ADAPTIVE IMMUNE

RESPONSE
Lecture 23-26
1. It is systemic: Immunity is not restricted to the initial infection site.

2. It has “memory”: After an initial exposure, it recognizes and mounts even stronger
attacks on the previously encountered pathogens.

Adaptive immune response has two important parts and these are humoral
immunity mediated by B lymphocytes and cell mediated immunity mediated by T
lymphocytes.

Humoral immunity is part of adaptive immunity and (hu′mor-ul), also called

antibody-mediated immunity, is provided by antibodies present in the body’s
“humors,” or fluids (blood, lymph, etc.). Though they are produced by B-
lymphocytes (or their offspring), antibodies circulate freely in the blood and
lymph, where they bind primarily to bacteria, to bacterial toxins, and to free
viruses, inactivating them temporarily and marking them for destruction by
phagocytes or complement.

When lymphocytes themselves rather than antibodies defend the body, the
immunity is called cellular or cell-mediated immunity because the protective
factor is living cells. Cellular immunity also has cellular targets—virus-infected or
parasite-infected tissue cells, cancer cells, and cells of foreign grafts. The
lymphocytes act against such targets either directly, by killing the foreign cells, or
indirectly, by releasing chemical mediators that enhance the inflammatory
response or activate other lymphocytes or macrophages. Thus, as you can see,
although both arms of the adaptive immune system respond to virtually the same
foreign substances, they do it in very different ways. Unlike innate immune responses,
the adaptive responses are highly specific to the particular pathogen that induced them. They
can also provide long-lasting protection.

Innate and adaptive immune responses.

The function of adaptive immune responses is to destroy invading pathogens and any toxic
molecules they produce. Because these responses are destructive, it is crucial that they be
made only in response to molecules that are foreign to the host and not to the molecules of
the host itself. The ability to distinguish what is foreign from what is self in this way is a
fundamental feature of the adaptive immune system. Occasionally, the system fails to
make this distinction and reacts destructively against the host's own molecules.
Such autoimmune diseases can be fatal.

Lymphocytes Are Required for Adaptive Immunity

There are about 2 × 1012 lymphocytes in the human body, making the immune
system comparable in cell mass to the liver or brain. Despite their abundance, their central
role in adaptive immunity was not demonstrated until the late 1950s.

The Innate and Adaptive Immune Systems Work Together

Lymphocytes usually respond to foreign antigens only if the innate immune system is first
activated. The innate immune responses to an infection are rapid. They depend on pattern
recognition receptors that recognize patterns of pathogen-associated molecules
(immunostimulants) that are not present in the host organism, including microbial DNA,
lipids, and polysaccharides, and proteins that form bacterial flagella. Some cells of the
innate immune system directly present microbial antigens to T cells to initiate
an adaptive immune response. The cells that do this most efficiently are
called dendritic cells, which are present in most vertebrate tissues. They recognize and
phagocytose invading microbes or their products at a site of infection and then migrate with
their prey to a nearby peripheral lymphoid organ. There they act as antigen-
presenting cells, which directly activate T cells to respond to the microbial antigens. Once
activated, some of the T cells then migrate to the site of infection, where they help other
phagocytic cells, mainly macrophages, destroy the microbes.

Cells of the Adaptive Immune System: An Overview

The three crucial cell types of the adaptive immune system are two distinct populations
of lymphocytes, and antigen-presenting cells (APCs). B lymphocytes or B cells oversee
humoral immunity. T lymphocytes or T cells are non-antibody-producing lymphocytes that
constitute the cell-mediated arm of adaptive immunity. Unlike the lymphocytes, APCs do not
respond to specific antigens but instead play essential auxiliary roles

Lymphocytes

T cells (thymus cells) and B cells (bone marrow) are the major cellular components of the
adaptive immune response. T cells are involved in cell-mediated immunity, whereas B cells
are primarily responsible for humoral immunity (relating to antibodies).

Once T and B cells have identified an invader, the cells generate specific responses that
are tailored maximally to eliminate specific pathogens or pathogen-infected cells. B cells
respond to pathogens by producing large quantities of antibodies which then neutralize
foreign objects like bacteria and viruses. In response to pathogens some T cells, called T
helper cells, produce cytokines that direct the immune response, while other T cells,
called cytotoxic T cells, produce toxic granules that contain powerful enzymes which
induce the death of pathogen-infected cells.
Thus, innate immune responses are activated mainly at sites of infection,
whereas adaptive immune responses are activated in peripheral lymphoid organs. The two
types of responses work together to eliminate invading pathogens.

B Lymphocytes Develop in the Bone Marrow; T Lymphocytes Develop in

the Thymus

T cells and B cells derive their names from the organs in which they develop. T cells develop
in the thymus, and B cells, in mammals, develop in the bone marrow in adults or the liver in
fetuses.

Despite their different origins, both T and B cells develop from the same pluripotent
hemopoietic stem cells, which give rise to all of the blood cells, including red blood cells,
white blood cells, and platelets. These stem cells, are located primarily in hemopoietic tissues
—mainly the liver in fetuses and the bone marrow in adults. T cells develop in the thymus
from precursor cells that migrate there from the hemopoietic tissues via the blood. In most
mammals, including humans, B cells develop from stem cells in the hemopoietic tissues
themselves. Because they are sites where lymphocytes develop from precursor cells, the
thymus and hemopoietic tissues are referred to as central (primary) lymphoid organs.
Most lymphocytes die in the central lymphoid organ soon after they develop, without
ever functioning. Others, however, mature and migrate via the blood to the peripheral
(secondary) lymphoid organs—mainly, the lymph nodes, spleen, and epithelium-
associated lymphoid tissues in the gastrointestinal tract, respiratory tract, and skin. As
mentioned earlier, it is in the peripheral lymphoid organs that T cells and B cells react
with foreign antigens.

Both are activated by antigen to proliferate and mature into effector cells. Effector
B cells secrete antibodies. In their most mature form, called plasma cells, they are filled
with an extensive rough endoplasmic reticulum. In contrast, effector T cells, contain
very little endoplasmic reticulum and do not secrete antibodies.

The Adaptive Immune System Works by Clonal Selection

The most remarkable feature of the adaptive immune system is that it can respond to millions
of different foreign antigens in a highly specific way. How do B cells produce such a
diversity of specific antibodies? According to this theory, an animal first randomly
generates a vast diversity of lymphocytes, and then those lymphocytes that can react
against the foreign antigens that the animal actually encounters are specifically selected
for action. As each lymphocyte develops in a central lymphoid organ, it becomes committed
to react with a particular antigen before ever being exposed to the antigen. It expresses this
commitment in the form of cell-surface receptor proteins that specifically fit the antigen.
When a lymphocyte encounters its antigen in a peripheral lymphoid organ, the binding of the
antigen to the receptors activates the lymphocyte, causing it both to proliferate and to
differentiate into an effector cell.

An antigen therefore selectively stimulates those cells that express complementary antigen-
specific receptors and are thus already committed to respond to it. This arrangement is what
makes adaptive immune responses antigen-specific. The enormous diversity of receptors
and lymphocytes, thereby enabling the immune system to respond to an almost unlimited
diversity of antigens.

The learning process that leads to self-tolerance can involve killing the self-
reactive lymphocytes (clonal deletion), functionally inactivating them (clonal
anergy or inactivation), stimulating the cells to produce modified receptors that no longer
recognize the self-antigen (receptor editing), or the suppression of self-
reactive lymphocytes by a special type of regulatory T cell. The process begins in the central
lymphoid organs when newly formed self-reactive lymphocytes first encounter their self-
antigen. Instead of being activated by binding antigen, the immature lymphocytes are induced
to either alter their receptors or die by apoptosis. Lymphocytes that could potentially respond
to self-antigens that are not present in the central lymphoid organs often die or are either
inactivated or suppressed after they have matured and migrated to peripheral lymphoid
organs.

Why does the binding of self-antigen lead to tolerance rather than activation? As we discuss
later, for a lymphocyte to be activated in a peripheral lymphoid organ, it must not only bind
its antigen but must also receive a costimulatory signal. The latter signal is provided by
a helper T cell in the case of a B lymphocyte and by an antigen-presenting cell in the case of
a T lymphocyte. The production of costimulatory signals usually depends on exposure to
pathogens, and so a self-reactive lymphocyte normally encounters its antigen in the absence
of such signals. Without a costimulatory signal, an antigen tends to kill or inactivate
a lymphocyte rather than activate it.

Induction of immunological tolerance to self-antigens in central and

peripheral lymphoid organs
Lymphocytes Continuously Circulate Through Peripheral
Lymphoid Organs

Pathogens generally enter the body through an epithelial surface, usually through the skin,
gut, or respiratory tract. How do the microbial antigens travel from these entry points to a
peripheral lymphoid organ, such as a lymph node or the spleen, where lymphocytes are
activated The route and destination depend on the site of entry. Antigens that enter through
the skin or respiratory tract are carried via the lymph to local lymph nodes; those that enter
through the gut end up in gut-associated peripheral lymphoid organs such as Peyer's patches;
and those that enter the blood are filtered out in the spleen. In most cases, dendritic cells carry
the antigen from the site of infection to the peripheral lymphoid organ, where they become
antigen-presenting cells, specialized for activating T cells (as we discuss later).

But the lymphocytes that can recognize a particular microbial antigen in a

peripheral lymph organ are only a tiny fraction of the total lymphocyte population. How do
these rare cells find an antigen-presenting cell displaying their antigen? The answer is that
they continuously circulate between the lymph and blood until they encounter their antigen.

The path followed by lymphocytes as they continuously circulate between the lymph
and blood

The circulation through a lymph node is shown here. Microbial antigens are carried into the
lymph node by dendritic cells, which enter via afferent lymphatic vessels draining an infected
tissue. T and B cells, by contrast, enter the lymph node via an artery and migrate out of the
bloodstream through postcapillary venules. Unless they encounter their antigen, the T and
B cells leave the lymph node via efferent lymphatic vessels, which eventually join the
thoracic duct. The thoracic duct empties into a large vein carrying blood to the heart. A
typical circulation cycle takes about 12–24 hours.
 A circulating lymphocyte adheres weakly to the surface of the specialized
endothelial cells lining a postcapillary venule in a lymph node.

Chemokines are small, secreted, positively charged proteins that have a central role in
guiding the migrations of various types of white blood cells. They are all structurally related
and bind to the surface of endothelial cells, and to negatively charged proteoglycans of
the extracellular matrix in organs. By binding to G-protein-linked receptors on the surface of
specific blood cells, chemokines attract these cells from the bloodstream into an organ, guide
them to specific locations within the organ, and then help stop migration. T and
B cells initially enter the same region of a lymph node but are then attracted by different
chemokines to separate regions of the node—T cells to the paracortex and
B cells to lymphoid follicles. Unless they encounter their antigen, both types of cells soon
leave the lymph node via lymphatic vessels. If they encounter their antigen, however, they
remain in the node, proliferate, and differentiate into either effector cells or memory cells.

A simplified drawing of a human lymph node

B cells are primarily clustered in structures called lymphoid follicles, whereas T cells are
found mainly in the paracortex. Both types of lymphocytes are attracted by chemokines to
enter the lymph node from the blood via postcapillary venules. They then migrate to their
respective areas, attracted by different chemokines. If they do not encounter their
specific antigen, both T cells and B cells then enter the medullary sinuses and leave the node
via the efferent lymphatic vessel . This vessel ultimately empties into the bloodstream,
allowing the lymphocytes to begin another cycle of circulation through a secondary lymphoid
organ.

B lymphocytes, also known as B cells, are white blood cells that produce antibodies to
fight harmful bacteria, viruses, and toxins. B cells are a vital part of the immune system,
which protects the body from pathogens that can make you sick.

Functions of B lymphocytes:

 Cell-mediated immune responses: B lymphocytes are responsible for cell-

mediated immune responses.

 Protective antibodies: B lymphocytes produce protective innate and adaptive

antibodies.

 Antigen recognition: B cells produce antibodies in response to antigens, which

are markers that identify substances in the body.

 Neutralizing pathogens: Antibodies bind to pathogens or foreign substances to

neutralize them. For example, an antibody can bind to a virus to prevent it from
entering a normal cell and causing infection. B cells develop in primary lymphoid
tissue and mature in secondary lymphoid tissue. B-cell development can lead to
congenital immunodeficiency, leukaemia/lymphoma, and autoimmune disease.
 T lymphocytes, functions:

T cells, are a type of white blood cell that help the immune system fight off disease
and infection:

 Destroy infected cells: T cells recognize antigens on the surface of infected cells
and induce apoptosis, or programmed cell death.

 Direct the immune response: T cells help B lymphocytes eliminate pathogens

by sending signals to other immune cells.

 Regulate immune responses: T cells regulate the intensity of adaptive immune

responses.

 Induce inflammation: T cells can induce inflammatory responses by releasing

soluble factors.

 Synthesize cytokines: T cells synthesize and secrete cytokines, which are

soluble intercellular messengers.

 There are two main types of T cells:

 Cytotoxic T cells: Destroy infected cells.

 Helper T cells: Send signals to other immune cells to fight infection.

Cytokines are a group of proteins and signal molecules that transmit signals to cells
about survival, differentiation, proliferation, and functional activity. Some types of
cytokines include:

 Interferons: A broad class of cytokines that help the body fight viruses and
cancers. Interferons are named after the first three letters of the Greek alphabet,
such as IFN-alfa, IFN-beta, and IFN-gamma.

 Interleukins: A group of cytokines that act as chemical signals between white

blood cells. Interleukins regulate immune and inflammatory responses.

 Chemokines: A type of cytokine that signals immune cells to move toward

infection sites. Chemokines are also known as chemoattractants.
  Tumor necrosis factor (TNF): A type of cytokine that can destroy cells,
including cancer cells.

 Lymphokines: Cytokines that are produced by lymphocytes.

Other cytokines include:

 Granulocyte-macrophage colony-stimulating factor (GM-CSF)

 Thymic stromal lymphopoietin (TSLP)

 Leukemia inhibitory factor (LIF)

 Oncostatin M (OSM)

 Ciliary neurotrophic factor (CNTF)

 Cardiotrophin-1 (CT-1)

 Antigens

Antigens are substances that can mobilize the immune system and provoke an
immune response. As such, they are the ultimate targets of all immune responses. Most
antigens are large, complex molecules (both natural and synthetic) that are not
normally present in the body. Consequently, as far as our immune system is concerned,
they are intruders, or nonself.

Complete Antigens and Haptens

Antigens can be complete or incomplete. Complete antigens have two important functional
properties:

1. Immunogenicity, which is the ability to stimulate proliferation of specific lymphocytes

and antibodies. (Antigen is a contraction of “antibody generating,” which refers to this
particular antigenic property.)
2. Reactivity, which is the ability to react with the activated lymphocytes and the antibodies
released by immunogenic reactions.
An almost limitless variety of foreign molecules can act as complete antigens,
including virtually all foreign proteins, many large polysaccharides, and some lipids and
nucleic acids. Of these, proteins are the strongest antigens. Pollen grains and
microorganisms—such as bacteria, fungi, and virus particles—are all immunogenic
because their surfaces bear many different foreign macromolecules.

As a rule, small molecules—such as peptides, nucleotides, and many hormones—are

not immunogenic. But, if they link up with the body’s own proteins, the adaptive
immune system may recognize the combination as foreign and mount an attack that is
harmful rather than protective. (These reactions, called hypersensitivities, are described
later in the chapter.) In such cases, the troublesome small molecule is called a hapten.

Antigenic Determinants

The ability of a molecule to act as an antigen depends on both its size and its complexity.
Only certain parts of an entire antigen, called antigenic determinants, are
immunogenic. Free antibodies or lymphocyte receptors bind to these sites in much the
same manner an enzyme binds to a substrate.

Antigenic determinants. Antibodies (and related receptors on lymphocytes) bind to

antigenic determinants on the antigen surface. Most antigens have several different
antigenic determinants, which means that different antibodies can bind to a given
antigen. In this example, three types of antibodies react with different antigenic
determinants on the same antigen molecule. (On a real antigen molecule, each antigenic
determinant would be represented many times.)

Self-Antigens: MHC Proteins

The external surfaces of all our cells are dotted with a huge variety of protein molecules.
Assuming our immune system has been properly “programmed,” these self-antigens are not
foreign or antigenic to us, but they are strongly antigenic to other individuals. (This is the
basis of transfusion reactions and graft rejection.) Among the cell surface proteins that
mark a cell as self is a group of glycoproteins called MHC proteins, coded for by genes
of the major histocompatibility complex (MHC). Because millions of combinations of
these genes are possible, it is unlikely that any two people except identical twins have the
same MHC proteins. There are two major groups of MHC proteins, distinguished by location.
Class I MHC proteins are found on virtually all body cells, but class II MHC proteins
are found only on certain cells that act in the immune response. In healthy cells,
peptides displayed by class I MHC come from the breakdown of cellular proteins
during normal protein recycling and tend to be quite diverse. However, in infected cells,
class I MHC also binds to fragments of foreign antigens that come from within the
infected cell. Peptides displayed by class II MHC come from outside the cell. These
displayed peptides play a crucial role in mobilizing the immune system.

MHC class I pathway: Proteins in the cytosol are degraded by the proteasome, liberating peptides internalized
by TAP channel in the endoplasmic reticulum, there associating with MHC-I molecules freshly synthesized.
MHC-I/peptide complexes enter Golgi apparatus, are glycosylated, enter secretory vesicles, fuse with the cell
membrane, and externalize on the cell membrane interacting with T lymphocytes

.
 Characteristic MHC-I pathway MHC-II pathway

Composition of the Polymorphic chain α and

Polymorphic chains α and β, peptide binds
stable peptide-MHC β2 macroglobulin, peptide
to both
complex bound to α chain

Dendritic cells, mononuclear

Types of antigen-
All nucleated cells phagocytes, B lymphocytes, some
presenting cells (APC)
endothelial cells, epithelium of thymus

T lymphocytes able to Cytotoxic T

Helper T lymphocytes (CD4+)
respond lymphocytes (CD8+)

cytosolic proteins (mostly

Proteins present
Origin of antigenic synthetized by the cell; may
in endosomes or lysosomes (mostly
proteins also enter from the extracellular
internalized from extracellular medium)
medium via phagosomes)

Enzymes responsible Proteases from endosomes and lysosomes

Cytosolic proteasome
for peptide generation (for instance, cathepsin)

Location of loading the

peptide on the MHC Endoplasmic reticulum Specialized vesicular compartment
molecule

Molecules implicated
in transporting the
TAP (transporter associated
peptides and loading DM, invariant chain
with antigen processing)
them on the MHC
molecules
Lecture 27-30
CAPTURE OF PROTEIN ANTIGENS BY ANTIGEN-PRESENTING CELLS

Protein antigens of microbes that enter the body are captured mainly by dendritic cells
and concentrated in the peripheral lymphoid organs, where immune responses are
initiated. Microbes usually enter the body through the skin (by contact), the
gastrointestinal tract (by ingestion), and the respiratory tract (by inhalation). Some
insect-borne microbes may be injected into the bloodstream as a result of insect bites,
and some infections are acquired through the genitourinary tract.

Microbial antigens can also be produced in any infected tissue. Because of the vast
surface area of the epithelial barriers and the large volume of blood, connective
tissues, and internal organs, it would be impossible for lymphocytes of all possible
specificities to efficiently patrol all these sites searching for foreign invaders; instead,
antigens are taken to the lymphoid organs through which lymphocytes recirculate.

This process involves a series of events following the encounter of dendritic cells with
microbes—capture of antigens, activation of the dendritic cells, migration of the
antigen-carrying cells to lymph nodes, and display of the antigen to T cells.

Antigen Capture and Presentation to Lymphocytes

B and T lymphocytes differ in the types of antigens they recognize. The antigen receptors of
B lymphocytes—namely, membrane-bound antibodies—can recognize a variety of
macromolecules (proteins, polysaccharides, lipids, nucleic acids), in soluble form or cell
surface–associated form, as well as small chemicals. Therefore, B cell–mediated humoral
immune responses may be generated against many types of microbial cell wall and soluble
antigens.
 The antigen receptors of most T lymphocytes, on the other hand, can see only peptide
fragments of protein antigens, and only when these peptides are presented by specialized
molecules that bind peptides generated inside a host cell and then display them on the cell
surface. Therefore, T cell–mediated immune responses may be generated only against protein
antigens that are either produced in or taken up by host cells. This chapter focuses on the
nature of the antigens that are recognized by lymphocytes.
APC: B lymphocytes, dendritic cells, macrophages

Antigen-presenting cells

Antigen presentation stimulates immature T cells to become either mature "cytotoxic" CD8+
cells or mature "helper" CD4+ cells.

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound
by major histocompatibility complex (MHC) proteins on its surface; this process is
known as antigen presentation. T cells may recognize these complexes using their T cell
receptors (TCRs). APCs process antigens and present them to T-cells.

Almost all cell types can present antigens in some way. They are found in a variety of
tissue types. Professional antigen-presenting cells, including macrophages, B
cells and dendritic cells, present foreign antigens to helper T cells, while virus-infected
cells (or cancer cells) can present antigens originating inside the cell to cytotoxic T cells.
In addition to the MHC family of proteins, antigen presentation relies on other
specialized signaling molecules on the surfaces of both APCs and T cells.

Types and functions

Antigen-presenting cells fall into two categories: professional and non-professional.

Those that express MHC class II molecules along with co-stimulatory molecules
and pattern recognition receptors are often called professional antigen-presenting cells.
[1]
The non-professional APCs express MHC class I molecules.

T cells must be activated before they can divide and perform their function. This is
achieved by interacting with a professional APC which presents an antigen recognized
by their T cell receptor. The APC involved in activating T cells is usually a dendritic
cell. T cells cannot recognize (and therefore cannot respond to) "free" or soluble
antigens. They can only recognize and respond to antigen that has been processed and
presented by cells via carrier molecules like MHC molecules.

Helper T cells can recognize exogenous antigen presented on MHC class II; cytotoxic T cells
can recognize endogenous antigen presented on MHC class I. Most cells in the body can
present antigen to CD8+ cytotoxic T cells via MHC class I; however, the term "antigen-
presenting cell" is often used specifically to describe professional APCs. Such cells express
MHC class I and MHC class II molecules and can stimulate CD4+ helper T cells as well as
cytotoxic T cells.[2][3]

APCs can also present foreign and self lipids to T cells and NK cells by using the CD1 family
of proteins, which are structurally similar to the MHC class I family.[4]

Professional APCs

Professional APCs specialize in presenting antigens to T cells. [5] They are very efficient
at internalizing antigens, either by phagocytosis (e.g. macrophages), or by receptor-
mediated endocytosis (B cells), processing the antigen into peptide fragments and then
displaying those peptides (bound to a class II MHC molecule) on their membrane. [1] The
T cell recognizes and interacts with the antigen-class II MHC molecule complex on the
membrane of the antigen-presenting cell. An additional co-stimulatory signal is then
produced by the antigen-presenting cell, leading to activation of the T cell. The expression of
co-stimulatory molecules and MHC class II are defining features of professional APCs. [1] All
professional APCs also express MHC class I molecules as well.[2]

The main types of professional antigen-presenting cells are dendritic cells, macrophages and
B cells.[1]

Dendritic cells (DCs)

Dendritic cells have the broadest range of antigen presentation and are necessary for
activation of naive T cells. [1] DCs present antigen to both helper and cytotoxic T cells. They
can also perform cross-presentation, a process by which they present exogenous antigen on
MHC class I molecules to cytotoxic T cells. Cross-presentation allows for the activation of
these T cells.[2] Dendritic cells also play a role in peripheral tolerance, which contributes to
prevention of auto-immune disease.[6]h

Macrophages

Macrophages can be stimulated by T cell secretion of interferon.[9] After this activation,

macrophages are able to express MHC class II and co-stimulatory molecules, including the
B7 complex and can present phagocytosed peptide fragments to helper T cells. [7][8] Activation
can assist pathogen-infected macrophages in clearing the infection.[10]

B cells

B cells can internalize antigen that binds to their B cell receptor and present it to helper T
cells.[1] Unlike T cells, B cells can recognize soluble antigen for which their B cell receptor is
specific. They can then process the antigen and present peptides using MHC class II
molecules. When a T helper cell with a TCR specific for that peptide binds, the B cell marker
CD40 binds to CD40L on the T cell surface. When activated by a T cell, a B cell can undergo
antibody isotype switching, affinity maturation, as well as formation of memory cells.[2]

Non-professional APCs

Non-professional antigen presenting cells include all nucleated cell types in the body. They
use an MHC class I molecule to display endogenous peptides on the cell membrane. These
peptides originate within the cell itself, in contrast to the exogenous antigen displayed by
professional APCs using MHC class II molecules. Cytotoxic T cells are able to interact with
endogenous antigen presented using an MHC class I molecule. [2] Non-professional APCs do
not typically express MHC class II molecules. However, it has been observed that antigen
presentation to CD4+ cells via MHC class II is not restricted to the classically professional
APCs. Other leukocytes, including granulocytes such as mast cells and neutrophils, can be
induced to do so, as can endothelial and epithelial cells under certain circumstances.

Interaction with T cells

After dendritic cells have phagocytosed pathogens, they usually migrate to the vast network
of lymph vessels and are carried by lymph flow to the draining lymph nodes. Each lymph
node is a collection point where APCs can interact with T cells. [1] During the migration, DCs
undergo a process of maturation: they lose most of their ability to further engulf pathogens
and they mature by changing surface expression of MHC and co-stimulatory molecules, as
well as increased production of cytokines. The internalized antigen is digested into smaller
peptides containing epitopes, which are then presented to T cells by the MHC.[2][12]

B cells reside in the lymph node. Once their B cell receptor binds to an antigen, they can
interact with activated helper T cells, as described above.

The major role of antigen-presenting cells (APCs) in immunity is to engulf antigens and then
present fragments of them, like signal flags, on their own surfaces where they can be
recognized by T cells—that is, they present antigens to the cells that will deal with the
antigens. The major types of cells acting as APCs are dendritic cells (present in connective
tissues and in the epidermis, where they are also called Langerhans’ cells), macrophages, and
B lymphocytes.

Notice that all these cell types are in sites that make it easy to encounter and process
antigens. Dendritic cells are at the body’s frontiers, best situated to act as mobile sentinels.
Macrophages are widely distributed throughout the lymphoid organs and connective tissues.
When they present antigens, dendritic cells and macrophages activate T cells.
Macrophages tend to remain fixed in the lymphoid organs, as if waiting for antigens to
come to them. But lymphocytes, especially the T cells (which account for 65–85% of
bloodborne lymphocytes), circulate continuously throughout the body. This circulation
greatly increases a lymphocyte’s chance of coming into contact with antigens located in
different parts of the body, as well as with huge numbers of macrophages and other
lymphocytes. Although lymphocyte recirculation appears to be random, the lymphocyte
emigration to the tissues where their protective services are needed is highly specific,
regulated by homing signals (CAMs) displayed on vascular endothelial cells. Because
lymphatic capillaries pick up proteins and pathogens from nearly all body tissues, immune
cells in lymph nodes are in a strategic position to encounter a large variety of antigens.
Lymphocytes and APCs in the tonsils act primarily against microorganisms that invade the
oral and nasal cavities, whereas the spleen acts as a filter to trap bloodborne antigens.
In addition to T cell recirculation and passive delivery of antigens to lymphoid organs by
lymphatics, a third delivery mechanism—migration of dendritic cells to secondary lymphoid
organs—may be an even more important way of ensuring that the immune cells encounter
invading antigens. With their long veil-like extensions, dendritic cells are very efficient
antigen catchers, and once they have internalized antigens by phagocytosis, they enter nearby
lymphatics to get to the lymphoid organ where they will present the antigens to T and B cells.
Indeed, dendritic cells are the most effective antigen presenters known—it’s their only job.
Dendritic cells are a key link between innate and adaptive immunity, initiating adaptive
immune responses particularly tailored to the type of pathogen that they have encountered.
Humoral Immune Response
The antigen challenge, the first encounter between an immunocompetent but naive
lymphocyte and an invading antigen, usually takes place in the spleen or in a lymph node, but
it may happen in any lymphoid tissue.

If the lymphocyte is a B cell, the challenging antigen provokes the humoral immune
response, in which antibodies are produced against the challenger.

Clonal Selection and Differentiation of B Cells

An immunocompetent but naive B lymphocyte is activated (stimulated to complete its

differentiation) when antigens bind to its surface receptors and cross-link adjacent receptors
together. Antigen binding is quickly followed by receptor-mediated endocytosis of the cross-
linked antigen-receptor complexes. These events (plus some interactions with T cells
described shortly) trigger clonal selection (klo′nul). That is, the events stimulate the B cell to
grow and then multiply rapidly to form an army of cells all exactly like itself and bearing the
same antigen-specific receptors (Figure 21.10). The resulting family of identical cells, all
descended from the same ancestor cell, is called a clone. It is the antigen that does the
selecting in clonal selection by “choosing” a lymphocyte with complementary receptors.

Most cells of the clone become plasma cells, the antibody-secreting effector cells of the
humoral response. Although B cells secrete limited amounts of antibodies, plasma cells
develop the elaborate internal machinery (largely rough endoplasmic reticulum) needed to
secrete antibodies at the unbelievable rate of about 2000 molecules per second. Each plasma
cell functions at this breakneck pace for 4 to 5 days and then dies. The secreted antibodies,
each with the same antigen-binding properties as the receptor molecules on the surface of the
parent B cell, circulate in the blood or lymph, where they bind to free antigens and mark them
for destruction by other innate or adaptive mechanisms. Clone cells that do not differentiate
into plasma cells become long-lived .memory cells that can mount an almost immediate
humoral response if they encounter the same antigen again at some future time.

Immunological Memory
The cellular proliferation and differentiation just described constitute the primary immune
response, which occurs on first exposure to a particular antigen. The primary response
typically has a lag period of 3 to 6 days after the antigen challenge. This lag period mirrors
the time required for the few B cells specific for that antigen to proliferate and for their
offspring to differentiate into plasma cells. After the mobilization period, plasma antibody
levels rise, reach peak levels in about 10 days, and then decline.

Active and Passive Humoral Immunity

When your B cells encounter antigens and produce antibodies against them, you are
exhibiting active humoral immunity . Active immunity is (1) naturally acquired when you
get a bacterial or viral infection, during which time you may develop symptoms of the disease
and suffer a little (or a lot), and (2) artificially acquired when you receive vaccines. Indeed,
once it was realized that secondary responses are so much more vigorous than primaries, the
race was on to develop vaccines to “prime” the immune response by providing a first meeting
with the antigen.

Most vaccines contain dead or attenuated (living, but extremely weakened) pathogens, or
their components. Vaccines provide two benefits: Vaccine booster shots, which may
intensify the immune response at later meetings with the same antigen, are also available
Vaccines have wiped out smallpox and have substantially lessened the illness caused by such
former childhood killers as whooping cough, polio, and measles. Although vaccines have
dramatically reduced hepatitis B, tetanus, and pneumonia in adults, immunization of
adults. Conventional vaccines have shortcomings. Although it was originally believed that
the immune response was about the same regardless of how an antigen got into the body
(under its own power or via a vaccine), that has proved not to be the case.
 Passive humoral immunity differs from active immunity, both in the antibody source and
in the degree of protection it provides. Instead of being made by your plasma cells, the
antibodies are harvested from the serum of an immune human or animal donor. As a result,
your B cells are not challenged by antigens, immunological memory does not occur, and the
protection provided by the “borrowed” antibodies ends when they naturally degrade in the
body.
Passive immunity is conferred naturally on a fetus or infant when the mother’s antibodies
cross the placenta or are ingested with the mother’s milk. For several months after birth, the
baby is protected from all the antigens to which the mother has been exposed. Passive
immunity is artificially conferred via a serum such as gamma globulin, which is administered
after exposure to hepatitis. Other immune sera are used to treat poisonous snake bites
(antivenom), botulism, rabies, and tetanus (antitoxin) because these rapidly fatal diseases
would kill a person before active immunity could be established. The donated antibodies
provide immediate protection, but their effect is short-lived (two to three weeks).

Antibodies

Antibodies, also called immunoglobulins (Igs) constitute the gamma globulin part of blood
proteins. As mentioned earlier, antibodies are proteins secreted by activated B cells or plasma
cells in response to an antigen, and they are capable of binding specifically with that antigen.
They are formed in response to an incredible number of different antigens. Despite their
variety, all antibodies can be grouped into one of five Ig classes, each slightly different in
structure and function. Before seeing how these Ig classes differ from one another, let’s take
a look at how all antibodies are alike.

Basic Antibody Structure

Regardless of its class, each antibody has a basic structure consisting of four looping
polypeptide chains linked together by disulfide (sulfur-to-sulfur) bonds. Two of these chains,
the heavy (H) chains, are identical to each other and contain more than 400 amino acids each.
The other two chains, the light (L) chains, are also identical to each other, but only about half
as long as each H chain. The heavy chains have a flexible hinge region at their approximate
“middles.”

Antibody Classes

The five major immunoglobulin classes are designated IgM, IgA, IgD, IgG, and IgE, on the
basis of the C regions in their heavy chains. (Remember the name MADGE to recall the five
Ig types.) As illustrated in Table 21.3, IgD, IgG, and IgE have the same basic Y-shaped
structure and thus are monomers. IgA occurs in both monomer and dimer (two linked
monomers) forms. (Only the dimer is shown in the table.) Compared to the other antibodies,
IgM is a huge antibody, a pentamer (penta = five) constructed from five linked monomers.
Mechanisms of Antibody Diversity

Recall from that the billions of different kinds of antibodies produced by plasma cells come
about as the result of somatic recombination of a limited number of genes. The genes for the
heavy and light chains occur on separate chromosomes, but for each chain, the sections of
coding DNA (exons) are separated by chunks of noncoding DNA (introns); this structure is
essential for somatic recombination. The L and H chains are manufactured separately and
then joined to form the antibody monomer.

The random mixing of gene segments to make unique antibody genes specifying the H and L
chains accounts for only part of the huge variability seen in antibodies. Certain areas of the V
gene segments in activated B cells, the so-called hypervariable regions, are “hot spots” for
somatic mutations that enormously increase antibody variation.

Antibody Targets and Functions

Though antibodies cannot themselves destroy antigens, they can inactivate them and tag them
for destruction. The common event in all antibody-antigen interactions is formation of
antigen-antibody (or immune) complexes. Defensive mechanisms used by antibodies include
neutralization, agglutination, precipitation, and complement fixation, with the first two most
important.

Neutr aliz
ation, the

simplest effector mechanism, occurs when antibodies block specific sites on viruses or
bacterial exotoxins (toxic chemicals secreted by bacteria). As a result, the virus or exotoxin
loses its toxic effect because it cannot bind to receptors on tissue cells to cause injury. The
antigen-antibody complexes are eventually destroyed by phagocytes.
Because antibodies have more than one antigen-binding site, they can bind to the same
determinant on more than one antigen at a time; consequently, antigen-antibody complexes
can be cross-linked into large lattices. When cell-bound antigens are cross -linked the process
causes clumping, or agglutination, of the foreign cells. In precipitation, soluble molecules
(instead of cells) are cross-linked into large complexes that settle out of solution. Like
agglutinated bacteria, precipitated antigen molecules are much more easily captured and
engulfed by phagocytes than are freely moving antigens. Complement fixation and activation
is the chief antibody ammunition used against cellular antigens, such as bacteria or
mismatched red blood cells. When antibodies bind to cells, the antibodies change shape to
expose complement-binding sites on their stem