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(1)

Learning Objectives
Introduction to Immunology
Please define
Antigen
Substance which canbe recognized by the immune system.
Antigenic Determinant
Part of the antigen that fits into the receptor, which is recognized by the immune system.
Toll-Like Receptor (TLR)
Participating protein class in innate immunity, these proteins recognize non-human
molecular structures. When bound to foreign particles, they induce a signaling cascade to
stimulate inflammation.
Pattern-Recognition Receptor (PRR)
Proteins expressed by cells of the innate immune system to recognize foreign molecular
structures known as pathogen-associated molecular patterns (PAMP).
Pathogen-Associated Molecular Pattern (PRR)
Foreign molecular structures that are recognized by TLRs or PRRs.
Cytokine
Factors synthesized by the PAMP-stimulated cell.
Chemokine
Factors synthesized by the PAMP-stimulated cell.
Discuss the role of the innate immune system.
The role of the innate immune system is to recognize molecular signales or motifs and to
respond and act based on these recognized signals. It recognizes PAMP, DAMP, and the
absence of self markers.
Describe how innate immunity can lead to adaptive immunity,
and name the cell that bridges the two systems.
If the innate response cannot handle the infection, then adaptive immune system is needed.
Immature phagocytic cells known as dendritic cells (DC) get activated by cytokines and
chemokines, and indiscriminately engulf foreign antigens. Activated dendritic cells leave the
local area and travel (through the lymphatic system) to the nearest lymph node, where they
present antigen-presenting cells. This allows development of an adaptive immune response.
Give an example each of how the immune system can be helpful
or harmful to its host.
Helpful
The immune system can be helpful by stopping infections that are present in the immune
system. The human body can respond well to a second infection without actually repeating
the whole series of infection.
(2)
Harmful
It can be harmful in terms of blood transfusion or organ transplantation, mainly because
these tissues are necessary to sustain the life of the host. However, the immune system
responds by destroying the foreign tissue.
Describe the recognition and effector functions of the immune
system. Distinguish recognizing and effector cells.
The recognition functions of the immune system are to recognize non-self antigens in the
presence of self during antigen presentation. Recognizing cells are known for their receptors
that respond to certain protein sequences that are on an antigen. Recognition is important
because it is necessary to activate effector cells to attack the antigens in question. Activation
cannot occur without recognition.

The effector functions of the immune system are to activate the effector cells (lymphocytes) to
ensure the destruction of the foreign antigens. Effector cells are known for originating in the
lymph node and moving into the blood stream or tissue in response to infection.
Discuss the similarities and differences between T cell-
mediated and antibody-mediated.
T cell-mediated immunity involves the helper T cells directly recognizing antigens by surface
receptors. When they are activated, they proliferate into daughter T cells and travel
systemically in an effort to find antigen-infiltrated cells. They also utilize killer T cells to
activate and proliferate in an effort to destroy the infected cells.

Antibody-mediated immunity is run by the B cells of the body and protects extracellular
spaces by releasing antibody. When they arrange for phagocytosis and destruction, they also
secrete antibodies to do the work.
Describe at least 2 functions of T cells.
T Lymphocyte Molecular
Marker
Functions
Type 1 Helper T Cells (Th1) CD4 Recognize antigen and make a lymphokine that attracts
macrophages to the area where antigen has been recognized.
Th17 Helper T Cells (Th17) CD4 Cause focused inflammation, implicated in many serious forms of
autoimmunity.
Type 2 Helper T Cells (Th2) CD4 Stimulate macrophages to become alternatively activated, and
then function in walling-off pathogens and promoting healing, a
process that usually takes place after the pathogen-killing Th1
response. Important in parasite immunity.
Follicular Helper T Cells
(Tfh)
CD4 Stimulated by antigen and migrate from T cell areas of lymph nodes
into the B cell follicles, where they help B cells get activated and
make the IgM, IgG, IgE, and IgA antibody subclasses.
Regulatory T Cells (Treg) CD4 Synthesize cytokines that suppress the activation and function of
Th1, Th17, and Th2 cells, so they keep the immune response in
check.
Cytotoxic/Killer T Cells
(CTL)
CD8 Destroy any body cell they identify as bearing a foreign or abnormal
antigen on its surface.

Describe at least two functions of the complement system.
Complement System: Utilizes a system of proteins that enhances inflammation and pathogen
destruction.
1. Important in disease resistance.
2. Can lyse a bacterium by making holes in its membrane.
(3)
3. Others diffuse away from the site where antibody is interacting with antigen, and
attract phagocytic cells.

Define the concept of immunopathology, and give two
examples.
Immunopathology is the branch of medicine that deals with immune responses to disease.
There are four common mechanisms of immunopathology:
Mechanism Definition Cause Example
Type I
Immunopathology
Immediate
hypersensitivity to
pathogens
Too much IgE to respond to environmental
antigen
Allergies, Asthma,
Anaphylactic Shock
Type II
immunopathology
Autoimmunity due
to antibodies
(Reaction against
self.
Foreign antigens look like self, causing a cross
reaction with self. Based on normal antibody
immunity. Antibody binds, complement is
activated, phagocytes areattracted, and they
attempt to eat the antigens.
Graft v. Host,
Transfusion reaction
Type III
immunopathology
When an antibody
is made against a
soluble antigen.
Immune complexes of antigen and antibody are
usually eaten by phagocytes, but are too small,
and may get trapped in the basement membrane
of capillaries they circulate through. Happens
where there is a net outwar movement of fluid
from blood to tissues. The trapped complexes
activate complement and the inflammatory
response occurs.
Arthritis, Systemic
Lupus
Erythematosus
Type IV
immunopathology
T cell mediated
(autoimmune)
T cells attack body cells due to the presence of
foreign antigens.
Tuberculosis or
Acute Viral Hepatitis
AIDS Immunodeficiency
by a virus, namely
human
immunodeficiency
virus.
The AIDS virus, HIV-1, infects Th cells because
its envelope glycoprotein, gp120, binds to the
CD4 cmolecules they have on their surface.
Inside it uses its enzymes (reverse ranscriptase,
to copy its RNA into DNA which becomes
inserted into the cells own DNA.
HIV

Anatomy and Physiology of the Immune System
Define:
Leukocytes
Nucleated cells of the blood; white blood cells.
Mononuclear Cells
Leukocytes whose nucleus has a smooth outline. Examples: Monocytes and Lymphocytes.
Polymorphonuclear Cells
Cells whose nucleus is lobulated, also called granulocytes because they have (usually) rather
prominent cytoplasmic granules. Exmaples: Eosinophils, Neutrophils, and Basophils.
Granulocytes
Cells that contain prominent cytoplasmic granules. Found typically in polymorphonuclear
cells.
Mast Cells
Cell in recognizing tissues that contain histamin and heparin granules. Most prominent in
hypersensitivity responses such as allergy and anaphylaxis.
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Plasma and Serum
Plasma is the yellow component of blood, which suspends blood cells, composing of 55% of the
total blood volume. It contains fibrinogen, and contains dissolved proteins, glucose, clotting
factors, ions, hormones, and carbon dioxide. Blood serum is plasma without the fibrinogen or
clotting factors.
Sketch schematically a neutrophil; eosinophil; basophil; small
lymphocyte; lymphoblast; plasma cell; monocyte. Indicate the
characteristic features which distinguish each cell type.
Cell Sketch Characteristic Features
Neutrophil

- Multilobulated nuclei.
- Colorless granules.
Eosinophil

- Multi-lobulated nuclei.
- Red granules
Basophil

- Multi-lobulated nuclei
- Blue granules
Small
Lymphocyte

- Cytoplasmic halo
- Large nucleus
- Single nucleus
CELLS, ORGANS, AND MOLECULES:
ANATOMY AND PHYSIOLOGY OF THE IMMUNE SYSTEM

ANTIGEN, IMMUNOGEN, TOLEROGEN. Antigen refers to a substance which can be
recognized by the immune system. !An antigen frequently is also an immunogen, which is an
antigen in a form which can give rise to an immune response, that is, which can immunize. For
example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by
antibody, but is too small to trigger an immune response. Competing pandemic (H1N1)2009
vaccines, all nicely antigenic, were tested to see which was the best immunogen. A tolerogen is
antigen delivered in a form, or by a route, which does not give rise to an immune response, and
which furthermore prevents an immune response to subsequently administered immunogen
which has the same epitopesto be discussed later. You can imagine how useful a tolerogen
might be. We dont have any clinical tolerogens at present, though, except our whole bodies, to
which we do not usually respond (but other people would, so we know that our tissues are
antigenic and therefore potentially immunogenic.)

ASK YOURSELF: If you could turn any antigen into a tolerogen, which would you
choose?

THE CELLS OF THE BLOOD FROM AN IMMUNOLOGISTS PERSPECTIVE.
Erythrocytes: Red blood cells (~5 x 10
6
/L) (~5 x 10
12
/L) of blood.

Leukocytes: Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated
blood, they sediment on top of the packed red cells, forming the buffy coat.

Mononuclear cells: Leukocytes whose nucleus has a smooth outline; monocytes (immature,
becoming mature macrophages in the tissues), and lymphocytes. In tissues its sometimes hard
to tell the difference between macrophages and lymphocytes.

Polymorphonuclear cells: Cells whose nucleus is lobulated, also called granulocytes because
they have (usually) rather prominent cytoplasmic granules. They are:

Eosinophils; Basophils (closely related to tissue mast cells); and Neutrophils.

Blood smear
stained with
Wrights-Giemsa.

(tissues are usually
stained with the
similar H&E
(hematoxylin
(blue)
and eosin (red)))
CELLS, ORGANS, AND MOLECULES:
ANATOMY AND PHYSIOLOGY OF THE IMMUNE SYSTEM

ANTIGEN, IMMUNOGEN, TOLEROGEN. Antigen refers to a substance which can be
recognized by the immune system. !An antigen frequently is also an immunogen, which is an
antigen in a form which can give rise to an immune response, that is, which can immunize. For
example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by
antibody, but is too small to trigger an immune response. Competing pandemic (H1N1)2009
vaccines, all nicely antigenic, were tested to see which was the best immunogen. A tolerogen is
antigen delivered in a form, or by a route, which does not give rise to an immune response, and
which furthermore prevents an immune response to subsequently administered immunogen
which has the same epitopesto be discussed later. You can imagine how useful a tolerogen
might be. We dont have any clinical tolerogens at present, though, except our whole bodies, to
which we do not usually respond (but other people would, so we know that our tissues are
antigenic and therefore potentially immunogenic.)

ASK YOURSELF: If you could turn any antigen into a tolerogen, which would you
choose?

THE CELLS OF THE BLOOD FROM AN IMMUNOLOGISTS PERSPECTIVE.
Erythrocytes: Red blood cells (~5 x 10
6
/L) (~5 x 10
12
/L) of blood.

Leukocytes: Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated
blood, they sediment on top of the packed red cells, forming the buffy coat.

Mononuclear cells: Leukocytes whose nucleus has a smooth outline; monocytes (immature,
becoming mature macrophages in the tissues), and lymphocytes. In tissues its sometimes hard
to tell the difference between macrophages and lymphocytes.

Polymorphonuclear cells: Cells whose nucleus is lobulated, also called granulocytes because
they have (usually) rather prominent cytoplasmic granules. They are:

Eosinophils; Basophils (closely related to tissue mast cells); and Neutrophils.

Blood smear
stained with
Wrights-Giemsa.

(tissues are usually
stained with the
similar H&E
(hematoxylin
(blue)
and eosin (red)))
CELLS, ORGANS, AND MOLECULES:
ANATOMY AND PHYSIOLOGY OF THE IMMUNE SYSTEM

ANTIGEN, IMMUNOGEN, TOLEROGEN. Antigen refers to a substance which can be
recognized by the immune system. !An antigen frequently is also an immunogen, which is an
antigen in a form which can give rise to an immune response, that is, which can immunize. For
example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by
antibody, but is too small to trigger an immune response. Competing pandemic (H1N1)2009
vaccines, all nicely antigenic, were tested to see which was the best immunogen. A tolerogen is
antigen delivered in a form, or by a route, which does not give rise to an immune response, and
which furthermore prevents an immune response to subsequently administered immunogen
which has the same epitopesto be discussed later. You can imagine how useful a tolerogen
might be. We dont have any clinical tolerogens at present, though, except our whole bodies, to
which we do not usually respond (but other people would, so we know that our tissues are
antigenic and therefore potentially immunogenic.)

ASK YOURSELF: If you could turn any antigen into a tolerogen, which would you
choose?

THE CELLS OF THE BLOOD FROM AN IMMUNOLOGISTS PERSPECTIVE.
Erythrocytes: Red blood cells (~5 x 10
6
/L) (~5 x 10
12
/L) of blood.

Leukocytes: Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated
blood, they sediment on top of the packed red cells, forming the buffy coat.

Mononuclear cells: Leukocytes whose nucleus has a smooth outline; monocytes (immature,
becoming mature macrophages in the tissues), and lymphocytes. In tissues its sometimes hard
to tell the difference between macrophages and lymphocytes.

Polymorphonuclear cells: Cells whose nucleus is lobulated, also called granulocytes because
they have (usually) rather prominent cytoplasmic granules. They are:

Eosinophils; Basophils (closely related to tissue mast cells); and Neutrophils.

Blood smear
stained with
Wrights-Giemsa.

(tissues are usually
stained with the
similar H&E
(hematoxylin
(blue)
and eosin (red)))
CELLS, ORGANS, AND MOLECULES:
ANATOMY AND PHYSIOLOGY OF THE IMMUNE SYSTEM

ANTIGEN, IMMUNOGEN, TOLEROGEN. Antigen refers to a substance which can be
recognized by the immune system. !An antigen frequently is also an immunogen, which is an
antigen in a form which can give rise to an immune response, that is, which can immunize. For
example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by
antibody, but is too small to trigger an immune response. Competing pandemic (H1N1)2009
vaccines, all nicely antigenic, were tested to see which was the best immunogen. A tolerogen is
antigen delivered in a form, or by a route, which does not give rise to an immune response, and
which furthermore prevents an immune response to subsequently administered immunogen
which has the same epitopesto be discussed later. You can imagine how useful a tolerogen
might be. We dont have any clinical tolerogens at present, though, except our whole bodies, to
which we do not usually respond (but other people would, so we know that our tissues are
antigenic and therefore potentially immunogenic.)

ASK YOURSELF: If you could turn any antigen into a tolerogen, which would you
choose?

THE CELLS OF THE BLOOD FROM AN IMMUNOLOGISTS PERSPECTIVE.
Erythrocytes: Red blood cells (~5 x 10
6
/L) (~5 x 10
12
/L) of blood.

Leukocytes: Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated
blood, they sediment on top of the packed red cells, forming the buffy coat.

Mononuclear cells: Leukocytes whose nucleus has a smooth outline; monocytes (immature,
becoming mature macrophages in the tissues), and lymphocytes. In tissues its sometimes hard
to tell the difference between macrophages and lymphocytes.

Polymorphonuclear cells: Cells whose nucleus is lobulated, also called granulocytes because
they have (usually) rather prominent cytoplasmic granules. They are:

Eosinophils; Basophils (closely related to tissue mast cells); and Neutrophils.

Blood smear
stained with
Wrights-Giemsa.

(tissues are usually
stained with the
similar H&E
(hematoxylin
(blue)
and eosin (red)))
(5)
Lymphoblast

- Presence of Golgi
Apparatus
- Multiple nucleoli
Plasma Cell

- Presence of Rough
Endoplasmic Reticulum
- Three nucleoli
Monocyte

- U-shaped nucleus
- Large size

Define antigen, and compare it to immunogen. Discuss a
potential use, if any, antigen could be made into a tolerogen.
Antigen is a substance that induces an immune response. An immunogen is an antigen,
which can give rise to an immune response, that is, which can immunize a host. Not every
antigen is an immunogen. Potential uses to antigen that can be made into tolerogens is the
desensitization of pollen or even a faster recovery rate in organ transplantation. Tolerogens
do not generate an immune response. Creating antigens that do not spur an immune
response allow the body to function properly without the side effects associated with an
immune response.
LYMPHOCYTE DIFFERENTIATION.



When a stimulated T cell becomes large and differentiated, it is called a lymphoblast. This is a
confusing name, and Im sorry, but I didnt name it. The misnomer comes from the early
pathologists who thought these wells were early lymphocyte precursors
2
(-blasts), not
differentiated descendents. A B cell also becomes a (B) lymphoblast and then goes beyond that
to the incredibly specialized cell !called a plasma cell, which works so hard to pump out
antibody that many of them will die in a few days.

ASK YOURSELF: The cells of your immune system are kept out of your brain by a
blood-brain barrier. If this barrier were to break down accidentally, would your brain then
be foreign to your immune system? (Another way of thinking about this is, Do you think
your brain is a tolerogen to your immune system, or a potential immunogen which your
immune system has simply not had a chance to see?) Do you think you would make an
(auto)immune response? Would that be harmful?


2
Blast in Greek means sprout or germ.
LYMPHOCYTE DIFFERENTIATION.



When a stimulated T cell becomes large and differentiated, it is called a lymphoblast. This is a
confusing name, and Im sorry, but I didnt name it. The misnomer comes from the early
pathologists who thought these wells were early lymphocyte precursors
2
(-blasts), not
differentiated descendents. A B cell also becomes a (B) lymphoblast and then goes beyond that
to the incredibly specialized cell !called a plasma cell, which works so hard to pump out
antibody that many of them will die in a few days.

ASK YOURSELF: The cells of your immune system are kept out of your brain by a
blood-brain barrier. If this barrier were to break down accidentally, would your brain then
be foreign to your immune system? (Another way of thinking about this is, Do you think
your brain is a tolerogen to your immune system, or a potential immunogen which your
immune system has simply not had a chance to see?) Do you think you would make an
(auto)immune response? Would that be harmful?


2
Blast in Greek means sprout or germ.
CELLS, ORGANS, AND MOLECULES:
ANATOMY AND PHYSIOLOGY OF THE IMMUNE SYSTEM

ANTIGEN, IMMUNOGEN, TOLEROGEN. Antigen refers to a substance which can be
recognized by the immune system. !An antigen frequently is also an immunogen, which is an
antigen in a form which can give rise to an immune response, that is, which can immunize. For
example, an isolated antigenic determinant is not usually an immunogen; it can be recognized by
antibody, but is too small to trigger an immune response. Competing pandemic (H1N1)2009
vaccines, all nicely antigenic, were tested to see which was the best immunogen. A tolerogen is
antigen delivered in a form, or by a route, which does not give rise to an immune response, and
which furthermore prevents an immune response to subsequently administered immunogen
which has the same epitopesto be discussed later. You can imagine how useful a tolerogen
might be. We dont have any clinical tolerogens at present, though, except our whole bodies, to
which we do not usually respond (but other people would, so we know that our tissues are
antigenic and therefore potentially immunogenic.)

ASK YOURSELF: If you could turn any antigen into a tolerogen, which would you
choose?

THE CELLS OF THE BLOOD FROM AN IMMUNOLOGISTS PERSPECTIVE.
Erythrocytes: Red blood cells (~5 x 10
6
/L) (~5 x 10
12
/L) of blood.

Leukocytes: Nucleated cells of the blood; white blood cells. When you centrifuge anticoagulated
blood, they sediment on top of the packed red cells, forming the buffy coat.

Mononuclear cells: Leukocytes whose nucleus has a smooth outline; monocytes (immature,
becoming mature macrophages in the tissues), and lymphocytes. In tissues its sometimes hard
to tell the difference between macrophages and lymphocytes.

Polymorphonuclear cells: Cells whose nucleus is lobulated, also called granulocytes because
they have (usually) rather prominent cytoplasmic granules. They are:

Eosinophils; Basophils (closely related to tissue mast cells); and Neutrophils.

Blood smear
stained with
Wrights-Giemsa.

(tissues are usually
stained with the
similar H&E
(hematoxylin
(blue)
and eosin (red)))
(6)
Discuss lymphocyte activation by antigen with respect to:
receptor binding, proliferation, and differentiation.

Antibody Structure
Define
H (Heavy) chain
Chain of polypeptides that has a molecular weight of ~50,000.
L (Light) chain
Chain of polypeptides that has a molecular weight of ~25,000.
Kappa and lambda chains
Types of L chains. Remain the same during change of H chains.
Hinge region
Proline-rich portion of an immunoglobulin heavy chain between the Fc and Fab regions that
confers mobility on the two Fab arms of the antibody molecule, allowing it to combine better
with two epitopes.
Fab, F(ab)2, Fc
Fab (fragment antigen-binding: region on an antibody that binds to antigens.
F(ab)2 (fragment antigen binding, divalent): divalent fragments that contain two light
chains and two variable region heavy chains.
Fc (fragment, crystallizable): Complement-fixing domain (tail-region) that interacts with Fc
receptors of the complement system. Utilized to activate the immune system.
Complementarity-determining region
Regions within immunoglobulins where proteins interact with antigens. Determine the
proteins affinity and specificity for antigens.
Variable V and constant C regions
Variable V region: Sequence between antibodies of different specificities. Comprises the
antibodys combining site, which binds antigen.
Constant C region: Region that is essentially identical, no matter what the specificities of the
antibodies are. Made up of 1 (in L chains) to 4 (in epsilon and mu) compact, structurally-
similar domains.
VL and CL
VL: Variable domain in light chain
Receptor Binding
Lymphocytes have receptors.
T cells have alpha and beta
chains. B cells have samples
of antibodies that the cell
will secrete. Antigen part
that fits onto the receptor is
the epitope.
To activate the T or B cell:
Fit between receptor and
antigen is good enough
(several receptors bound by
antigen)
For T cells, other cell
surface molecules must be
involved.
Proliferation
T cells and B cells because to
divide and produce daughter
cells.
Differentiation
Lymphocytes mature and
specialize, becoming
lymphoblasts.
T lymphocytes become T
lymphoblasts.
B lymphocytes become B
lymphoblasts, which turn
into plasma cells.
(7)
CL: Constant domain in light chain
Name the 5 antibody classes, and their characteristic heavy
chains.
Clas
s
Norm.
Value
(mg/dL)
Diagram Charact
eristic
Heavy
Chains
Molecular
Weight
Function
IgG 1000

2 Light
and 2
Gamma
Chains
150,000 Main antibody in
blood and tissue
fluids. It neutralizes
toxins, binds bacteria
and facilitates their
destruction by
activating complement
and by binding them
to phagocytic cells.
IgE 0.02

2 Light
and 2
Epsilon
Chains
190,000 (an
extra
constant
domain, CH4,
and 18%
carbohydrate)
Dimer form in
secretions, where
secretory component
protects it from
proteolysis.
IgD 5

2 Light
and 2
Delta
Chains
180,000 (an
extra-long
hinge region)
First antibody to
appear in the serum
after immunization,
and it is very efficient
at activating
complement. IT does
not get into tissue
fluids very efficiently.
IgA 200

4 Light,
4 Alpha,
1 J, and
1 S.C.
chain
Secreted form
400,000
(monomer is
160,000; J
chain is
15,000 and
Secretory
Component is
70,000)
Functions mainly as a
receptor on B cells.
IgM 100

10 light,
10 mu,
and 1 J
chain
900,000 (5 x
180,000; an
extra CH4
domain plus a
J chain)
Antibody which causes
Type I
immunopathology. It
is also called
immediate
hypersensitivity or
allergy. Also
important in
resistance to
parasites.


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J

(8)
Draw a diagram of the structure of typical molecules of each
class. Label the heavy and light chains; Fc and Fab parts; J
chains; antibody combining sites; main interchain disulfide
bonds; secretory component.

Typical antibody molecule.

Class Diagram
IgG

IgE

IgD

IgA

2
ANTIBODY STRUCTURE. To get at the structure of these large molecules it was necessary
to disassemble them into smaller, workable pieces. The first good attempt at this was by R. R.
Porter in 1959, who treated antibody (mostly gamma globulin) with the enzyme papain and an
agent that reduced some disulfide bonds (-S---S- reduced to -SH HS-) and found that the
antibody broke up into 3 fragments: !two identical ones that are now each called Fab, and one
Fc. At the same time G. Edelman treated antibody with a strong reducing agent that broke all
interchain disulfide bonds and a denaturant to straighten out and separate the polypeptides. !He
found that the molecule was composed of two identical light (MW about 25,000) and two
identical heavy (MW about 50,000) chains. These studies led to the complete determination of
the structure of immunoglobulins, and Porter and Edelman shared the Nobel Prize in 1972.

A TYPICAL IMMUNOGLOBULIN MOLECULE.






!If you adjust conditions during antibody digestion with proteolytic enzymes, you can get 2 Fab
fragments (SS bonds between the H chains fully reduced) or you can leave the 2 Fabs still
joined; thats called F(ab)
2
. Fab is univalent; like IgG, F(ab)
2
is divalent.




4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J

(9)
IgM


Discuss the significance of the fact that in any antibody
molecule, both H and both L chains are identical.
Both H and both L chains are identical in order to maintain rotational symmetry and to
maintain its structure. This also allows multiple binding sites to be present in an antibody.
Describe the structure of antibody combining sites.
When an IgG or IgM binds to at least one of its binding sites there is an obvious change in
the angle. IT becomes Y or T shaped!

1. BINDING/RECOGNITION Binding to phagocytic cells, especially PMNs,
eosinophils, and macrophages, which have receptors (FcR) for the altered Fc of IgG
but not of IgM.
2. PERFORMANCE OF FUNCTION C1q, first component of complement system,
binds to two adjacent Fcs and is activated.

4
5 CLASSES OF IMMUNOGLOBULINS. As indicated already, there was evidence of more
than one class of immunoglobulin based on either structural or functional differences. In humans,
five major classes have been described:
STRUCTURE MOLECULAR WEIGHT
IgG: 2 light and 2 gamma (!) chains 150,000
IgE: 2 light and 2 epsilon (") chains 190,000 (an extra constant
domain, CH4, and 18%
carbohydrate)
IgD: 2 light and 2 delta (#) chains 180,000 (an extra-long
hinge region)
IgA: 4 light, 4 alpha ($), I J, and 1 S.C. chain Secreted form 400,000
(monomer is 160,000;
J chain is 15,000 and Secretory
Component is 70,000)
IgM: 10 light, 10 mu (), and 1 J chain 900,000 (5 x 180,000; an
extra CH4 domain plus a J
chain)
S.C.
J
J


7

IgDs role in blood, if any, is uncertain; it seems to function mainly as a receptor on B cells.

IgE is the antibody which causes Type I immunopathology, also called immediate
hypersensitivity or allergy; it also is important in resistance to parasites.



ANTIGEN-ANTIBODY INTERACTION. When an IgG or IgM antibody binds antigen with
at least one of its binding sites, there may be a change in the angle between the two Fab parts, so
that the molecule may be more ! !! ! or " "" " shaped than before (this explains why the region between
Fabs and Fc is called the Hinge.) This results in a bulging of the structure of the Fc part so that
one or two very important biological activities are initiated:

1. !Binding to phagocytic cells, especially PMNs, eosinophils, and macrophages, which have
receptors (FcR) for the altered Fc of IgG but not of IgM, and

2. !C1q, the first component of the complement system, now binds to two adjacent Fcs and is
activated (see Antibody Function.) Note: As shown in the figure below, 2 IgGs will have to be
binding close together on the same (usually bacterial) surface, but one IgM can do it alone,
because it carries 5 Fcs at all times. This makes IgM much better at activating complement.



It is always helpful to think about antigen-antibody interactions in
steps: first there is binding (recognition), and then the antibody can do
something else, like cross-link two antigen molecules, or activate
complement (the 5-branched molecule marked C in the picture at left),
or bind to a phagocyte (function). Some important defense mechanisms,
and also useful tests, depend only on the first step, and others involve
the secondary events as well.



ASK YOURSELF: Can you imagine a defense mechanism that might depend only on
the first, binding, step?



Y
Y
Ab
C


(10)
Explain why complementarity-determining regions are also
called hypervariable regions.

Complementarity-determining regions (CDR) are called hypervariable regions because of
variability along 3 areas of the V domain, and not distributed uniformly. These
hypervariable regions comprise of the actual antigen-binding site.
Give an example of a subclass, an allotype, an idiotype.
Subclass
IgG1, IgG2, IgG3, IgG4
IgA1, IgA2
IgM1, IgM2
IgD
IgE
Allotype
Gm (heavy chain) and km (light chain)

Idiotype
VL and VH in an antibody.

Define Fc receptors. Name the inflammatory cells that have
them.
Fc receptors are receptors with a protein that stimulate phagocytic or cytotoxic cells to
destroy microbes, or infected cells in antibody-mediated immunity.

Receptor name
Principal
antibody ligand
Affinity for
ligand
Cell distribution
Effect following binding
to antibody
FcRI (CD64) IgG1 and IgG3
High (Kd ~
10

9
M)
Macrophages
Neutrophils
Eosinophils
Dendritic cells
Phagocytosis
Cell activation
Activation of respiratory
burst
Induction of microbe killing
FcRIIA (CD32) IgG Low (Kd > 10

7
M)
Macrophages
Neutrophils
Eosinophils
Platelets
Langerhans cells
Phagocytosis
Degranulation (eosinophils)
FcRIIB1 (CD32) IgG Low (Kd > 10

7
M) B Cells No phagocytosis

5
In summary: !each molecule is made up of a basic unit consisting of four chains: 2 heavy (H)
and 2 light (L) chains. Secreted IgA is a dimer of two of these basic units, and IgM is a
pentamer. The basic units in IgA and IgM are held together by J chains, and IgA is wrapped by
Secretory Component. In any one antibody, the H chains are identical, and so are the L chains,
so the molecule has rotational symmetry.

The 5 kinds of H chains (gamma, alpha, mu, epsilon, delta) define the class of antibody to which
the molecule belongs. L chains come in 2 varieties: kappa or lambda (the original light chain
gene family duplicated itself). Although each cell that makes an antibody has a choice of using
kappa or lambda, it uses only one kind. So, for example, an IgA molecule will be kappa or
lambda type, while another IgA might be the other. As well discuss soon, a single cell may
switch from making, say, IgM to making IgA. !When this happens, the heavy chain changes
(mu replaced by alpha) but the L chain, either kappa or lambda, stays the same during the
switch.

Examine the diagram below. When the amino acids in many antibody molecules are sequenced,
one finds that for each chain type there is a region that is essentially identical, no matter what the
specificities of the antibodies were. !This is the constant region, and it is made up of 1 (in L
chains) to 4 (in epsilon and mu) compact, structurally-similar domains called C domains. Each
chain also has, at its N-terminal (conventionally shown on the left), a domain !that is different
in sequence between antibodies of different specificities: the variable domain or V. The
antibodys combining site, which binds antigen, is made up of the V domains of both the H and
L chain (VH and VL.)




Amino acid sequence variability is not
distributed uniformly along the V
domain; most of the variability is in 3
areas called, therefore, hypervariable
regions. It is more functionally
significant to call them
!complementarity-determining
regions, CDR, because the amino acids
in the hypervariable regions comprise
the actual antigen-binding site.













ASK YOURSELF: Valence refers to the number of antigenic determinants an antibody
molecule can bind. What is the valence of IgG? of secreted IgA? of IgM? of Fab? of
F(ab)2 ? How about of an isolated VL or VH?

CDR
CDR
epitope
V
H
V
L
C
L
C
H1
C
H2
C
H3
hinge
CDR
CDR
epitope
V
H
V
L
C
L
C
H1
C
H2
C
H3
hinge

(11)
Mast cells Inhibition of cell activity
FcRIIB2 (CD32) IgG Low (Kd > 10

7
M)
Macrophages
Neutrophils
Eosinophils
Phagocytosis
Inhibition of cell activity
FcRIIIA
(CD16a)
IgG Low (Kd > 10

6
M)
NK cells
Macrophages (certain
tissues)
Induction of antibody-
dependent cell-mediated
cytotoxicity (ADCC)
Induction of cytokine
release by macrophages
FcRIIIB
(CD16b)
IgG Low (Kd > 10

6
M)
Eosinophils
Macrophages
Neutrophils
Mast cells
Follicular dendritic
cells
Induction of microbe killing
FcRI IgE
High (Kd ~
10

10
M)
Mast cells
Eosinophils
Basophils
Langerhans cells
Degranulation

Antibody Specificity, Diversity, Genes
Define
Toxoid
Bacterial toxin that has been weakened or suppressed by chemical or heat, while the
immunogenicity is maintained. Often used in vaccines, to induce an immune response to the
toxin or increase the response to another antigen.
DNA recombination
Changing the relative positions of two pieces of DNA.
RNA splicing
Modification of RNA after transcription.
Somatic hypermutation
Mechanism for immune system adaptation after encountering foreign microbes.
Define cross-reactivity. Give an example of a non-self antigen
which cross-reacts with a self antigen. Explain, in terms of
lymphocyte activation, how a self antigen might not itself elicit
antibody, but might react with antibody elicited by a cross-
reacting antigen.
Cross-reactivity is the tendency of one antibody to react with more than one antigen, or a
reaction between the antibody and antigen that differs from the immunogen. It has to do
with goodness of fit. What happens is that it is against an antigen if it was immunized or in
a react with the antigen with a high association constant. This allows the adaptive immune
response to respond to toxoids and immune itself to toxins. This is the reasoning behind
vaccinations and immunizations, as the exposure to a toxoid (the harmless) allows resistance
to the toxin (the not-so-harmless).
Discuss the Clonal Selection Theory.
Model of how the immune system responds to infection. It states that:
(12)
- The immune system (B and T cells) is programmed to make only one antibody
- The choice of which antibody the cell will make is random, not dependent on outside
information.
- Entire population preexists in a normal individual, even before any contact with
antigens.
- When a new antigen is introduced into the body, it comes into contact with a huge
number of lymphocytes.
- When it encounters one to whose receptors it binds with sufficient affinity, it
activates it, resulting in expansion of that clone and production of that antibody.
In short, the best-fitting clones are selected by antigen.
Define allotypic exclusion. Demonstrate your knowledge of the
concept by first stating the number of chromosomes in a cell
which bear H or L genes, and then the number that actually
contribute to a particular B cells antibody product.
Allotypic exclusion is the process by which only one heavy chain (maternal or paternal) and
one light chain (kappa or lambda) is synthesized by an individual B cell, regardless of its
potential to make two different heavy chains and four different light chains.
Draw a diagram of the heavy and light chain gene regions of
human DNA. Indicate V, D, J and C subregions. Show how a
heavy or light chain gene is assembled out of these subregions
during the differentiation of a B cell.
Start:

3
chains, and therefore, by random combination, many different antibodies? It doesnt happen;
!only one H chain (maternal or paternal in origin) and one L chain (either kappa or lambda,
either maternal or paternal) are synthesized in any one B cell. All the other genes are silenced.
Though the person can make two allotypes, each individual B cell makes only one
2
. It is
reminiscent of the way each female cell turns off one or the other of its X chromosomes; and this
fact makes our job of understanding how we generate antibody diversity a little simpler.

EARLY WORK ON DNA RECOMBINATION. In the 70s people probing germ line (sperm
or egg) DNA found many genes encoding Variable domains, but only one of each set of
Constant domain genes (i.e., one gene for the constant part of the delta chain, one C gene for mu,
etc.) per haploid genome. What exists, they concluded, must be something like this:

V1 V2 V3 V 4 Vn
C C! ! ! ! C" "" "


Whereas what is expressed by a B cell might be:




!So they found that the DNA rearranges in developing B cells, to bring one of many Vs
together with the correct C so that the unit could be copied into messenger RNA. Changing the
relative positions of two pieces of DNA is called recombination. But even the V region gene
was soon found to be broken up into smaller sets of minigenes.


MODERN SYNTHESIS: THE FINE STRUCTURE OF VARIABLE DOMAIN GENES.
We need to agree on some terminology here: lets call the DNA which codes for the variable
domain of an L or H chain the V domain gene region rather than the V locus. This is because it
turns out that at the DNA level, the information to code for a variable domain is actually broken
up into segments or minigenes. !The variable domain region of heavy chain genes is
composed of multiple V, multiple D, and multiple J gene segments; the V region of light
chains into V and J segments, so generically we say V(D)J. The cell will choose one of its Vs,
one D, and one J to make a V
H
domain gene region.



2
This is good, because you wouldnt want a B cell that responds to mumps to also release antibody against, say,
your kidneys. Specificity is important.
1 2 3 4 5 6 7...n 1 2 3...n 1 2 3...n ! "1 "2 # $ ...
D J V C
V region

V31 C!
(13)

In heavy chains, basically:
1. Developing B cell first brings randomly one D segment close to one J. The DNA is
cut, the intervening DNA is excited and the ends joined.
2. The V segment is brought to the recombined DJ, and repeats the cutting and joining
process.
3. The entire region from the assembled VDJ unit through the end of the delta (of IgD)
constant region gene is then transcribed into nuclear RNA.
4. The primary RNA transcripts are alternatively processed by splicing, first to make
only VDJ-Cmu, and later to make both VDJ-Cmu and VDJ-Cdelta messages.

In light chains, basically:
The rearrangement is similar, but there are only V and J segments, no D, and only one C
domain gene.
Describe the somatic recombination model, which explains how
antibodies of the same specificity (idiotype) can be found in two
or more different classes (class switching).
The somatic recombination model is a model of diversity generation by utilizing randomizing
mechanisms. It first utilizes exonucleases to remove a few nucleotides after the DNA is cut
4
ASSEMBLING A HEAVY CHAIN GENE. As we just said, its variable domain is coded by
V, D, and J segments. The developing B cell first brings randomly one D segment close to one J;
the DNA is cut, the intervening DNA is excised and the ends joined. It then brings a V segment
up to the recombined DJ, and repeats the cutting and joining process (there are splice acceptor
and donor sites adjacent to each segment). The entire region from the assembled VDJ unit
through to the end of the delta (of IgD) constant region gene, is then transcribed into nuclear
RNA. !These primary RNA transcripts are alternatively processed by splicing, first to make
only VDJ-C", and later to make both VDJ-C" and VDJ-C# messages. Read this sequence down:






1 2 3 4 5 6 7 2 2 3...n ! "1 "2...
!!!!!!!!!!!!"#$!!!!!!!!!!!!!!!!!!!!!!!%
1 2 3 4 5 6...n 1 2 3...n 1 2 3...n ! "1 "2...
# $
1 2 3 4 5 6...n 1 2 2 3...n ! "1 "2...
"!!!!!!!!!!!!!!!!!!!!!!!!!!!!#$!!!!!!!!!!!!!!!!!!!!!!!%
1 2 3 4 5 6 7 1 2 2 3...n ! "1 "2...
!!!!!!!"!!!!!!!!!!!!!!!#$!!!!!!!!!!!!!!!!!!!!!!!%
7 2 2
!!!!!!!!!!!!"#$%
7 2 2 3...n !
!!!!!!!!!!!!"#$!!!!!!!!!!!!!!!!!%
7 2 2!
!!!!!!!!!!!!"#$%

D is brought to
J; one random D is joined
to one random J; the
intervening DNA is
excised
Then V is brought to D-J;
one V is joined to the D-J
pair; the intervening
DNA is excised
A primary RNA transcript
is made, from just left of the
chosen V all the way through
to the right of the delta
constant region gene
The primary transcript RNA is
alternatively spliced to make
VDJ or VDJ! messages; the
cell makes IgM and, later, IgD
too.
This is the
germ-line
situation
1 2 3 4 5 6 7...n 1 2 3...n 1 2 3...n ! "1 "2 # $ ...
D J V C

(14)
but before two gene segments (D to J, and V to DJ) are joined. Afterwards, it adds a few,
random nucleotides to the N region by utilizing an enzyme called terminal deoxynucleotidyl
transferase (TdT). This will cause a frame-shift mutation, and can cause termination of
transcription.

The change in the transcription leads to a change in mRNA. This is class switching is due to
the DNA mutation, from which a change from VDJ-mu can create VDJ-alpha, VDJ-gamma,
or VDJ-epsilon. However, it cannot return to VDJ-mu because the frameshift mutation
caused removal of the mu functions. It can be found in two or more different classes (causing
class switching) by randomly mutating production of the mu, delta, alpha, or epsilon genes.
Define somatic mutation, and describe the essential difference
between the somatic mutation and germ line hypotheses of
immunological diversity.
Somatic mutation is the theory that during embryonic lymphoid development, the genes
underwent repeated (somatic) mutation until a full complement of antibodies was produced,
and that not many V genes were in the germ line. This differed from the germ line theory,
which stated that the V genes were in the germ line, and that in the fertilized ovum, one
could predict all potential antibodies that an individual would have.
Describe the mechanisms by which more diversity is created by
nucleotide insertion and removal during V(D)J recombination.
Mechanism B Cell Details T Cell Details
2-chain receptors
(combinatorial
diversity)
Each chain provides
half the receptors
CDRs
Heavys times lights Each chain provides
half the receptors
CDRs
Alphas times Betas
Recombination of
germ-line segments
(combinatorial
diversity) RAG-1
and RAG-2
H chains: 65 V, 27
D, 6 J = 10,500
combinations
L chains:
35 V, no D, 5 J = 175
10,500 times 175 =
about 2 million
antibodies
Beta chains:
50 V, 2 D, 13 J =
1,300 combos
alpha chains:
70 V, no D, 60 J =
4,200 combos
4,200 times 1,300 =
about 5.5 million T
cells
Optional diversity B cell can choose
kappa or lambda L
chains
Roughly doubles
number of
antibodies
There are also T
cells with
gamma/delta
receptors
Perhaps 5% of T
cells are
gamma/delta
N region diversity
(somatic)
Random nucleotides
added or subtracted
at VD and DJ joins
Estimated to
produce 100 times
more diversity than
the germ line
Random nucleotides
added or subtracted
at VD and DJ joins
Estimated to
produce 10,000
times more diversity
than the germ line
Somatic
hypermutation
After exposure to
antigen
Mutation rate is
about 1 in 10
4
cell
divisions
Does not occur
Total diversity
(including somatic
hypermutation
~10
14
antibodies possible; many fewer
actually found in blood
~10
11
TCR (T cell receptors) possible; about
10
8
found in blood
Antibody Function and Complement
Define:
Valence
Number of components of an antigen molecule to which an antibody molecule can bind. An
expression of the number of antigen-binding sites for one molecule of any given antibody or
the number of antibody-binding sites for any given antigen.
(15)
Affinity
Attraction between an antigen and an antibody.
Precipitation
Moplecules react with antibodies, become insoluble, and fall out of solution.
Agglutination
Cells react with antibodies, become insoluble, and fall out of solution.
Distinguish the five classes of immunoglobulins in terms of:
Passage across the placenta, ability to activate complement by
the classical pathway, ability to activate complementby the
alternative pathway, involvement in allergic diseases, First
line of defense, most resistant to enzymatic digestion
Class Passage
across the
placenta
Ability to
activate
complement by
the classical
pathway
Ability to
activate
complement by
the alternative
pathway
Involvement in
allergic
diseases
First line
of
defense
Most
resistant to
enzymatic
digestion
IgM No. Yes. No. No. Yes. No.
IgG Yes. Yes. No. No. No. No.
IgD No. No. No. No. No. No.
IgA No. No. Yes. No. Yes. Yes.
IgE No. No. No. Yes. No. No.

Compare and contrast precipitation and agglutination in terms
of the nature of the antigens involved, and sensitivity of the
tests.
Precipitation Agglutinations
Antigens Involved Molecules Cells
Sensitivity of the Tests Less readily detected/Less sensitive More readily detected/More sensitive
Discuss how complement plays roles in both innate and
adaptive immunity.
Complement has three different pathways: the classical, the alternative, and the lectin. The
classical is spurred by complexes of IgG or IgM antibodies with the antigen. It causes a 1-4-
2-3-5-6-7-8-9 C pathway, and it involved in adaptive immunity. The alternative is activated
by IgA-complexes and by cell wall structures, because the presence of certain cell wall
structures (dextrans, endotoxins) may also allow alternative to occur, so this would be innate
and adaptive. The lectin pathway is solely innate, because is is mediated by mannose-
binding protein, a lectin that attacks carbohydrates.
(16)
List the components of complement in the order in which they
become activated in the classical pathway. Name those that are
also activated in the alternative pathway.

Classical Pathway: C1, C4, C2, C3, C5, C6, C7, C8, C9
Alternative Pathway: C3, C5, C6, C7, C8, C9
Discuss the lectin-mediated pathway of complement activation.
The lectin-mediated pathway is mainly part of innate immunity. It is mediated by mannose-
binding protein, MBP or MBL, a lectin (proteins that bind to foreign carbohydrates. MBP
binds certain mannose-containing structures found in carbohydrates of bacteria but not
humans. MBP is functionally similar to C1q in the classical complement pathway.
Associating with MBP when it binds mannose are some serine proteases (MASPs) that
activate C2 and C4 and continue the cascade.
Discuss the different ways in which complement is activated
by: IgG; IgM; IgA; polysaccharides.
Antibody/Molecule Pathway Type of
Immunity
How Complement is Activated
IgG Classical Adaptive Two IgGs close together binds to Fc portions of
antibodies after interaction with antigen, causing
changes in Fc portions and allows binding and
activation of C1q.
IgM Classical Adaptive Single IgM binds to Fc portions of of antibodies
after interaction with antigen, causing changes in
Fc portions and allows binding and activation of
C1q.
IgA Alternative Innate or
Adaptive
Presence of IgA-antigen complexes or cell wall
structures of foreign microorganisms, such as
dextrans, levans, zymosan, or endotoxin.

4
IgA. This antibody is preferentially made by plasma cells in lymphoid tissues near mucous
membranes. It is assembled into a dimer by the !addition of the J chain while in the plasma cell,
and then secreted into the interstitial space. Adjacent epithelial cells have receptors for IgA
which binds to them, is taken up and moved through the epithelial cell to the luminal (mucous
membrane) side. There the IgA is exocytosed, still bound to the receptor, !which is now called
Secretory Component. Secretory Component protects the IgA from digestion in the gut, and
makes it work well as our first line of immunological defense against invading organisms. There
is some monomer and dimer IgA in the plasma, where it can bind pathogens and !activate
complement by the alternative pathway.
IgD. Although there is some IgD in the plasma, it is believed that the only important role for IgD
is as a B cell receptor. We will discuss its role in the activation of B cells soon.
IgE. !Because its Fc end adheres to mast cells and basophils, forming a trigger for these
histamine-loaded cells, this antibody is the cause of immediate hypersensitivity or allergy (see
Type I Immunopathology). Why does it exist? It is important for resistance to parasites, where it
triggers the mast cells to release eosinophil chemotactic factor. Eosinophils are uniquely
effective at killing parasites.

COMPLEMENT. Complement is the main inflammatory mediator of the humoral immune
system. A long time ago it was noted that fresh serum from a person who had survived a
bacterial infection would agglutinate and lyse the appropriate bacteria. Old stored antiserum
could cause agglutination, but the bacteria were not lysed. If fresh serum, even from a non-
immune donor, was then added, the agglutinated bacteria were rapidly lysed. Obviously, there
was something in fresh serum that complemented the antibodys action: thus, complement. It was
soon found that complement is, in fact, a large number of proteins, similar to the blood clotting
system in that each exists in an inactive form, and when the first is activated the rest follow in a
sort of cascade. There are at least three ways to activate the C cascade; the one that is most
familiar is the classical pathway. More recently, an alternative and a lectin pathway have been
described. Each pathway gets started differently !but all come together by C5:





















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Lectin pathway
MBL
MASP-1
MASP-2

(17)
Polysaccharides Lectin Innate Use of mannose-binding protein (MBP) to target
mannose-containing structures in carbohydrates
of bacteria, but not in humans.

Identify the complement components which are: opsonizing;
lytic; anaphylatoxic; and chemotactic.
Components C1 C2 C3 C4 C5 C6 C7 C8 C9
Opsonizing No No Yes
(C3b)
No No No No No No
Lytic No No No No Yes Yes Yes Yes Yes
Anaphlatoxic No No Yes
(C3a)
Yes
(C4a)
Yes
(C5a)
No No No No
Chemotactic No No No No Yes
(C5a)
No No No No
Ontogeny, T and B Cells
Define:
Stem Cell
Cells that can differentiate into specialized cell types and renew themselves to produce more
stem cells.
B Cell
Main cell involved in humoral immune response. The principal function of B cells is to make
antibodies, present as antigen-presenting cells, and develop into memory cells after
encountering antigens.
T Cell
Main cell in cell-mediated immunity.
Pre-B Cell
Precursor to development of B cells.
Pre-T Cell
Precursor to development ot T cells.
Self-tolerance
Process by which immune system does not attack self-antigens.
(18)
Describe the sequence of appearance of cytoplasmic and
surface immunoglobulins in developing B cells. Using these
data, derive a model that could explain self-tolerance at the B
cell level (clonal abortion).

Basically, the pro-B cell is basically a progenitor cell with only a mu chain. When
cytoplasmic IgM is produced, with kappa or lambda chains, a pre-B cell is developed. As
soon as a surface antibody emerges (sIgM), then it becomes an immature B cell. Finally a
mature B cell emerges when surface IgM and surface IgD emerges.
Draw a graph showing the antibody response to a typical
antigen in a primary and in a secondary response. Show both
IgM and IgG antibody levels.

Basically, IgM is typically the major player in primary antibody response. In secondary
response, IgG is the major actor in secondary antibody response, with the help of helper T
cells.
Draw a graph, which shows relative IgG and IgM levels in a
normal infant from conception to one year of age. Distinguish
maternal from infants antibodies.


2
called the Bursa of Fabricius. The bursa is located at the hind end of the gut, and many
immunologists tried to find a human bursa equivalent in Gut-Associated Lymphoid Tissues
(GALT); but it isnt there. !B cells in mammals develop in the Bone marrow.

!B cell progenitors can be identified as such when they begin to synthesize immunoglobulin
components. The first to be detectable is mu chain in the cytoplasm; then complete cytoplasmic
IgM (cIgM). This indicates that B cells rearrange their heavy chain genes before their light
chains. A cell with cytoplasmic IgM but no surface IgM is called a pre-B cell. Next there
appears surface IgM (sIgM), which is an IgM monomer with an extra membrane-embedded
extension at the end of its Fc. Finally, when the cell is fully mature, both IgM and IgD (of the
same specificity, of course) are found on the cell surface. All of this results from alternative
splicing of the VDJ-mu-delta primary RNA transcripts, which you might like to review now.
Functionally important point: an immature B cell has sIgM only, and a mature B cell has sIgM
and sIgD:



CLONAL ABORTION. When a mature B cell is exposed to its correct antigen it moves its
receptors (IgD and IgM) to one spot on the surface (caps them) and then takes them inside by
endocytosis. The antigen is partially digested (processed), and if other conditions (that well
learn about later) are right, the cell will go on to differentiate into an antibody secretor. !If an
immature B cell (sIgM but no sIgD) is similarly exposed to antigen, this signal causes the cell to
try receptor editing; if that fails it activates a suicide program (apoptosis), and dies. This deletion
mechanism is called clonal abortion, and it partially explains why we do not make antibody to
self: in the bone marrow pre-B cells are differentiating into immature B cells; you can imagine
that any cell whose receptors happen to be anti-self will almost surely encounter self in the
environment of the bone marrow, and either make a new receptor, or be aborted. If it does not
encounter antigen (because its receptors are not against self) then it will mature further so that it
expresses both sIgM and sIgD. Then, when it meets antigen, it will be stimulated, not aborted.
Please note, though, that many anti-self B cells (usually to scarce antigens, not seen in the
marrow; or with low affinity to more common antigens) escape clonal abortion and other
measures are necessary to keep them inactivated; well consider some of these when we discuss
T cells, and autoimmunity.

!During primary (initial exposure) B cell responses to antigen, IgM is secreted first, then for
most antigens, helper T cells get involved and there is a switch to IgG, or possibly to IgA or IgE.
The helper T cells in the gut and lung preferentially drive the M to A switch. The switch helper
mechanism indicates that B cells in general do what T cells tell them to. As well see later, an
inappropriate antibody response may often be the T cells fault.

3
!In response to secondary (booster) immunizations the IgM response is about the same as in a
primary, but the IgG response, efficiently helped by T cells, is sooner, faster, higher
1
and more
prolonged:


ASK YOURSELF: What would you expect to see if your patient had no functional T
cells?

ONTOGENY OF ANTIBODY RESPONSES. !The fetus makes IgM before birth, but only
acquires the capacity to make IgG about 3-6 months postnatally. However, at birth the baby has
as much IgG in its blood as does an adult; this IgG is maternal, because IgG crosses the placenta,
by active transport, from mother to fetus (no other class of immunoglobulin does). The half life
of IgG is about 3 weeks, so in 7 half lives = 21 weeks after birth there is less than 1% of the
starting amount of maternal IgG left; fortunately, the infant should be making reasonable
amounts of its own IgG from about 12 weeks. IgA also starts about 2-3 months.



















ASK YOURSELF: A baby is born and fails to thrive. At three weeks its serum level of
antibody to cytomegalovirus is high. Did it have an intrauterine infection with CMV? Do
you have enough information to decide?


1
This led to the Olympic motto: citius-altius-fortius; quicker, higher, stronger.


3
!In response to secondary (booster) immunizations the IgM response is about the same as in a
primary, but the IgG response, efficiently helped by T cells, is sooner, faster, higher
1
and more
prolonged:


ASK YOURSELF: What would you expect to see if your patient had no functional T
cells?

ONTOGENY OF ANTIBODY RESPONSES. !The fetus makes IgM before birth, but only
acquires the capacity to make IgG about 3-6 months postnatally. However, at birth the baby has
as much IgG in its blood as does an adult; this IgG is maternal, because IgG crosses the placenta,
by active transport, from mother to fetus (no other class of immunoglobulin does). The half life
of IgG is about 3 weeks, so in 7 half lives = 21 weeks after birth there is less than 1% of the
starting amount of maternal IgG left; fortunately, the infant should be making reasonable
amounts of its own IgG from about 12 weeks. IgA also starts about 2-3 months.



















ASK YOURSELF: A baby is born and fails to thrive. At three weeks its serum level of
antibody to cytomegalovirus is high. Did it have an intrauterine infection with CMV? Do
you have enough information to decide?


1
This led to the Olympic motto: citius-altius-fortius; quicker, higher, stronger.

(19)
Mothers IgG is the primary antibody for the fetus, as it is able to pass through the human
placenta.
Given a newborns antibody titer, interpret its significance if
the antibody is IgG, or IgM. If IgG, calculate what the titer will
be at 4 months of age, and state the assumptions you made
when you did the calculation.

The significance of whether the antibody is IgG or IgM is the rate of production of each
antibody. Infant IgG is not produced until 3 months after birth. However, IgM is produced
since approximately 3 months post-conception. Maternal IgG allows the fetuss immune
system to be maintained.
T Cells 1 and 2
List the four main types of T cells, and define their functions.
Type of T Cell Surface
Marker
Helper or
Killer
Functions
Th1 (delayed
hypersensitivity)
CD4 Helper - Secretion of lymphokines (interferon gamma/INF-gamma) when
encountering an antigen.
- IFN-gamma is pro-inflammatory, being chemotactic for blood
monocytes and tissue macrophages, and causes stimulation of
phagocytes.
Th17 CD4 Helper - Makes inflammatory lymphokine IL-17.
- Resembles Th1 in that its main job seems to be causing
inflammation.
Th2 CD4 Helper
Tfh (follicular
helper)
CD4 Helper
Treg CD4 Helper
CTL CD8 Killer

Describe the surface markers that can be used to distinguish
between T and B cells in humans.
Cell Type Surface Markers
B sIgD, sIgM
T CD3, CD4, CD8

3
!In response to secondary (booster) immunizations the IgM response is about the same as in a
primary, but the IgG response, efficiently helped by T cells, is sooner, faster, higher
1
and more
prolonged:


ASK YOURSELF: What would you expect to see if your patient had no functional T
cells?

ONTOGENY OF ANTIBODY RESPONSES. !The fetus makes IgM before birth, but only
acquires the capacity to make IgG about 3-6 months postnatally. However, at birth the baby has
as much IgG in its blood as does an adult; this IgG is maternal, because IgG crosses the placenta,
by active transport, from mother to fetus (no other class of immunoglobulin does). The half life
of IgG is about 3 weeks, so in 7 half lives = 21 weeks after birth there is less than 1% of the
starting amount of maternal IgG left; fortunately, the infant should be making reasonable
amounts of its own IgG from about 12 weeks. IgA also starts about 2-3 months.



















ASK YOURSELF: A baby is born and fails to thrive. At three weeks its serum level of
antibody to cytomegalovirus is high. Did it have an intrauterine infection with CMV? Do
you have enough information to decide?


1
This led to the Olympic motto: citius-altius-fortius; quicker, higher, stronger.

(20)
Describe markers that Th1, Th2, and killer T cell (CTL)
subpopulations in humans have on their surfaces.
T Cell Markers
Th1 CD3, CD4
Th2 CD3, CD4
CTL CD3, CD8
Define lymphokine and cytokine, and give an example of each.
Name Definition Example
Cytokines Short-range mediators made by any cell, that affect the behavior of
the same or another cell
IL-1, TNF-alpha, IL-12
Lymphokines Short-range mediators made by lymphocytes, that affect the behavior
of the same or another cell. A subset of cytokines.
IL-2, IFN-gamma, IL-4,
IL-5, IL-109
Chemokines Small (6-14 kD) short-range mediators made by any cell, that
primarily cause inflammation.
MIP-1 to MIP-4,
RANTES, CCL28,
CXCL16, Eotaxin, IL-8

Describe an activity of interferon-gamma.
Interferon-gamma is a lymphokine that is the main activator for monocytes and
macrophages. What it does is activate the macrophages to M1, where it becomes involved in
aggressively ingesting bacteria and foreign pathogens, causing also releasing of
macrophages cytokines to intensify inflammation.
Define mitogen, and name two T cell mitogens. Name a mitogen
that stimulates both B and T cells in humans.
Mitogen is a T cell mitosis stimulant. Basically, it promotes cell division of T cells. Two
examples of mitogens are phytohemagglutinin (PHA) and concanavalin A (Con A). A
mitogen that stimulates both B and T cells in humans is known as pokeweed mitogen
(PWM).
Distinguish between the effects of a mitogen and an antigen
when added to normal blood lymphocytes.
Protein Effect
Mitogen Triggers cell division in lymphocytes
Antigen Triggers production of antibodies.

Compare and contrast the antigen receptors of T and B cells.



Cells Antigen Receptors
T - Structurally reminiscent of antibody two chains are called alpha and beta and has a common
ANTIGEN PRESENTATION TO T CELLS. When an antigen enters the body! lets
use a virus as an example! it will infect locally, cause an innate response, and
eventually it or its
breakdown products will
get ingested by a
dendritic cell. Within the
endosome viral proteins
are broken down to
peptides. The endosome
fuses with other vesicles
which have MHC
molecules embedded in
their membrane, facing
in. Some of the peptides
associate with the MHC molecules. The endosome recycles to the cells surface and fuses
to the plasma membrane, thus exposing MHC molecules bearing antigenic peptides to the
outside world. !We call cells that do this antigen-presenting cells, APC. Dendritic
cells are the best at this. Its this MHC-antigen complex that is presented to, and
recognized by, the receptor of an appropriate T cell.


When the first MHC (Class II, see below) was
crystallized its two chains (", #) were seen to be
folded so that a sort of cleft appeared in the end
that would be facing towards a T cell. The clefts
base is a beta sheet and its sides are two alpha
helices. In this was a small peptide; the MHC
molecule had been crystallized in the act of
presenting a fragment of an antigen. The picture
shows a T cells-eye view of the complex.
!Because T cells see antigen only when it is complexed with cell-surface MHC
molecules, T cells focus their attention on cell surfaces, and do not interact with free
antigen; that is a job for the B cell and its antibodies.
T CELL RECEPTOR. The T cell receptor for antigen (TCR) is structurally reminiscent
of antibody, and sequence data indicate a common ancestral gene long ago. !The two
chains are called alpha and beta (dont confuse these with the " and # of Class II MHC),
and each has a common and a variable portion. The T cell makes its receptor out of V,
(D) and J regions recombined as in B cells, and like antibody, !each chain has 3 CDRs
2
;
the process takes place in the thymus. Both alpha and beta chains have transmembrane
domains, unlike surface Ig, in which only the heavy chains are transmembrane:








2
Complementarity-determining regions.
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(21)
and variable portion.
- T cell makes its receptor out of V (D) and J regions recombined as in B cells and like antibody.
- Each chain has 3 CDRs2; the process takes place in the thymus.
- Both alpha and beta chains have transmembrane domains, unlike surface Ig, in which only the
heavy chains are transmembrane.
B - Consist of a ligand binding moiety and a signal transduction moiety.
- T Cell Receptor may have an evolved ancestor with B cell receptors, as structure is similar.
Discuss the structures recognized by T cell receptors.
Distinguish between what is recognized by helper and
cytotoxic T cells.

T cell receptors typically recognize major histocompatibility complexes (MHC I or II).

Major Histocompatibility
Complex
Recognizing Cells
I + Antigen CTL
II + Antigen Th1, Th17, Tfh, Treg, Th2
Discuss what is meant by MHC-restriction. Name the classes
of MHC molecules by which CTL, Th1 and Th2 are restricted.
MHC restriction involves not seeing antigen alone, but only antigen presented to them on the
surface of a genetically-identical cell. The T cell and the antigen-presenting cell must come
from individals who share alleles at a group of genetic loci coding for surface glycoprotein
molecles.

Major Histocompatibility
Complex
Recognizing Cells
I CTL
II Th1, Th17, Tfh, Treg, Th2

Class I products are on all nucleated cells, while Class II are presented on the surfaces of
dendritic and macrophage-type cells.
Intimately associated with the TCR is a
complex of molecules called CD3; it has at
least 5 chains. It serves to transduce TCR
signals for the T cell. This means that when a
T cell binds the correct antigen + MHC with
its TCR, the actual signal that turns the T cell
on is transmitted by CD3. Why things have to
be so complicated is not known (to
immunologists). When a Th1 binds to a good
APC like a dendritic cell, the APC will give
the T cell an activating boost by secreting IL-
12 and other cytokines. The T cell thus gets
multiple hits!one via its TCR/CD3
complex, and one from dendritic cell
cytokines. In addition, the T cell gets a whole
range of activating signals from interactions between molecules on its surface and
corresponding molecules on the APC (examine, but dont memorize, this figure). !If it
doesnt get all the right signals, it may be turned off instead of on. Biochemical events
follow that are typical of cells being stimulated: a rise in intracellular calcium, breakdown
of membrane phospholipids, activation of protein kinases which in turn activate
transcription factors. IL-2 receptors are upregulated. The cell goes into cycle
(proliferation) and begins to secrete lymphokines (differentiation).

MHC RESTRICTION, PART 2. The major histocompatibility complex is a large group
of genes whose products have related functions. Well make it more comprehensible
later. At this point, though, wed like to formally introduce two kinds of MHC molecules:
Class I and Class II. Class I products are on all nucleated cells. Class II products are
expressed on the surfaces of dendritic and macrophage-type cells, B cells, and just a few
other cell types, all of which are involved in some way in presenting antigenic peptides to
Th cells.

When antigen is endocytosed and presented by a dendritic cell (DC) it associates
primarily with Class II MHC molecules in the endocytic vesicle, and these complexes are
what the DC presents to the T cell. Th1, Th17, Tfh, Treg, and Th2 are programmed to
recognize peptides on Class II molecules.
Class I MHC molecules associate best with peptides that are sampled from proteins
synthesized within the cell itself, not taken up by endocytosis. Most peptides would be
from normal self proteins, but antigens would include abnormal (mutated) molecules
and especially internal pathogens such as virus-encoded molecules. CTL are
programmed to see antigen in association with MHC Class I molecules.
!Its important to know that helpers see antigen + Class II, while CTL see antigen +
Class I. And its easier to remember if you consider this: CTL are necessary for getting
rid of virus by killing virus-infected cells; they must be able to see any infected cell, so
they are naturally restricted by the ubiquitous Class I molecules. Helpers have to work
together to get the immune response going, and to attract and activate macrophages to eat
a foreign invader; its natural that they would see antigen presented to them on Class II,
which is predominantly on the sorts of cells that would initially trap, process, and present
something foreign.


(22)
Describe the role of T cells in ridding the body of a viral
infection.

1. Antigen enters body, causing innate response, and dendritic cell ingests breakdown
products.
2. Within the endosome, viral proteins are broken down by products.
3. Endosome fuses with other vesicles which have MHC molecules embedded in their
membrane, facing in. Some of the peptides associate with the MHC molecules.
4. Endosome recycles to the cells surface and fuses to the plasma membrane, thus
exposing MHC molecules bearing antigenic peptides to the outside world.
CREATION OF ANTIGEN-PRESENTING CELLS.
5. T cells receptors recognize APCs and induce immune response, because T cells only
see antigen when complexed with surface MHC molecules, because it also does not
recognize free antigen.

Describe the characteristics of T-independent antigens.
Major
Characteristic
Description
Composition Molecules with the same, repeated epitope. Found commonly in complex carboydrates.
Response Almost all IgM, need T cell help to convert to IgG, IgA, or IgE.
Discuss the mechanism by which T cells help B cells.
Observations
1. T cell and B cell must come from donors with the same MHC Class II.
2. T ell and B cell need not be specific for the same epitope, but the epitopes they are
specific for must both be on the same antigen molecule.
3. If you poison the B cells ability to endocytose it cannot be helped by a T cell or make
antibody.
Process

ANTIGEN PRESENTATION TO T CELLS. When an antigen enters the body! lets
use a virus as an example! it will infect locally, cause an innate response, and
eventually it or its
breakdown products will
get ingested by a
dendritic cell. Within the
endosome viral proteins
are broken down to
peptides. The endosome
fuses with other vesicles
which have MHC
molecules embedded in
their membrane, facing
in. Some of the peptides
associate with the MHC molecules. The endosome recycles to the cells surface and fuses
to the plasma membrane, thus exposing MHC molecules bearing antigenic peptides to the
outside world. !We call cells that do this antigen-presenting cells, APC. Dendritic
cells are the best at this. Its this MHC-antigen complex that is presented to, and
recognized by, the receptor of an appropriate T cell.


When the first MHC (Class II, see below) was
crystallized its two chains (", #) were seen to be
folded so that a sort of cleft appeared in the end
that would be facing towards a T cell. The clefts
base is a beta sheet and its sides are two alpha
helices. In this was a small peptide; the MHC
molecule had been crystallized in the act of
presenting a fragment of an antigen. The picture
shows a T cells-eye view of the complex.
!Because T cells see antigen only when it is complexed with cell-surface MHC
molecules, T cells focus their attention on cell surfaces, and do not interact with free
antigen; that is a job for the B cell and its antibodies.
T CELL RECEPTOR. The T cell receptor for antigen (TCR) is structurally reminiscent
of antibody, and sequence data indicate a common ancestral gene long ago. !The two
chains are called alpha and beta (dont confuse these with the " and # of Class II MHC),
and each has a common and a variable portion. The T cell makes its receptor out of V,
(D) and J regions recombined as in B cells, and like antibody, !each chain has 3 CDRs
2
;
the process takes place in the thymus. Both alpha and beta chains have transmembrane
domains, unlike surface Ig, in which only the heavy chains are transmembrane:








2
Complementarity-determining regions.
!"#
$%#&''
()#%#'*++%,,
*-./0&-


Antigen enters body,
causing innate
response, and
dendritic cell ingests
breakdown products.
Within the
endosome, viral
proteins are broken
down by products.
Endosome fuses
with other vesicles
which have MHC
molecules embedded
in their membrane,
facing in. Some of
the peptides
associate with the
MHC molecules.
Endosome recycles
to the cells surface
and fuses to the
plasma membrane,
thus exposing MHC
molecules bearing
antigenic peptides to
the outside world.
CREATION OF
ANTIGEN-
PRESENTING
CELLS.
T cells receptors
recognize APCs and
induce immune
response, because T
cells only see
antigen when
complexed with
surface MHC
molecules, because
it also does not
recognize free
antigen.
(23)


1. B Cell binds the epitope on a foreign molecule that its receptor is specific for.
2. IT then endocytoses the bound molecule, and breaks it down in the endocytic vesicle.
3. Peptide fragments bind to MHC Class II molecules brought in by other vesicles that
fuse with the endosome, and then move to the surface.
4. Tfh sees epitope + Class II on the B cells surface.
5. Tfh binds to epitope and class II and focuses surface interactions and helper
lymphokines on the B cell.
a. Epitope does not have to be the same as the one the B cell saw.



Immunity and Vaccines
Compare the roles of cell-mediated and humoral immunity in
virus infections with regard to: preventing the infection;
controlling spread of viruses in the body; which is responsible
for recovery from disease; how each can cause
immunopathology.
Type of Immunity Cell-Mediated Humoral
Preventing the Infection X
Controlling the Spread of
Virus in the body
X
Which is responsible for
recovery from disease
X
How each can cause
immunopathology
Viruses which never appear in the blood or
lymph, or go latent and express few proteins
are very hard to deal with.
Lack of antibodies caiuses viruses to
infect cells or kill them.

Inferences on the immune system:
1. Local immunity on the surface that is being invaded can prevent the invesion
secretory IgA. good levels of antibody indicates that patient is probably not
susceptible that virus.
Heres a wonderful thing: The dendritic cell, which gets everything going, is special in that
it allows peptides from antigens its eaten to leak over into its intrinsic pathway, so that it
can present them on Class I as well as Class II MHC at the same time. Thus it can bring
samples in from the periphery and arrange not just for a Th1 and Th2 response, but also for
CTL. !This is called cross-presentation. Antigen presentation is summarized in diagrams
on the last page of these T cell notes.

ACCESSORY MOLECULES IN T CELL ACTIVATION. CD4 is on Th1, Th17,
Treg, Tfh, and Th2. It binds to MHC Class II; not to the peptide-binding cleft, but to the
unvarying base which is the same in everybody. Thus when a Th is seeing antigen +
Class II (as it should), the CD4 will help by increasing the strength of the bond.
Similarly, CD8 binds to the base of Class I, increasing the binding affinity of CTL to
antigen + Class I. Without prior TCR binding, the CD molecules binding to MHC cant
activate the cells!that would lead to chaos. They just increase the affinity of cell binding
that got started by specific recognition. There is evidence that CD4 and CD8 also
transduce some activating signals.

T CELLS HELPING B CELLS. For protein antigens a vigorous class-switched
antibody response requires help from T cells, as we have mentioned previously. How
does a Tfh cell help a B cell get activated and make antibody? Three experimental
observations gave us the clues: First, the T cell and the B cell must come from donors
with the same MHC Class II. Second: The T cell and the B cell need not be specific for
the same epitope, but the epitopes they are specific for must both be on the same antigen
molecule. Third: If you poison the B cells ability to endocytose it cannot be helped by a
T cell or make antibody.
! ASK YOURSELF: It might be interesting for you to stop here, consider what
you already know and what youve just read, and see whether you can put this
together into a model before reading on.

Welcome back. !Heres what happens: The B cell binds the epitope on a foreign
molecule that its receptor is specific for. It then endocytoses the bound molecule, and
breaks it down in the endocytic vesicle. Peptide fragments bind to MHC Class II
molecules brought in by other vesicles that fuse with the endosome, and then move to the
surface; the B cell now displays antigen + Class II. (Sound familiar?) Eventually, along
comes the correct Tfh and sees its epitope + Class II on the B cells surface. It binds and
focuses surface interactions and helper lymphokines on the B cell. Note that the epitope
that the T cell sees does not have to be the same as the one the B cell saw, and it hardly
ever is.










Y
Th2
B cell
MHC class II
antigen
Y
Th2
B cell
MHC class II
Y
Th2
B cell
MHC class II
antigen

Tfh
BCellDisplayofAntigen+Class
II
BindingofTfHtoBCell
(24)
Discuss the possible roles of Th1 and CTL in recovery from
virus infection.
Cell Roles
Th1 - Presented by the dendritic cell on MHC II by.
CTL - Presented by dendritic cell on MHC I.
Define local immunity and give an example.
Local immunity is innate or acquired immunity limited to a certain organ or tissue.
Examples include the Peyers patches in the small intestine, the appendix in the large
intestine or the tonsils.
Identify those organisms against which cell-mediated immunity
is most effective.
Cell-mediated immunity is most effective against:
- Bacteria
- Intracellular bacteria
- Viruses (recovery from viruses)
Identifythoseorganismsagainstwhichhumoralimmunityismosteffective.
- Parasites (IgE)
- Prevention of viruses
Identify the types of organisms against which IgE immunity
may play an important role; discuss possible mechanisms.
- Parasites
Mechanisms:
- Worms produce a weak innate response, but there may be an uncharacterized
pattern recognition receptor that responds to their parasite-ness and strong
stimulates a Th2/Tfh response.
- Production of IgG and IgE
o IgG binds, activated complement, and C3a and C5a attract neutrophils.
o Neutrophils seize opsonized worm. Neutrophils lack helminthocidal
mechanism.
o Worm sheds antigens that diffuse to nearby mast cells loaded with anti-
helminth IgE.
o IgE is cross-linked by the antigens and the mast cells degranulate.
o Histamine causes gut smooth muscle contraction and violent peristalsis can
help expel worms.
o Late-Phase response prostaglandins and leukotrienes are elaborated
ECF-A they attract eosinophils in large numbers.
Eosinophils have Fc receptors for IgG eosinophils releases Major
Basic Protein toxic to helminthes.
Describe the mechanism by which trypanosomes in sleeping
sickness evade the hosts humoral immune response.
Trypanosomes evade humoral response by extensive antigenic variation of parasite surface
glycoproteins known as major variant surface glycoprotein, contributing to its virulence.
(25)
Give an example of a human and an animal antitoxin; a toxoid;
a killed virus vaccine; and a live virus vaccine. Identify the one
which produces the longest-lasting immunity. Discuss possible
hazards of each type of preparation.
Type of Vaccine Definition Examples Produces longest-
lasting immunty
Hazards of each preparation
Human Antitoxin Use of human serum Tetanus
Immune
Globulin
Not enough to distribute for high
demand.
Animal Antitoxin Use of animal serum Horse
antitoxin
Readily causes serum sickness.
Toxoid Inactivated toxin Tetanus
toxoid
X The dirtier the vaccine, the more
likely unpleasant side effects
occur.

Evolved infectious agents can
evade immune response to toxoid.
Killed Virus Vaccine Preparations by
which killed agents
(whole) are
introduced.
Former
pertussis
and
typhoid
vaccines
Live preparations provide better
immunity than do killed
preparations.

The dirtier the vaccine the more
likely unpleasant side effects
occur.
Live Virus Vaccine Preparation by
which live agents
(attenuated to
removed disease but
still be antigenic)
are introduced
Smallpox
vaccine
Possiblility of infection and death
from the vaccine (administration
of the organism)
State the appropriate times for immunization of children
against diphtheria, pertussis (whooping cough), tetanus, polio,
and measles. Discuss why live viral vaccines tend to be
ineffective in the very young.
Age0-6

This schedule includes recommendations in eect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and
feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Considerations should include provider assessment, patient preference,
and the potential for adverse events. Providers should consult the relevant Advisory Committee on Immunization Practices statement for detailed recommendations: http://www.cdc.gov/vaccines/
pubs/acip-list.htm. Clinically signicant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at http://www.vaers.hhs.gov or by
telephone, 800-822-7967.
1. Hepatitis B vaccine (HepB). (Minimum age: birth)
At birth:
Administer monovalent HepB to all newborns before hospital discharge.
f mother is hepatitis B surface antigen (HBsAg)-positive, administer HepB
and 0.5 mL of hepatitis B immune globulin (HBG) within 12 hours of birth.
f mother's HBsAg status is unknown, administer HepB within 12 hours
of birth. Determine mother's HBsAg status as soon as possible and, if
HBsAg-positive, administer HBG (no later than age 1 week).
Doses following the birth dose:
The second dose should be administered at age 1 or 2 months. Monovalent
HepB should be used for doses administered before age 6 weeks.
nfants born to HBsAg-positive mothers should be tested for HBsAg and anti-
body to HBsAg 1 to 2 months after completion of at least 3 doses of the HepB
series, at age 9 through 18 months (generally at the next well-child visit).
Administration of 4 doses of HepB to infants is permissible when a combina-
tion vaccine containing HepB is administered after the birth dose.
nfants who did not receive a birth dose should receive 3 doses of HepB on
a schedule of 0, 1, and 6 months.
The fnal (3rd or 4th) dose in the HepB series should be administered no
earlier than age 24 weeks.
2. Rotavirus vaccine (RV). (Minimum age: 6 weeks)
Administer the frst dose at age 6 through 14 weeks (maximum age: 14
weeks 6 days). Vaccination should not be initiated for infants aged 15 weeks
0 days or older.
The maximum age for the fnal dose in the series is 8 months 0 days
f Rotarix is administered at ages 2 and 4 months, a dose at 6 months is
not indicated.
3. Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP).
(Minimum age: 6 weeks)
The fourth dose may be administered as early as age 12 months, provided
at least 6 months have elapsed since the third dose.
4. Haemophilus inuenzae type b conjugate vaccine (Hib). (Minimum age:
6 weeks)
f PRP-OMP (PedvaxHB or Comvax [HepB-Hib]) is administered at ages 2
and 4 months, a dose at age 6 months is not indicated.
Hiberix should not be used for doses at ages 2, 4, or 6 months for the pri-
mary series but can be used as the fnal dose in children aged 12 months
through 4 years.
5. Pneumococcal vaccine. (Minimum age: 6 weeks for pneumococcal conju-
gate vaccine [PCV]; 2 years for pneumococcal polysaccharide vaccine [PPSV])
PCV is recommended for all children aged younger than 5 years. Administer
1 dose of PCV to all healthy children aged 24 through 59 months who are
not completely vaccinated for their age.
A PCV series begun with 7-valent PCV (PCV7) should be completed with
13-valent PCV (PCV13).
A single supplemental dose of PCV13 is recommended for all children aged
14 through 59 months who have received an age-appropriate series of PCV7.
A single supplemental dose of PCV13 is recommended for all children aged
60 through 71 months with underlying medical conditions who have received
an age-appropriate series of PCV7.
The supplemental dose of PCV13 should be administered at least 8 weeks
after the previous dose of PCV7. See MMWR 2010:59(No. RR-11).
Administer PPSV at least 8 weeks after last dose of PCV to children aged
2 years or older with certain underlying medical conditions, including a
cochlear implant.
6. Inactivated poliovirus vaccine (IPV). (Minimum age: 6 weeks)
f 4 or more doses are administered prior to age 4 years an additional dose
should be administered at age 4 through 6 years.
The fnal dose in the series should be administered on or after the fourth
birthday and at least 6 months following the previous dose.
7. Inuenza vaccine (seasonal). (Minimum age: 6 months for trivalent inactivat-
ed infuenza vaccine [TV]; 2 years for live, attenuated infuenza vaccine [LAV])
For healthy children aged 2 years and older (i.e., those who do not have
underlying medical conditions that predispose them to infuenza complica-
tions), either LAV or TV may be used, except LAV should not be given to
children aged 2 through 4 years who have had wheezing in the past 12 months.
Administer 2 doses (separated by at least 4 weeks) to children aged 6 months
through 8 years who are receiving seasonal infuenza vaccine for the frst time
or who were vaccinated for the frst time during the previous infuenza season
but only received 1 dose.
Children aged 6 months through 8 years who received no doses of monovalent
2009 H1N1 vaccine should receive 2 doses of 2010-2011 seasonal infuenza
vaccine. See MMWR 2010;59(No. RR-8):33-34.
8. Measles, mumps, and rubella vaccine (MMR). (Minimum age: 12 months)
The second dose may be administered before age 4 years, provided at least
4 weeks have elapsed since the frst dose.
9. Varicella vaccine. (Minimum age: 12 months)
The second dose may be administered before age 4 years, provided at least
3 months have elapsed since the frst dose.
For children aged 12 months through 12 years the recommended minimum
interval between doses is 3 months. However, if the second dose was
administered at least 4 weeks after the frst dose, it can be accepted as valid.
10. Hepatitis A vaccine (HepA). (Minimum age: 12 months)
Administer 2 doses at least 6 months apart.
HepA is recommended for children aged older than 23 months who live in
areas where vaccination programs target older children, who are at increased
risk for infection, or for whom immunity against hepatitis A is desired.
11. Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age:
2 years)
Administer 2 doses of MCV4 at least 8 weeks apart to children aged 2 through
10 years with persistent complement component defciency and anatomic
or functional asplenia, and 1 dose every 5 years thereafter.
Persons with human immunodefciency virus (HV) infection who are vac-
cinated with MCV4 should receive 2 doses at least 8 weeks apart.
Administer 1 dose of MCV4 to children aged 2 through 10 years who travel
to countries with highly endemic or epidemic disease and during outbreaks
caused by a vaccine serogroup.
Administer MCV4 to children at continued risk for meningococcal disease
who were previously vaccinated with MCV4 or meningococcal polysac-
charide vaccine after 3 years if the frst dose was administered at age 2
through 6 years.
Range of
recommended
ages for certain
high-risk groups
Range of
recommended
ages for all
children
Vaccine ! Age "
Birth
1
month
2
months
4
months
6
months
12
months
15
months
18
months
1923
months
23
years
46
years
Hepatitis B
1
HepB
Rotavirus
2
RV RV RV
2
Diphtheria, Tetanus, Pertussis
3
DTaP DTaP DTaP
see
footnote
3
Haemophilus inuenzae type b
4
Hib Hib Hib
4
Pneumococcal
5
PCV PCV PCV
nactivated Poliovirus
6
IPV IPV
nfuenza
7
Measles, Mumps, Rubella
8
see footnote
8
Varicella
9
see footnote
9
Hepatitis A
10
Meningococcal
11
HepB HepB
DTaP DTaP
Hib
IPV IPV
MMR
Varicella Varicella
MMR
PCV
HepA Series
MCV4
Inuenza (Yearly)
PPSV
HepA (2 doses)
Recommended Immunization Schedule for Persons Aged 0 Through 6 Years~United States 2011
For those who fall behind or start late, see the catch-up schedule
The Recommended mmunization Schedules for Persons Aged 0 Through 18 Years are approved by the Advisory Committee on mmunization Practices
(http://www.cdc.gov/vaccines/recs/acip), the American Academy of Pediatrics (http://www.aap.org), and the American Academy of Family Physicians (http://www.aafp.org).
Department of Health and Human Services Centers for Disease Control and Prevention
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Age7-18

Whylivevaccinestendtobeveryineffectiveintheveryyoung
Children in their first year or two of life are poor at T-independent antibody responses, thus
conjugate vaccines are used (because the carbohydrate is coupled to a protein carrier so Tfh
cells could respond and focus help on the B cells).
Discuss the use of IgG and IgM antibody titers in the diagnosis
of intrauterine and neonatal infections.
Titers are the reciprocal of the maximal dilution of a patients serum that is still positive in
some defined test. This is important because intrauterine and neonatal infections can cause
fetal abnormalities, and cause congenital malformations. Infection in utero causes
production of IgM in response to the disease, and its determination will allow indication of
congenital infection.
Identify the oral and parenteral polio vaccines by the names of
their developers. Discuss their relative advantages and
disadvantages, and note which is currently used in the USA.
Type of
Vaccine
Definition Developers Advantages Disadvantages
Oral Administration
through
mouth.

Sabin
Long-lasting immunity,
prevention of reinfection of the
digestive tract, and lower cost.
More stable and less likely to
freeze.
Cannot be used for
patients with
compromised immune
systems because it still
live.
Parenteral Administration
through vein,
artery, bone, or
muscle)
Salk Immunity for
immunocompromised
individuals and can use dead
agents for vaccination.
Expensive, less table,
and more likely to
freeze.

Discuss the pros and cons and advances in pertussis (whooping
cough) immunization.
In 1940, before the production of the vaccine, there were 250,000 cases with 7,000 deaths,
and there is no protection in herd immunity. When it first came out, it did prevent pertussis,
but it caused febrile states and brain damage in 1 per 310,000 doses. Now, it has been
replaced with acellular vaccines, which is ten times safer. However, one must take into
account that the bacteria can also evolve, and such evolution may reduce the effectiveness of
the vaccine.
The Recommended Immunization Schedules for Persons Aged 0 Through 18 Years are approved by the Advisory Committee on Immunization Practices (http://www.
cdc.gov/vaccines/recs/acip), the American Academy of Pediatrics (http://www.aap.org), and the American Academy of Family Physicians (http://www.aafp.org).
Department of Health and Human Services Centers for Disease Control and Prevention
This schedule includes recommendations in effect as of December 21, 2010. Any dose not administered at the recommended age should be administered at a
subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines.
Considerations should include provider assessment, patient preference, and the potential for adverse events. Providers should consult the relevant Advisory Committee
on Immunization Practices statement for detailed recommendations: http://www.cdc.gov/vaccines/pubs/acip-list.htm. Clinically signicant adverse events that follow
immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS) at http://www.vaers.hhs.gov or by telephone, 800-822-7967.
1. Tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap).
(Minimum age: 10 years for Boostrix and 11 years for Adacel))
Persons aged 11 through 18 years who have not received Tdap should receive
a dose followed by Td booster doses every 10 years thereafter.
Persons aged 7 through 10 years who are not fully immunized against
pertussis (including those never vaccinated or with unknown pertussis vac-
cination status) should receive a single dose of Tdap. Refer to the catch-up
schedule if additional doses of tetanus and diphtheria toxoidcontaining
vaccine are needed.
Tdap can be administered regardless of the interval since the last tetanus
and diphtheria toxoidcontaining vaccine.
2. Human papillomavirus vaccine (HPV). (Minimum age: 9 years)
Quadrivalent HPV vaccine (HPV4) or bivalent HPV vaccine (HPV2) is recom-
mended for the prevention of cervical precancers and cancers in females.
HPV4 is recommended for prevention of cervical precancers, cancers, and
genital warts in females.
HPV4 may be administered in a 3-dose series to males aged 9 through 18
years to reduce their likelihood of genital warts.
Administer the second dose 1 to 2 months after the rst dose and the third
dose 6 months after the rst dose (at least 24 weeks after the rst dose).
3. Meningococcal conjugate vaccine, quadrivalent (MCV4). (Minimum age:
2 years)
Administer MCV4 at age 11 through 12 years with a booster dose at age 16 years.
Administer 1 dose at age 13 through 18 years if not previously vaccinated.
Persons who received their rst dose at age 13 through 15 years should receive
a booster dose at age 16 through 18 years.
Administer 1 dose to previously unvaccinated college freshmen living in a
dormitory.
Administer 2 doses at least 8 weeks apart to children aged 2 through 10 years
with persistent complement component deciency and anatomic or functional
asplenia, and 1 dose every 5 years thereafter.
Persons with HIV infection who are vaccinated with MCV4 should receive 2
doses at least 8 weeks apart.
Administer 1 dose of MCV4 to children aged 2 through 10 years who travel to
countries with highly endemic or epidemic disease and during outbreaks caused
by a vaccine serogroup.
Administer MCV4 to children at continued risk for meningococcal disease who
were previously vaccinated with MCV4 or meningococcal polysaccharide vac-
cine after 3 years (if rst dose administered at age 2 through 6 years) or after 5
years (if rst dose administered at age 7 years or older).
4. Inuenza vaccine (seasonal).
For healthy nonpregnant persons aged 7 through 18 years (i.e., those who
do not have underlying medical conditions that predispose them to inuenza
complications), either LAIV or TIV may be used.
Administer 2 doses (separated by at least 4 weeks) to children aged 6 months
through 8 years who are receiving seasonal inuenza vaccine for the rst
time or who were vaccinated for the rst time during the previous inuenza
season but only received 1 dose.
Children 6 months through 8 years of age who received no doses of mon-
ovalent 2009 H1N1 vaccine should receive 2 doses of 2010-2011 seasonal
inuenza vaccine. See MMWR 2010;59(No. RR-8):3334.
5. Pneumococcal vaccines.
A single dose of 13-valent pneumococcal conjugate vaccine (PCV13) may
be administered to children aged 6 through 18 years who have functional or
anatomic asplenia, HIV infection or other immunocompromising condition,
cochlear implant or CSF leak. See MMWR 2010;59(No. RR-11).
The dose of PCV13 should be administered at least 8 weeks after the previ-
ous dose of PCV7.
Administer pneumococcal polysaccharide vaccine at least 8 weeks after the
last dose of PCV to children aged 2 years or older with certain underlying
medical conditions, including a cochlear implant. A single revaccination
should be administered after 5 years to children with functional or anatomic
asplenia or an immunocompromising condition.
6. Hepatitis A vaccine (HepA).
Administer 2 doses at least 6 months apart.
HepA is recommended for children aged older than 23 months who live
in areas where vaccination programs target older children, or who are at
increased risk for infection, or for whom immunity against hepatitis A is
desired.
7. Hepatitis B vaccine (HepB).
Administer the 3-dose series to those not previously vaccinated. For those
with incomplete vaccination, follow the catch-up schedule.
A 2-dose series (separated by at least 4 months) of adult formulation
Recombivax HB is licensed for children aged 11 through 15 years.
8. Inactivated poliovirus vaccine (IPV).
The nal dose in the series should be administered on or after the fourth
birthday and at least 6 months following the previous dose.
If both OPV and IPV were administered as part of a series, a total of 4 doses
should be administered, regardless of the childs current age.
9. Measles, mumps, and rubella vaccine (MMR).
The minimum interval between the 2 doses of MMR is 4 weeks.
10. Varicella vaccine.
For persons aged 7 through 18 years without evidence of immunity (see
MMWR 2007;56[No. RR-4]), administer 2 doses if not previously vaccinated
or the second dose if only 1 dose has been administered.
For persons aged 7 through 12 years, the recommended minimum interval
between doses is 3 months. However, if the second dose was administered
at least 4 weeks after the rst dose, it can be accepted as valid.
For persons aged 13 years and older, the minimum interval between doses
is 4 weeks.
Vaccine ! Age " 710 years 1112 years 1318 years
Tetanus, Diphtheria, Pertussis
1
Human Papillomavirus
2
see footnote
2
Meningococcal
3
Inuenza
4
Pneumococcal
5
Hepatitis A
6
Hepatitis B
7
Inactivated Poliovirus
8
Measles, Mumps, Rubella
9
Varicella
10
Tdap
HPV (3 doses)(females)
MCV4 MCV4
Tdap
HPV series
MCV4
Inuenza (Yearly)
Pneumococcal
HepA Series
Hep B Series
IPV Series
MMR Series
Varicella Series
Range of
recommended
ages for
catch-up
immunization
Range of
recommended
ages for all
children
Range of
recommended
ages for certain
high-risk groups
Recommended Immunization Schedule for Persons Aged 7 Through 18 Years~United States 2011
For those who fall behind or start late, see the schedule below and the catch-up schedule