercially prepared antibodies are used:
To provide passive immunity
In research, clinical testing, and treatment of certain
cancers
Monoclonal antibodies are pure antibody
preparations
Specific for a single antigenic determinant
Produced from descendents of a single cell
Monoclonal Antibodies

5
4
Chapter 21, Immune
System
Hybridomas – cell hybrids made from a fusion of a
tumor cell and a B cell
Have desirable properties of both parent cells –
indefinite proliferation as well as the ability to
produce a single type of antibody
Monoclonal Antibodies

5
5
Chapter 21, Immune
System
 Since antibodies are useless against intracellular antigens,
cell-mediated immunity is needed
 Two major populations of T cells mediate cellular immunity
 CD4 cells (T4 cells) are primarily helper T cells (TH)
 CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy
cells harboring foreign antigens
 Other types of T cells are:
 Suppressor T cells (TS)
 Memory T cells
Cell-Mediated Immune Response

Major Types of T Cells
Fig7u7re21.14

5
7
Chapter 21, Immune
System
Soluble antibodies
The simplest ammunition of the immune response
Interact in extracellular environments such as body
secretions, tissue fluid, blood, and lymph
Importance of Humoral Response

5
8
Chapter 21, Immune
System
T cells recognize and respond only to processed
fragments of antigen displayed on the surface of
body cells
T cells are best suited for cell-to-cell interactions,
and target:
Cells infected with viruses, bacteria, or intracellular
parasites
Abnormal or cancerous cells
Cells of infused or transplanted foreign tissue
Importance of Cellular Response

5
9
Chapter 21, Immune
System
Immunocompetent T cells are activated when the V
regions of their surface receptors bind to a
recognized antigen
T cells must simultaneously recognize:
Nonself (the antigen)
Self (a MHC protein of a body cell)
Antigen Recognition and MHC
Restriction

6
0
Chapter 21, Immune
System
Endogenous antigens are:
Degraded by proteases and enter the endoplasmic
reticulum
Transported via TAP (transporter associated with
antigen processing)
Loaded onto class I MHC molecules
Displayed on the cell surface in association with a
class I MHC molecule
Class I MHC Proteins

Class I MHC Proteins
Figu8r3e21.15a

6
2
Chapter 21, Immune
System
Class II MHC proteins are found only on mature B
cells, some T cells, and antigen-presenting cells
A phagosome containing pathogens (with exogenous
antigens) merges with a lysosome
Invariant protein prevents class II MHC proteins
from binding to peptides in the endoplasmic
reticulum
Class II MHC Proteins

Class II MHC Proteins
Figu8re621.15b

Regulatory cells that play a central role in the
adaptive immune response
Once primed by APC presentation of antigen, they:
Chemically or directly stimulate proliferation of
other T cells
Stimulate B cells that have already become bound
to antigen
Without TH,there is no immuneresponse
64
Chapter 21, Immune
System
Helper T Cells (TH

Helper T Cells (TH
Fig1u0r1e21.17a

 TCcells, or killer T cells, are the only T cells that can directly
attack and kill other cells
 They circulate throughout the body in search of body cells
that display the antigen to which they have been sensitized
 Their targets include:
Virus-infected cells
 Cells with intracellular bacteria or parasites
 Cancer cells
 Foreign cells from blood transfusions or transplants
66
Chapter 21, Immune
System
Cytotoxic T Cell (Tc

In some cases, TCcells:
Bind to the target cell and release perforin into its
membrane
In the presence of Ca2+perforin causes cell lysis
by creating transmembrane pores
Other TC cells induce cell death by:
Secreting lymphotoxin, which fragments the target
cell’s DNA
Secreting gamma interferon, which stimulates
phagocytosis by macrophages
67
Chapter 21, Immune
System
Mechanisms of Tc Action

Mechanisms of Tc Action
107
Figure 21.18a, b

Summary of the Primary Immune Response
Fig10u9re21.19

• Molecular markers of innate immunity and
inflammation in therapeutic intervention

TLRs in cancer and anti-cancer
immunotherapy
 The TLR3 has been shown to be receptor for
viral dsRNA, and also seems to be potentially
promising in anti-cancer therapy. Reports have
shown that cancer cells themselves express
TLR3 in vivo
and agonist ploy (I:C) is activating the signalling
pathway leading to the anticancer effects (O'Neill
et al., 2011)

NF-κB and cancer therapy
 NF-kB regulates the expression of genes involved
in many processes that play a key role in the
development and progression of cancer such as
proliferation, migration and apoptosis.
 constitutive NF-kB activation has been
detected in many human malignancies.
 some anti-inflammatory drugs may inhibit NF-kB
by interfering with IKK activity.

Tumor necrosis factor(TNF) as
therapeutic target
 In patients with meningococcal meningitis serum levels
of TNF-α have been shown to correlate with
mortality(Arditi,1990) , but other authors have failed to
show significant increases in TNF-α in septic
patients(Casey,1993).
 In a rodent model, mortality after an injection of
endotoxin was signifantly decreased by pre-treatment
with TNF-a antibodies.(Beutler,1987)
 the antibody approach has produced little
evidence of benefit in man although
improvements in the haemodynamics of patients
have been observed.(Exley,1990)

Evaluation and importance of innate & adaptive immunity Dr. ihsan edan abdulkareem alsaimary

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