Antigen Structure and Receptor Interactions

3.0 Antigens
Prepared by Pratheep Sandrasaigaran
Lecturer at Manipal International University

By the end of this chapter you
should be able to understand:
1. Overview on antigen-receptor
2. Structure of antigens and receptors
3. Genetic control of immune
response
4. Antigens processing by antigen
presenting cell
5. Role of MHC and accessory
molecules
6. Antigen-antibody interactions
2
Diagram Adopted from Internet

3.1 Overview on antigen-receptor
3

Immune responses initiated by the
ligand-receptor protein interactions
4
If the binding is sufficient, the receptor is able to provide a signal to the cell
Diagram Adopted from Lippincott's Illustrated Reviews: Immunology, 2nd
ED

5
• Ligand-receptor protein interactions trigger the
activation of leukocytes or white blood cells.
• Ligands may be expressed by
• Cells as cell-surface molecules (e.g. on
microbes)
• Soluble molecules (e.g. the secreted products
of cells).

6
• Factors influence the binding of a ligand to a cell-
surface receptor:
• The shape and charge affect binding affinity
• The collective affinities where multiple
receptors may be involved (avidity)
• The intracellular signals that are triggered
• The presence of other receptors
• Cells receive signals can influence whether they
respond to those signals.

7
ED

8
• Ligands recognized by cells of both the
innate and adaptive immune systems are
collectively known as antigens.
• The smallest individually identifiable part
of an antigen that is bound by a receptor
is known as an epitope.

9
• The innate immune system
employs a limited set of receptors
to recognize epitopes expressed by
a wide range of microorganisms.
• The adaptive immune system, on
the other hand, generates a vast
number of epitope-specific
lymphocyte receptors.

Innate Adaptive
10
Types of immunity
Diagram Adopted from Lippincott's
Illustrated Reviews: Immunology, 2nd
ED

TEST YOUR KNOWLEDGE 1
11

12
1. Ligand and receptor has to bound tightly to
induce strong reactions?
2. All ligand automatically will trigger an
immune reactions.
3. The intracellular signals of immune cell will
determine the affinity of ligand-receptor
interactions.
4. All antigens will trigger immune response.
5. All immune cell use the same mechanism
during immune response

13
1. Define ligand and receptor. What is the
relationship of these two structure?
2. What is a antigen and epitope?
3. How does an immune response is triggered in
leukocytes?
4. How innate immunity antigen recognition varied to
adaptive immunity?
5. Does the priming of antigen/ epitope always result
in immune response? Explain your answer.

14
Why you
don’t get
chicken
pox
two
times..?

3.2 Structure of antigens and
receptors
15

Antigens
16

Antigens
17
• What is an antigen?
• An organism
• A molecule
• Part of a molecule
• Antigens should be able to be recognized by the
immune system.

Antigens
18
• What is antigen may made (molecule) of?
• May come in simple or complex
• Protein
• Carbohydrate
• Synthetic in origin molecules

a. Epitopes: The basic recognition unit
19
• Epitopes, the smallest part of an antigen that is
"seen" by somatically generated B- and T-cell
receptors.
• Different lymphocytes, each with a unique set of
receptors, may recognize different epitopes on the
same antigen.
• Antigens/epitopes are divided into three broad
functional types:
• Immunogens
• Haptens
• Tolerogens

a. Epitopes: The basic recognition unit
20
• Complex antigens may contain large
numbers of different epitopes.
Diagram Adopted from Lippincott's
Illustrated Reviews: Immunology, 2nd
ED

b. lmmunogens
21
• Immunogen is a substance or antigen that evokes a
specific, positive immune response
• Antigen mean a molecule or cell recognized by the
immune system.
• Some nonimmunogenic molecules (e.g . haptens)
can be bound to an immunogen and in this context,
the immunogen is referred to as a carrier.

c. Haptens
22
• Haptens are small , non-immunogenic molecules,
usually of non-biologic origin, that behave like
synthetic epitopes.
• Haptens are antigens and can bind to immune
receptors but cannot induce a specific immune
response by themselves; hence are not immunogenic.
• Therefore hapten has to be chemically bound to an
immunogen (carrier).
• Immune responses may be generated against both the
hapten and the epitopes on the immunogen.

23
Table adopted from
Lippincott's
Illustrated Reviews:
Immunology, 2nd
ED

d. Tolerogens
24
• During development of the immune repertoire
tolerance to self molecules and cells develops first.
• Non-self antigens are subsequently recognized as
foreign.
• Tolerance can also develop later in life, for example, to
antigens that are administered orally.
• Hence tolerogens induce adaptive immune un-
responsiveness; diminishes immune response rather
than an enhanced one.

Immunogen and lmmunogenicity
25
• Knowing only Immunogens induces immune response,
how do you determine whether a substance is an
antigen?
• Immunogen
• Hepten
• Tolerogen
1
Size 2
Complexity
3
Conformation
and
accessibility
4
Chemical
properties

26
• Size: Proteins greater than 10 kDa are usually more
immunogenic.
• Complexity: Complex proteins with numerous, diverse
epitopes are more likely to induce an immune response
than are simple peptides that contain only one or a few
epitopes.
• Conformation and accessibility: Epitopes must be
"seen by" and be accessible to the immune system.

27
• Chemical properties: A protein immunogen has to be
enzymatically cleavable by phagocytes.
• For example, L-amino acid-containing polypeptides are
generally good immunogens, whereas D-amino acid
containing polypeptides are poor immunogens as
proteolytic enzymes only able to cleave the L-amino
acids.
• Many carbohydrates, steroids, and lipids tend to be
poor immunegens.

28

29
1. Antigen and epitope are no different. Both
induce immune response.
2. Non-organic molecule can act as an antigen.
3. All Immunogens, haptens and tolerogens may
induce immune reaction.
4. An antigen’s complexity, accessibility and
chemical property are very crucial in order for it
act as an immunogen.
5. Laboratory synthesized amino acids may
spontaneously elicit an immune response when
come in encounter with the immune cells.

30
1. What could be an antigen?
2. What could be an epitope?
3. Distinguish between Immunogens, haptens and
tolerogens.
4. What is the difference between antigen and
immunogens?
5. Why most of the food that we ate does not
prompt immune response?
6. What would be possibly a substance can be an
antigen?

Receptors
31

Receptors
32
• The engagement of receptors provides to epitope/
antigen will initiate an event that can lead to a wide
variety of immune activities.
• Three functions of the receptors:
• Bind to molecules that then generate signals
between cells.
• Sample the environment to detect the presence of
intruders.
• Examine their neighbors to be sure that they
belong to self and do not present a threat.

Receptors
33
a. Preformed
receptors
b. Somatically
generated
receptors

Preformed receptors
34
• Known as receptors of innate immune system.
• Pattern recognition receptors.
• Toll - like receptors
• Killer activation receptors
• Killer inhibition receptors
• Complement receptors
• Fc receptors: Immunoglobulins Diagram Adopted from Internet

a. Pattern recognition receptors
35
• Receptors of the innate immune system recognize
broad structural motifs presented by microbes.
• Pattern recognition receptors (PRRs), are present in
soluble forms (complement proteins) or on host cell
surfaces.
• They recognize pathogen-associated molecular
patterns (PAMPs) associated with microbes:
• Sugars
• Some proteins
• Lipids
• Nucleic acids

a. Pattern recognition receptors
36
• PRR binding to PAMPs triggers various forms of inflammation intended to
destroy the pathogens.
ED

b. Toll - like receptors
37
• In humans, PRRs also include toll - like receptors (TLRs)
that are present on various host cells.
• When triggered by binding to a PAMPs on an infectious
organism, TLRs mediate the generation of defensive
responses that include
• Transcriptional activation
• Synthesis of cytokines
• Secretion of cytokines
• Cytokines are needed for promote inflammation, and
the attraction of immune cells to the site of infections.

38
Cytokines
Macrophages
Neutrophils
Natural killer
(NK) cells
Dendritic cells

c. Killer activation receptors
39
• NK cells are part of the lymphocyte lineage that do not
express the extremely variability like B cells and T cells.
• Instead, their receptors able to detect any alterations
in host cells that have been infected by pathogens,
particularly viruses.
• Killer activation receptors (KARs) on NK cells allow
them to recognize the presence of stress-related
molecules.
• Two stress-related molecules found in human; MICA
and MICB, expressed by host cells that are unhealthy
or abnormal cells

c. Killer activation receptors
40
• Binding of MICA or MICB molecules by the NK cell's KARs induces the NK cell
to attach and destroy the targeted (infected) host cell.
ED

d. Killer inhibition receptors
41
• NK cells also uses the killer inhibition receptors (KIRs),
to monitor the major histocompatibility complex (MHC)
class I molecules.
• MHC-I is normally displayed on the cell surfaces of all
nucleated cells in the body.
• By scrutinizing MHC class I molecules, NK cells
determine the normality of host cells.
• Many processes, including some cancers and some
types of viral infection, decrease the number of MHC
class I molecules displayed on the surface of the
affected cell.

d. Killer inhibition receptors
42
• Once bound to a target cell via its KARs, the NK cells
use their KIRs to assess the expression of MHC class I
molecules on that cell.
• If NK cells determine that the level is subnormal, they
proceed to kill the target cell.
• If they determine that normal levels are present, the
killing process is terminated and the target cell is
released unharmed.

e. Complement receptors
43
• The complement system is a complex set of soluble
molecules that generate various reactions that attract
immune cells to the site of infection and lead to
destruction of microbes.
• Some of these activities are accomplished by the
binding of certain complement components or their
fragments to microbial surfaces.
• This enables "tagging" for the microbes for destruction
by other elements of the immune system.

e. Complement receptors
44
• Cell-surface bound complement
receptors on phagocytic cells and
B cells will recognize these bound
complement fragments.
• This enable and facilitate the
binding, ingestion, and internal
degradation of the tagged
microbes.
Diagram Adopted from Lippincott's Illustrated
Reviews: Immunology, 2nd
ED

f. Fc receptors: Immunoglobulins
45
• These are including epitope-binding
immunoglobulins termed antibodies such as lgA ,
lgD, lgE, lgG, and lgM.
• Epitope binding by lgA, lgG, or lgM antibodies
triggers a conformational change in the ''tail" or
Fc portion of the antibody.

46

47
• Fc receptors (FcRs) are expressed on the surfaces of
phagocytic cells.
• Phagocytic cells recognize and bind epitope-engaged
antibodies. How?
• They are able to recognize epitope-engaged
antibodies when altered conformation of the Fc
region happens.
• This leads to the phagocytosis of the epitope-
antibody-FcR complex.

48
ED

49
• Antibodies that have not bound one or more
epitopes do not bind to FcRs, and in this way, an
antibody that has not bound to an epitope remains
in circulation.
• The Fc receptor that binds lgE has some exception.
• lgE molecules will bind to the Fc receptors prior to
epitopes encounter.
• However intracellular signaling does not occur until
the lgE antibody binds the appropriate antigen later.

50

51
1. Preformed and the somatically generated
receptors are the benchmark of adaptive
immunity.
2. Toll-like receptor are also the affiliate of PRRs.
3. When NK-cell encounter the stress related
molecules, they spontaneously elicit an immune
response.
4. Complements act as a ‘tagging’ for the phagocytes
to internalize the pathogens that they binds to.
5. Every Ig will undergo Fc region modification
before binding to the Fc receptors of immune cells

52
1. What are the function of receptors in leukocytes?
2. What is the different between preformed receptor
and somatically generated receptors?
3. Can you identify what are mechanism of
preformed receptor?
4. Can you identify the difference of pattern
recognition receptors and pathogen-associated
molecular patterns.
5. What are the function of cytokines?

53
6. What are the two stress-related molecules found
in human that activate NK cells?
7. Differentiate Killer activation receptors and Killer
inhibitor receptor receptors and how does this two
receptors function in NK cells?
8. How complement receptors function in prompting
immune response in immune cells?
9. What is a Fc region and Fc receptors. Where do Fc
receptors found?
10. Explain the mechanism of immune response
triggered by the Fc receptor: immunoglobulin.

Receptors
54
a. Preformed
receptors
b. Somatically
generated
receptors

3.3 Genetic control of immune
response
55

Somatically generated receptors
56
• The preformed receptors of the innate immune system
are encoded in the germline and passed on intact from
one generation to the next.
• In contrast, the specialized receptors of B cells and T
cells are regenerated anew in the lymphocytes of each
individual through random somatic chromosomal
rearrangements and mutations.

Somatically generated receptors
57
• What is advantage of somatically generated
receptors?
• Vast array of receptors specific for precise molecular
details found in unique epitopes that may be
encountered in the future.
• Somatically generated receptors:
• B-cell receptors
• T-cell receptors

a. B-cell receptors
58
• B-cell receptors (BCRs) are cell-surface
bound monomeric immunoglobulin
associated with disulfide-linked
heterodimers called lgα and lgβ.
• When a BCR binds an epitope, the
specialized cytoplasmic tails of lgα and lgβ
initiate an intracellular signaling cascade
that may lead to B-cell activation.
• In addition, some activated B cells
terminally differentiate into plasma cells,
which secrete immunoglobulins that have
the same epitope-binding specificity as
their BCR
ED

b. T-cell receptors
59
• Structurally similar to immunoglobulin
molecules, T-cell receptors (TCRs) are
heterodimers, consisting of either an αβ
or a γδ chain pair.
• TCRs are always membrane bound and
recognize antigen combined with MHC
molecules.
• They are associated with the cluster of
differentiation 3 or CD3 complex of
transmembrane surface molecules.
ED

b. T-cell receptors
60
• The CD3 complex functions much like
the lgα and lgβ of BCRs.
• The CD3 complex links the TCR with
intracellular signaling molecules.
• An additional accessory molecule (CD4
or CD8) is also present to serve as a
type of co-receptor for the TCR.
ED

61

62
1. The somatically generated receptors enables
lymphocytes to excel specific and precise
molecular details found in unique epitopes.
2. The CD 3 complex elicit the cascades of cell
activation in T cells.
3. CD 4 and CD 8 are the accessory molecules that
has minimal functions to T cells.
4. B cells does not go through the ‘advance
education’ as the T cells as they only develop in
the Bone marrow.

63
1. How does the Somatically generated receptors are generated
in compression to the preformed receptors?
2. What is advantage of somatically generated receptors?
3. What are the constituent of somatically generated
receptors?
4. Can you draw and identify the B-cell receptors (BCR)?
5. How do you distinguish BCR and antibody?
6. Can you draw and identify the T-cell receptors (TCR)?
7. Cluster of differentiation 3 or CD3. What do you understand
from the statement.

3.4 Antigens processing by antigen
presenting cell
64

Antigen processing
is necessary for TH-cell activation
65
• TH cells functions to secretes the cytokines for the
activation of both the humoral and cell-mediated
immune cells.
• Why such system has to be employed?
• An inappropriate T-cell response to self-components
can have fatal autoimmune consequences.
• How to ensure that they can be prompt to respond
only to the non-self?

Antigen processing
66
• TH cells can only recognize antigen that is displayed together with class MHC II
molecules on the surface of antigen-presenting cells (APCs).
Table Adopted from Kuby Immunology by Kindt Thomas J., W.H. Greeman and Company, 2007

Antigen processing
67
• Characteristics of APCs:
• Express class II MHC molecules on their membranes.
• Deliver a co-stimulatory signal for TH-cell activation.
• Antigen-presenting cells first has to internalize antigen
before processing via:
• Phagocytosis
• Endocytosis

Antigen processing
68
Diagram adopted from Nature Reviews: Immunology

Antigen processing
69
• Once the antigen is lysed, a part of the antigen is
displayed on their membrane bound to a class II MHC
molecule.
• TH cell able to recognize and interacts with the antigen–
class II MHC molecule complex on the membrane of the
APCs.
• An additional co-stimulatory signal is then produced by
the antigen-presenting cell, leading to activation of the
TH cell.

Antigen processing
70
• Electron micrograph of
an antigen-presenting
macrophage (right)
associating with a T
lymphocyte
Diagram Adopted from Kuby
Immunology by Kindt Thomas J., W.H.
Greeman and Company, 2007

Antigen processing
71
• Experiment by K.
Ziegler and E. R.
Unanue
• Experiment by K.
Ziegler and E. R.
Unanue R. P.
Shimonkevitz
Table Adopted from Kuby
Immunology by Kindt
Thomas J., W.H. Greeman
and Company, 2007
Diagram Adopted from Kuby Immunology by Kindt Thomas J., W.H. Greeman and Company, 2007

72

73
1. CTL secretes cytokines to that has to be
monitored to avoid autoimmune response.
2. Dendritic cells, macrophages and B cells are the
professional APCs.
3. Phagocytosis and endocytosis is part of
internalization process of the APCs.
4. When peptides are presented by the APCs to the
TH cells, this will immediately prompt the TH cell
activations.

3.5 Role of MHC and accessory
molecules
74

Major Histocompatibility Molecules
75
• The major histocompatibility complex (MHC) is a large
genetic complex with multiple loci.
• MHC loci encode two major classes of membrane-
bound glycoproteins: class I and class II MHC
molecules.
• MHC molecules function as antigen-recognition
molecules, but they do not possess it.

76
Diagram Adopted from Kuby Immunology by Kindt Thomas J., W.H. Greeman and Company, 2007
MHC Class I
MHC Class II
MHC Class I

77
• For a foreign protein antigen to be recognized by a T
cell, it must be degraded into small peptides that form
complexes with class I or class II MHC molecules.
• The MHC-associated peptide fragments is called
antigen processing and presentation.
• Question: Which antigen to be presented by MHC
class I or II and what determines this?

78
• Determined by the route that the antigen takes to
enter a cell:
• Exogenous antigen
• Endogenous antigen

Exogenous antigen lead to MHC
class II pathway
79
• Exogenous antigen is produced outside of the host cell
and enters the cell by endocytosis or phagocytosis.
• APCs degrade ingested exogenous antigen into
peptide fragments within the endocytic processing
pathway.
• Peptides produced by degradation of antigen in this
pathway bind to the cleft within the class II MHC
molecules.

Exogenous antigen lead to MHC
class II pathway
80
• Presentation of
exogenous peptide–
class II MHC complexes
is limited to APCs only.
Diagram Adopted from Kuby Immunology by Kindt
Thomas J., W.H. Greeman and Company, 2007

Endogenous antigen lead to MHC
class I pathway
81
• Endogenous antigen is produced within the host cell
itself.
• Two common examples:
• Viral proteins synthesized within virus-infected
host cells
• Unique proteins synthesized by cancerous cells.
• Endogenous antigens are degraded into peptide
fragments that bind to class I MHC molecules within
the endoplasmic reticulum.

class I pathway
82
• The peptide–class I MHC complex is then transported
to the cell membrane.
• All cells producing endogenous antigen use this route
to process the antigen… WHY?
• T cells displaying CD8 recognize antigen associated
with class I MHC molecules.
• Cytotoxic T cells attack and kill cells displaying the
antigen–MHC class I complexes

class I pathway
83
• Presentation of
endogenous peptide–
class I MHC complexes is
by all nucleated cells.
Diagram Adopted from Kuby Immunology by Kindt
Thomas J., W.H. Greeman and Company, 2007

Internalized antigen
digested by cells
Altered self-
cells
T cell receptors
recognize antigen
bound to MHC
molecules
Binding antigen-MHC
activates T cells
TH cells secretes cytokines and
activates T cells, B cells and
innate cells
Activated TC kill
altered cells
Antibody binds antigen
during humoral immune
reaction
B cells differentiate into
plasma cell when reacted
with antigen
Diagram Adopted from Kuby Immunology
by Kindt Thomas J., W.H. Greeman and
Company, 2007
84
Summary

3.5 Antigen-antibody interactions
85

Antigen-antibody interactions
86
• The antigen-antibody interaction is a bio-molecular
association similar to an enzyme-substrate
interaction.
• However it does not lead to an irreversible chemical
alteration in either the antibody or the antigen.
• The contact between antibody-antigen involves
various non-covalent interactions between epitope of
antigen and the variable-region (VH/VL) domain of the
antibody molecule.

Antigen-antibody interactions
87
Diagram Adopted from Kuby Immunology by Kindt Thomas J.,
W.H. Greeman and Company, 2007

Antigen Structure and Receptor Interactions

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