Overview of immune response

Properties and Overview
of Immune Response
Md. Murad Khan
Lecturer
Dept. of Microbiology
Jagannath University

Introduction
 The Latin term immunis, meaning “exempt,” gave rise to the English word
immunity, which refers to all the mechanisms used by the body to prevent
or limit infections by pathogenic microorganisms, such as bacteria, viruses,
parasites, and fungi.
 The collection of cells, tissues, and molecules that mediate resistance to
infections is called the immune system, and the coordinated reaction of
these cells and molecules to infectious microbes comprises an immune
response.
 Immunology is the study of the immune system, including its responses to
microbial pathogens and damaged tissues and its role in disease.

Historical Perspectives of Immunology
 The concept of immunity has existed since the ancient times. An example is
the Chinese custom of making children resistant to smallpox by making
them inhale powders made from the skin lesions of patients recovering
from the disease (a technique called variolation).
 In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador in
Constantinople, observed the positive effects of variolation on the native
Turkish population and had the technique performed on her own children.
 The first European mention of immunity is recorded by Thucydides in
Athens during the fifth century BC. In describing plague in Athens, he wrote
in 430 BC that only those who had recovered from plague could nurse the
sick, because they would not contract the disease a second time.

 The English physician Edward Jenner made a giant advance in the deliberate
development of immunity, again targeting smallpox. In 1798, intrigued by the fact
that milkmaids who had contracted the mild disease cowpox were subsequently
immune to the much more severe smallpox, Jenner reasoned that introducing fluid
from a cowpox pustule into people (i.e., inoculating them) might protect them
from smallpox. To test this idea, he inoculated an eight-year-old boy with fluid
from a cowpox pustule and later intentionally infected the child with smallpox. As
predicted, the child did not develop smallpox.
 Louis Pasteur had succeeded in growing the bacterium that causes fowl cholera in
culture, and confirmed this by injecting it into chickens that then developed fatal
cholera. After returning from a summer vacation, he and colleagues resumed their
experiments, injecting some chickens with an old bacterial culture.

 The chickens became ill, but to Pasteur’s surprise, they recovered. Interested,
Pasteur then grew a fresh culture of the bacterium with the intention of injecting
this lethal brew into some fresh, unexposed chickens. But as the story is told, his
supply of fresh chickens was limited, and therefore he used a mixture of previously
injected chickens and unexposed birds. Unexpectedly, only the fresh chickens died,
while the chickens previously exposed to the older bacterial culture were
completely protected from the disease.
 Pasteur hypothesized and later showed that aging had weakened the virulence of
the pathogen and that such a weakened or attenuated strain could be
administered to provide immunity against the disease. He called this attenuated
strain a vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work
with cowpox inoculation.

 Pasteur extended these findings to other diseases. Pasteur first vaccinated one
group of sheep with anthrax bacteria (Bacillus anthracis) that were attenuated by
heat treatment. He then challenged the vaccinated sheep, along with some
unvaccinated sheep, with a virulent culture of the anthrax bacillus. All the
vaccinated sheep lived and all the unvaccinated animals died. These experiments
marked the beginnings of the discipline of immunology.
 In 1885, Pasteur administered his first vaccine to a human, a young boy who had
been bitten repeatedly by a rabid dog. The boy, Joseph Meister, was inoculated
with a series of attenuated rabies virus preparations. Joseph lived, and later
became a caretaker at the Pasteur Institute, which was opened in 1887 to treat the
many rabies victims that began to flood in when word of Pasteur’s success spread;
it remains to this day an institute dedicated to the prevention and treatment of
infectious disease.

Types of Immunity: Innate and Adaptive Immunity
 Mechanisms for defending the host against microbes are present in all
multicellular organisms. Defense against microbes is mediated by the early
reactions of innate immunity and the later responses of adaptive
immunity.
 Innate and adaptive immune responses are components of an integrated
system of host defense in which numerous cells and molecules function
cooperatively. The mechanisms of innate immunity provide effective initial
defense against infections. However, many pathogenic microbes have
evolved to resist innate immunity, and their elimination requires the more
powerful mechanisms of adaptive immunity.

Innate Immunity
 Innate immunity is the resistance that an individual possesses by birth.
 The factors that may influence innate immunity of the host include age and
nutritional status of the host.
 Age: Extremes of age make an individual highly susceptible to various
infections.
 Immature immunity in child. Placental barrier protects fetus but human
immunodeficiency virus (HIV), rubella virus, cytomegalovirus, and Toxoplasma gondii
cross the placental barrier and cause congenital infections.
 Very old people are susceptible to suffer more than young people from a disease (e.g.,
pneumonia) and have high mortality. Measles, mumps, poliomyelitis, and chicken pox
are few examples of the diseases that cause more severe clinical illness in adults than in
young children. This may be due to more active immune response in an adult causing
greater tissue damage.

Innate Immunity
 Nutritional status: Both humoral and cell mediated immunities are lowered in
malnutrition. Examples are:
 Neutrophil activity is reduced, interferon response is decreased, and C3 and factor B of the
complement are decreased in protein–calorie malnutrition.
 Deficiency of vitamin A, vitamin C, and folic acid makes an individual highly susceptible to
infection by many microbial pathogens.
 Hormonal levels: Individuals with certain hormonal disorders become
increasingly susceptible to infection. For example,
 Individuals suffering from diabetes mellitus, hypothyroidism, and adrenal dysfunction are
increasingly susceptible to staphylococcal infection, streptococcal infection, candidiasis,
aspergillosis, and many other microbial infections.
 Pregnant women are more susceptible to many infections due to higher level of steroid
during pregnancy.

Mechanism of Innate Immunity
 Innate immunity of the host performs two most important functions: it kills
invading microbes and it activates acquired (adaptive) immune processes.
 The innate immunity is primarily dependent on four types of defensive barriers:
(a) anatomic barriers, (b) physiologic barriers, (c) phagocytosis, and (d)
inflammatory responses.
 Anatomic barriers: Anatomic barriers include skin and mucous membrane.
 The intact skin prevents entry of microorganisms.
 Breaks in the skin and/or bites of insects harboring pathogenic organisms (e.g.,
mosquitoes, mites, ticks, fleas, and sandflies), introduce the pathogens into the body and
transmit the infection.
 The sebum, secreted by the skin, consists of lactic acid and fatty acids that maintain the pH
of skin between 3 and 5, and this pH inhibits the growth of most microorganisms.

 Anatomic barriers: Mucous membranes form a large part of outer covering of
gastrointestinal, respiratory, genitourinary, and many other tracts of human host.
A number of nonspecific defense mechanisms act to prevent entry of
microorganisms through mucous membrane.
 Saliva, tears, and mucous secretions tend to wash away potential invading microorganisms,
thereby preventing their attachment to the initial site of infections. These secretions also
contain antibacterial or antiviral substances that kill these pathogens.
 Mucus is a viscous fluid secreted by the epithelial cells of mucous membranes that entraps
invading microorganisms.
 In lower respiratory tract, mucous membrane is covered by cilia, the hair-like protrusions of
the epithelial cell membranes. The synchronous movement of cilia propels mucus
entrapped microorganisms from these tracts.
 In addition, nonpathogenic organisms tend to colonize the epithelial cells of mucosal
surfaces. These normal flora generally compete with pathogens for attachment sites on the
epithelial cell surface and for necessary nutrients.

 Physiologic barriers: The physiologic barriers that contribute to innate
immunity include the following:
 Gastric acidity is an innate physiologic barrier to infection because very few ingested
microorganisms can survive the low pH of stomach contents.
 Lysozyme, interferon, and complement are some of the soluble mediators of innate
immunity.
 Lysozyme has antibacterial effect due to its action on the bacterial cell wall.
 Interferons are secreted by cells in response to products of viral infected cells. These
substances have a general antiviral effect by preventing the synthesis of viral structural
proteins.
 Complement is a group of serum-soluble substances that when activated damage the cell
membrane.

 Phagocytosis: Phagocytosis is a process of ingestion of extracellular
particulate material by certain specialized cells, such as blood monocytes,
neutrophils, and tissue macrophages. It is a type of endocytosis in which
invading microorganisms present in the environment are ingested by the
phagocytic cells.
 Inflammatory responses: Tissue damage caused by a wound or by an
invading pathogenic microorganism induces a complex sequence of events,
collectively known as the inflammatory responses. The end result of
inflammation may be the activation of a specific immune response to the
invasion or clearance of the invader by components of the innate immune
system. The four cardinal features of inflammatory responses are rubor
(redness), calor (rise in temperature), dolor (pain), and tumor (swelling).

Adaptive Immunity
 Adaptive immunity is also called
acquired immunity, since the potency
of immune response is acquired by
experience only.
 Active immunity is mediated by
humoral immunity and cell-
mediated immunity. These two
types of immunity are mediated by
different cells and molecules and
provide defense against extracellular
microbes and intracellular microbes,
respectively.
FIG: Types of adaptive immunity. In humoral immunity, B lymphocytes
secrete antibodies that eliminate extracellular microbes. In cell-
mediated immunity, different types of T lymphocytes recruit and
activate phagocytes to destroy ingested microbes and kill infected cells.

Adaptive Immunity
 Humoral immunity is mediated by proteins called antibodies, which are
produced by cells called B lymphocytes.
 Antibodies:
 enter the circulation and mucosal fluids, and they neutralize and eliminate microbes
and microbial toxins.
 stop microbes from gaining access to and colonizing host cells and thus prevent
infections from ever being established.
 cannot gain access to microbes that live and divide inside infected cells.
 themselves are specialized and may activate different mechanisms to combat microbes
(effector mechanisms).

Adaptive Immunity
 Defense against intracellular microbes is called cell-mediated immunity
because it is mediated by cells, which are called T lymphocytes.
 T lymphocytes:
 activate phagocytes to destroy microbes that have been ingested by the
phagocytes into intracellular vesicles.
 kill any type of host cells that are harboring infectious microbes in the
cytoplasm.
 in both cases, they recognize microbial antigens that are displayed on
host cell surfaces, which indicates there is a microbe inside the cell.

Adaptive Immunity
 Immunity may be induced in an individual by infection or vaccination (active immunity)
or conferred on an individual by transfer of antibodies or lymphocytes from an actively
immunized individual (passive immunity).
 Active immunity:
 The immunity induced by exposure to a foreign antigen is called active immunity. Active
immunity is the resistance developed by an individual after contact with foreign antigens,
e.g., microorganisms. This contact may be in the form of:
 clinical or subclinical infection,
 immunization with live or killed infectious agents or their antigens, or
 exposure to microbial products, such as toxins and toxoids.
 Active immunity develops after a latent period, during which immunity of the host is
geared up to act against the microorganism.
 However, once the active immunity develops, it is long-lasting and this is the major
advantage of the active immunity.

Adaptive Immunity
 The active immunity is of two types: natural active immunity and
artificial active immunity.
 Natural active immunity: It is acquired by natural clinical or subclinical
infections. Such natural immunity is long lasting. For example, individuals
suffering from smallpox become immune to second attack of the disease.
 Artificial active immunity: It is induced in individuals by vaccines. There is
a wide range of vaccines available against many microbial pathogens. These
may be live vaccines, killed vaccines, or vaccines containing bacterial
products.

Adaptive Immunity
 Passive immunity:
 When immunity is conferred by transfer of serum or lymphocytes from a specifically
immunized individual, it is known as passive immunity. This is a useful method for
conferring resistance rapidly, i.e., without waiting for the development of an active immune
response. Passive immunity may be natural or artificial.
 Natural passive immunity:
 IgG is passed from mother to fetus during pregnancy. This form the basis of prevention of
neonatal tetanus in neonates by active immunization of pregnant mothers.
1. administering tetanus toxoid to pregnant mothers during the last trimester of pregnancy.
2. production of high level of antibodies in mother against tetanus toxin.
3. subsequent transmission of antibodies from mother to fetus through placenta and protection of
neonates after birth against the risk of tetanus.
 Passage of IgA from mother to newborn during breast feeding.

Adaptive Immunity
 Artificial passive immunity: It is induced in an individual by
administration of preformed antibodies, generally in the form of antiserum,
raised against an infecting agent.
 The preformed antibodies against rabies and hepatitis A and B viruses, etc.
given during incubation period prevent replication of virus, and hence alter
the course of infection.
 Advantage: Immediate availability of large amount of antibodies is the
main advantage of passive immunity.
 Disadvantages: Short lifespan of these antibodies and the possibility of
hypersensitivity reaction, if antibodies prepared in other animal species are
given to individuals who are hypersensitive to these animal globulins (e.g.,
serum sickness).

Cardinal Features of Adaptive Immunity
 All humoral and cell-mediated immune responses to foreign antigens have a
number of fundamental properties:
 Specificity:
 Immune responses are specific for distinct antigens and, in fact, for
different portions of a single complex protein, polysaccharide, or other
macromolecule. The parts of such antigens that are specifically recognized
by individual lymphocytes are called determinants or epitopes.
 Functional significance:
 Ensures that the immune response to a microbe (or nonmicrobial antigen) is targeted
to that microbe (or antigen).

 Diversity: The total number of antigenic specificities of the lymphocytes in
an individual, called the lymphocyte repertoire, is extremely large. It is
estimated that the immune system of an individual can discriminate 107 to
109 distinct antigenic determinants. This ability of the lymphocyte
repertoire to recognize a very large number of antigens is the result of
variability in the structures of the antigen-binding sites of lymphocyte
receptors for antigens, called diversity.
 Enables the immune system to respond to a large variety of antigens.

 Memory: Exposure of the immune
system to a foreign antigen enhances its
ability to respond again to that antigen.
Responses to second and subsequent
exposures to the same antigen, called
secondary immune responses, are
usually more rapid, larger, and often
qualitatively different from the first, or
primary, immune response to that
antigen.
 Increases the ability to combat repeat
infections by the same microbe. FIG: Primary and secondary immune response: Antigens X and Y induce the
production of different antibodies (specificity). The secondary response to antigen
X is more rapid and larger than the primary response (memory). Antibody levels
decline with time after each immunization (contraction, the process that maintains
homeostasis). The same features are seen in cell-mediated immune responses.

 Clonal expansion: Lymphocytes specific for
an antigen undergo considerable
proliferation after exposure to that antigen.
The term clonal expansion refers to an
increase in the number of cells that express
identical receptors for the antigen and thus
belong to a clone. This increase in antigen
specific cells enables the adaptive immune
response to keep pace with rapidly dividing
infectious pathogens.
 Increases the number of antigen-specific
lymphocytes to keep pace with microbes.
FIG: Clonal selection. Mature lymphocytes with receptors for many antigens develop before encountering these antigens. A clone refers to a population of lymphocytes
with identical antigen receptors and therefore specificities; all of these cells are presumably derived from one precursor cell. Each antigen (e.g., X and Y) selects a preexisting clone
of specific lymphocytes and stimulates the proliferation and differentiation of that clone. The diagram shows only B lymphocytes giving rise to antibody-secreting cells, but the
same principle applies to T lymphocytes. The antigens shown are surface molecules of microbes, but clonal selection also is true for extracellular soluble and intracellular antigens.

 Specialization: Humoral immunity and cell-mediated immunity are elicited
by different classes of microbes or by the same microbe at different stages
of infection (extracellular and intracellular), and each type of immune
response protects the host against that class of microbe. Even within
humoral or cell-mediated immune responses, the nature of the antibodies
or T lymphocytes that are generated may vary from one class of microbe to
another.
 Generates responses that are optimal for defense against different types of microbes.

 Contraction and homeostasis: All normal immune responses wane with
time after antigen stimulation, thus returning the immune system to its
resting basal state, a state called homeostasis, prepared to respond to
another infection. This contraction of immune responses occurs largely
because responses that are triggered by antigens function to eliminate the
antigens, thus eliminating an essential stimulus for lymphocyte survival and
activation. Lymphocytes (other than memory cells) that are deprived of
these stimuli die by apoptosis.
 Allows the immune system to recover from one response so that it can effectively
respond to newly encountered antigens.

 Non-reactivity to self: One of the most remarkable properties of every
normal individual’s immune system is its ability to recognize, respond to,
and eliminate many foreign (non-self) antigens while not reacting harmfully
to that individual’s own (self) antigenic substances. Immunologic
unresponsiveness is also called tolerance.
 Abnormalities in the induction or maintenance of self-tolerance lead to
immune responses against self (autologous) antigens, which may result in
disorders called autoimmune diseases.
 Prevents injury to the host during responses to foreign antigens.

Local and Herd Immunity
 Local Immunity:
 The immunity at a particular site, generally at the site of invasion and
multiplication of a pathogen, is referred to as local immunity. Local immunity is
conferred by secretory IgA antibodies in various body secretions. These antibodies
are produced locally by plasma cells present on mucosal surfaces or in secretory
glands. Natural infection or attenuated live viral vaccines given orally or
intranasally induces local immunity at gut mucosa and nasal mucosa, respectively.
 Herd Immunity:
 Herd immunity refers to an overall level of immunity in a community. Eradication of
an infectious disease depends on the development of a high level of herd immunity
against the pathogen. Epidemic of a disease is likely to occur when herd immunity
against that disease is very low indicating the presence of a larger number of
susceptible people in the community.

Cells and Tissues of the Immune System

Cells of the Immune System
 The cells that serve specialized roles in innate and adaptive immune
responses are phagocytes, dendritic cells, antigen-specific lymphocytes, and
various other leukocytes that function to eliminate antigens.
 Although most of these cells are found in the blood, their responses to
microbes usually occur in lymphoid and other tissues and therefore may
not be reflected by changes in their numbers in the circulation.

Phagocytes
 Phagocytes, including neutrophils and macrophages, are cells whose primary
function is to ingest and destroy microbes and get rid of damaged tissues.
 The functional responses of phagocytes in host defense consist of sequential steps:
recruitment of the cells to the sites of infection, recognition of and activation by
microbes, ingestion of the microbes by the process of phagocytosis, and
destruction of ingested microbes.
 Phagocytes that normally circulate in the blood, including neutrophils and
monocytes, are rapidly recruited to sites of infection in the process called
inflammation. These leukocytes (white blood cells) ingest and destroy microbes
and then start the process of repairing damaged tissues. Because these
phagocytes, as well as some T lymphocytes, are responsible for the effect of the
immune response, which is to destroy microbes, they are sometimes called
effector cells.

Neutrophils
 Neutrophils, also called polymorphonuclear leukocytes, are the most abundant
population of circulating white blood cells and mediate the earliest phases of
inflammatory reactions.
 The nucleus of a neutrophil is segmented into three to five connected lobules,
hence the synonym polymorphonuclear leukocyte.
 The cytoplasm contains granules of two types. The majority, called specific
granules, are filled with enzymes such as lysozyme, collagenase, and elastase. The
remainder of the granules of neutrophils, called azurophilic granules, are
lysosomes that contain enzymes and other microbicidal substances, including
defensins and cathelicidins.
 Neutrophils may migrate to sites of infection rapidly after the entry of microbes.
After entering tissues, neutrophils function only for 1 to 2 days and then die.

Mononuclear Phagocytes
 The mononuclear phagocyte system includes circulating cells called
monocytes and tissue resident cells called macrophages.
 Macrophages, which are widely distributed in organs and connective tissue,
play central roles in innate and adaptive immunity.
 In adults, cells of the macrophage lineage arise from committed precursor
cells in the bone marrow. These precursors mature into monocytes, which
enter and circulate in the blood, and then migrate into tissues, especially
during inflammatory reactions, where they further mature into
macrophages.
 Monocytes have bean-shaped nuclei and finely granular cytoplasm
containing lysosomes and phagocytic vacuoles.

FIG: Maturation of mononuclear phagocytes. Tissue resident macrophages, which differentiate into
specialized forms in particular organs, are derived from precursors in the yolk sac and fetal liver during fetal life.
Monocytes arise from a precursor cell of the myeloid lineage in the bone marrow, circulate in the blood, and are
recruited into tissues in inflammatory reactions, where they further mature into macrophages.

Functions of Macrophages
 Tissue macrophages perform several important functions in innate
and adaptive immunity.
 A major function of macrophages in host defense is to ingest and kill
microbes. The mechanisms of killing include the enzymatic generation of
reactive oxygen and nitrogen species that are toxic to microbes, and
proteolytic digestion.
 In addition to ingesting microbes, macrophages also ingest dead host cells,
including cells that die in tissues because of trauma or interrupted blood
supply and neutrophils that accumulate at sites of infection. This is part of
the cleaning up process after infection or sterile tissue injury. Macrophages
also recognize and engulf apoptotic cells before the dead cells can release
their contents and induce inflammatory responses.

Functions of Macrophages
 Activated macrophages secrete several different cytokines that act on
endothelial cells lining blood vessels to enhance the recruitment of more
monocytes and other leukocytes from the blood into sites of infections,
thereby amplifying the protective response against the microbes.
 Macrophages serve as APCs that display antigens to and activate T
lymphocytes.
 Macrophages promote the repair of damaged tissues by stimulating new
blood vessel growth (angiogenesis) and synthesis of collagen-rich
extracellular matrix (fibrosis). These functions are mediated by cytokines
secreted by the macrophages that act on various tissue cells.

Mast Cells, Basophils, and Eosinophils
 Mast cells, basophils, and eosinophils are three additional cells that play
roles in innate and adaptive immune responses. All three cell types share
the common feature of having cytoplasmic granules filled with various
inflammatory and antimicrobial mediators. Another common feature of
these cells is their involvement in immune responses that protect against
helminths and reactions that cause allergic diseases.
 Mast cells:
 Mast cells are bone marrow–derived cells present in the skin and mucosal
epithelia, which contain abundant cytoplasmic granules filled with
histamine and other mediators.
 Normally, mature mast cells are not found in the circulation but are present
in tissues, usually adjacent to small blood vessels and nerves

 Mast cells express high affinity plasma membrane receptors for a type of
antibody called IgE and are usually coated with these antibodies. When the
antibodies on the mast cell surface bind antigen, signaling events are
induced that lead to release of the cytoplasmic granule contents into the
extracellular space.
 The released granule contents, including histamine, promote changes in the
blood vessels that cause inflammation. Mast cells function as sentinels in
tissues, where they recognize microbial products and respond by producing
cytokines and other mediators that induce inflammation. These cells
provide defense against helminths and other microbes, but are also
responsible for symptoms of allergic diseases

 Basophils:
 Basophils are blood granulocytes with many structural and functional similarities
to mast cells.
 Although they are normally not present in tissues, basophils may be recruited to
some inflammatory sites.
 Like mast cells, basophils express IgE receptors, bind IgE, and can be triggered by
antigen binding to the IgE.
 Because basophil numbers are low in tissues, their importance in host defense and
allergic reactions is uncertain.
 Eosinophils:
 Eosinophils are blood granulocytes that express cytoplasmic granules containing
enzymes that are harmful to the cell walls of parasites but can also damage host
tissues.

Antigen Presenting Cells
 Antigen-presenting cells (APCs) are cells that capture microbial and
other antigens, display them to lymphocytes, and provide signals that
stimulate the proliferation and differentiation of the lymphocytes.
 By convention, APC usually refers to a cell that displays antigens to T
lymphocytes. The major type of APC that is involved in initiating T cell
responses is the dendritic cell. Macrophages and B cells present antigens
to T lymphocytes in cell mediated and humoral immune responses,
respectively.
 A specialized cell type called the follicular dendritic cell displays antigens
to B lymphocytes during particular phases of humoral immune responses.

Antigen Presenting Cells
 Many APCs, such as dendritic cells and macrophages, also recognize and
respond to microbes during innate immune reactions and thus link innate
immune reactions to responses of the adaptive immune system.
 Specialized cells that display antigens to T cells and provide additional
activating signals sometimes are called professional APCs.
 The prototypic professional APCs are dendritic cells, but macrophages, B
cells, and a few other cell types may serve the same function in various
immune responses.

Dendritic Cells
 Dendritic cells are the most important APCs for activating naive T cells, and
they play major roles in innate responses to infections and in linking innate
and adaptive immune responses.
 They have long membranous projections and phagocytic capabilities and are
widely distributed.
 The majority of dendritic cells in skin, mucosa, and organ parenchyma, which are
called classical (or conventional) dendritic cells, respond to microbes by
migrating to lymph nodes, where they display microbial protein antigens to T
lymphocytes.
 One subpopulation of dendritic cells, called plasmacytoid dendritic cells, are
early cellular responders to viral infection. They recognize nucleic acids of
intracellular viruses and produce soluble proteins called type I interferons, which
have potent antiviral activities.

FIG: Maturation of dendritic cells. Dendritic cells arise from a common precursor cell of the myeloid lineage
in the bone marrow and further differentiate into subsets, the major ones being classical dendritic cells and
plasmacytoid dendritic cells. Inflammatory dendritic cells may arise from monocytes in inflamed tissues, and
some tissue-resident dendritic cells, such as Langerhans cells in the skin, may develop from embryonic
precursors.

Other Antigen-Presenting Cells
 In addition to dendritic cells, macrophages and B lymphocytes are important
antigen-presenting cells for CD4+ helper T cells.
 Macrophages present antigens to helper T lymphocytes at the sites of infection,
which leads to helper T cell activation and production of molecules that further
activate the macrophages. This process is important for the eradication of
microbes that are ingested by the phagocytes but resist killing; in these cases,
helper T cells greatly enhance the microbicidal activities of the macrophages.
 B cells present antigens to helper T cells, which is a key step in the cooperation of
helper T cells with B cells for antibody responses to protein antigens.
 Cytotoxic T lymphocytes (CTLs) are effector CD8+ T cells that can recognize
antigens on any type of nucleated cell and become activated to kill the cell.
Therefore, all nucleated cells are potentially APCs for CTLs.

Follicular Dendritic Cells (FDCs)
 A type of cell called the follicular dendritic cell (FDC) resides in the germinal
centers of lymphoid follicles in the peripheral lymphoid organs and displays
antigens that stimulate the differentiation of B cells in the follicles. FDCs do not
present antigens to T cells and differ from the dendritic cells described earlier that
function as APCs for T lymphocytes.
 Follicular dendritic cells (FDCs) are cells with membranous projections that are
found intermingled in collections of activated B cells in the lymphoid follicles of
lymph nodes, spleen, and mucosal lymphoid tissues.
 FDCs are not derived from precursors in the bone marrow and are unrelated to the
dendritic cells that present antigens to T lymphocytes.
 FDCs bind and display protein antigens on their surfaces for recognition by B
lymphocytes. This is important for the selection of B lymphocytes that express
antibodies that bind antigens with high affinity.

Lymphocytes
 Lymphocytes, the unique cells of adaptive immunity, are the only cells in
the body that express clonally distributed antigen receptors, each
specific for a different antigenic determinant.
 Each clone of T and B lymphocytes expresses antigen receptors with a
single specificity, which is different from the specificities of the receptors in
all other clones.
 These cells often are distinguishable by surface proteins that may be
identified using panels of monoclonal antibodies. The standard
nomenclature for these proteins is the CD (cluster of differentiation)
numerical designation, which is used to delineate surface proteins that
define a particular cell type or stage of cell differentiation and that are
recognized by a cluster or group of antibodies.

Lymphocytes
 All lymphocytes arise from stem cells in the bone marrow. B lymphocytes
mature in the bone marrow, and T lymphocytes mature in an organ
called the thymus. These sites in which mature lymphocytes are produced
(generated) are called the primary or generative lymphoid organs.
 Mature lymphocytes leave the generative lymphoid organs and enter the
circulation and the secondary or peripheral lymphoid organs, where
they may encounter antigen for which they express specific receptors.

FIG: Maturation of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs
(bone marrow and thymus). Mature lymphocytes enter the peripheral lymphoid organs, where they
respond to foreign antigens and recirculate in the blood and lymph. Some immature B cells leave the bone
marrow and complete their maturation in the spleen (not shown).

Lymphocytes
 B lymphocytes, the cells that produce antibodies, were so called because in birds
they were found to mature in an organ called the bursa of Fabricius. In mammals,
no anatomic equivalent of the bursa exists, and the early stages of B cell
maturation occur in the bone marrow. Thus, B lymphocytes now refer to bone
marrow–derived lymphocytes.
 B lymphocytes are the only cells capable of producing antibodies; therefore, they
are the cells that mediate humoral immunity.
 B cells express membrane forms of antibodies that serve as the receptors that
recognize antigens and initiate the process of activation of the cells. Soluble
antigens and antigens on the surface of microbes and other cells may bind to these
B lymphocyte antigen receptors, initiating the process of B cell activation. This
leads to the secretion of soluble forms of antibodies with the same antigen
specificity as the membrane receptors.

Lymphocytes
 T lymphocytes, the mediators of cellular immunity, arise in the bone marrow, and
migrate to and mature in the thymus; T lymphocytes refer to thymus-derived
lymphocytes.
 The antigen receptors of most T lymphocytes recognize only peptide fragments of
protein antigens that are bound to specialized peptide display molecules, called
major histocompatibility complex (MHC) molecules, on the surface of specialized
cells, called antigen-presenting cells.
 Among T lymphocytes, CD4+ T cells are called helper T cells because they help B
lymphocytes to produce antibodies and help phagocytes to destroy ingested
microbes.
 CD8+ T lymphocytes are called cytotoxic T lymphocytes (CTLs) because they kill
cells harboring intracellular microbes.
 Some CD4+ T cells belong to a special subset that functions to prevent or limit
immune responses; these are called regulatory T lymphocytes.

FIG: Classes of lymphocytes.
Different classes of lymphocytes in the
adaptive immune system recognize
distinct types of antigens and
differentiate into effector cells whose
function is to eliminate the antigens. B
lymphocytes recognize soluble or cell
surface antigens and differentiate into
antibody-secreting cells. Helper T
lymphocytes recognize antigens on the
surfaces of antigen-presenting cells
and secrete cytokines, which stimulate
different mechanisms of immunity and
inflammation. Cytotoxic T lymphocytes
recognize antigens in infected cells and
kill these cells. Regulatory T cells limit
the activation of other lymphocytes,
especially of T cells, and prevent
autoimmunity.

Lymphocytes
 When naive lymphocytes recognize microbial antigens and also receive
additional signals induced by microbes, the antigen-specific lymphocytes
proliferate and differentiate into effector cells and memory cells.
 Naive lymphocytes express receptors for antigens but do not perform the
functions that are required to eliminate antigens. These cells reside in and
circulate between peripheral lymphoid organs and survive for several weeks or
months, waiting to find and respond to antigen. If they are not activated by
antigen, naive lymphocytes die by the process of apoptosis and are replaced by
new cells that have arisen in the generative lymphoid organs. The differentiation
of naive lymphocytes into effector cells and memory cells is initiated by antigen
recognition, thus ensuring that the immune response that develops is specific for
the antigen.

Lymphocytes
 Effector lymphocytes are the differentiated progeny of naive cells that
have the ability to produce molecules that function to eliminate antigens.
The effector cells in the B lymphocyte lineage are antibody-secreting cells,
called plasma cells. Plasma cells develop in response to antigenic
stimulation in the peripheral lymphoid organs, where they may stay and
produce antibodies.
 Effector CD4+ T cells (helper T cells) produce proteins called cytokines that
activate B cells, macrophages, and other cell types, thereby mediating the
helper function of this lineage. Effector CD8+ T cells (CTLs) have the
machinery to kill infected host cells. Effector T lymphocytes are short-lived
and die as the antigen is eliminated.

FIG: Maturation of lymphocytes. Lymphocytes develop from bone marrow stem cells, mature in the
generative lymphoid organs (bone marrow and thymus for B and T cells, respectively), and then circulate
through the blood to secondary lymphoid organs (lymph nodes, spleen, regional lymphoid tissues such as
mucosa-associated lymphoid tissues). Fully mature T cells leave the thymus, but immature B cells leave the
bone marrow and complete their maturation in secondary lymphoid organs. Naive lymphocytes may respond
to foreign antigens in these secondary lymphoid tissues or return by lymphatic drainage to the blood and
recirculate through other secondary lymphoid organs.

Lymphocytes
 Memory cells, also generated from the progeny of antigen-stimulated lymphocytes, do
survive for long periods in the absence of antigen. Therefore, the frequency of memory
cells increases with age, presumably because of exposure to environmental microbes. In
fact, memory cells make up less than 5% of peripheral blood T cells in a newborn, but 50%
or more in an adult.
 As individuals age, the gradual accumulation of memory cells compensates for the reduced
output of new, naive T cells from the thymus, which involutes after puberty.
 Memory cells are functionally inactive; they do not perform effector functions unless
stimulated by antigen. When memory cells encounter the same antigen that induced their
development, the cells rapidly respond to initiate secondary immune responses. The
signals that generate and maintain memory cells are not well understood but include
cytokines.
 Memory B lymphocytes may express certain classes (isotypes) of membrane Ig, such as
IgG, IgE, or IgA, as a result of isotype switching, whereas naive B cells express only IgM and
IgD.

FIG: Steps in lymphocyte activation. Naive T cells emerging from the thymus and immature B cells emerging from the
bone marrow migrate into secondary lymphoid organs, including lymph nodes and spleen. In these locations, B cells
complete their maturation; naive B and T cells activated by antigens differentiate into effector and memory lymphocytes.
Some effector and memory lymphocytes migrate into peripheral tissue sites of infection. Antibodies secreted by effector B
cells in lymph node, spleen, and bone marrow (not shown) enter the blood and are delivered to sites of infection.

Tissues of the Immune System
 Lymphoid tissues are classified as generative organs, also called
primary or central lymphoid organs, where lymphocytes first express
antigen receptors and attain phenotypic and functional maturity, and
peripheral organs, also called secondary lymphoid organs, where
lymphocyte responses to foreign antigens are initiated and develop.
 Included in the generative lymphoid organs of adult mammals are the bone
marrow and the thymus, the sites of maturation of B cells and T cells,
respectively.
 The peripheral lymphoid tissues include the lymph nodes, spleen,
cutaneous immune system, and mucosal immune system.

Tissues of the Immune System
 B lymphocytes partially mature in the bone marrow, enter the circulation, then
populate secondary lymphoid organs, including spleen and lymph nodes, and
complete their maturation mainly in the spleen.
 T lymphocytes mature in the thymus, and then enter the circulation and populate
peripheral lymphoid organs and tissues.
 Two important functions shared by the generative organs are to provide growth
factors and other molecular signals needed for lymphocyte maturation and to
present self antigens for recognition and selection of maturing lymphocytes.
 All peripheral lymphoid organs also share common functions, including the
delivery of antigens and responding naive lymphocytes to the same location so
that adaptive immune responses can be initiated, and an anatomic organization
that allows T cells and B cells to interact cooperatively.

Generative Lymphoid Organs
Bone Marrow:
 The bone marrow is the site of generation of most mature circulating blood
cells, including red blood cells, granulocytes, and monocytes, and the site of
early events in B cell maturation.
 The generation of all blood cells, called hematopoiesis, occurs initially during
fetal development in blood islands of the yolk sac, then shifts to the liver between
the third and fourth months of gestation, and finally shifts to the bone marrow.
 Red blood cells, granulocytes, monocytes, dendritic cells, platelets, B and T
lymphocytes, and NK cells all originate from a common hematopoietic stem cell
(HSC) in the bone marrow.
 When the bone marrow is injured or when an exceptional demand for production
of new blood cells occurs, the liver and spleen often become sites of
extramedullary hematopoiesis.

Bone Marrow
 HSCs are pluripotent, meaning that a single HSC can generate all different
types of mature blood cells. HSCs are also self renewing because each time
they divide, at least one daughter cell maintains the properties of a stem
cell while the other can differentiate along a particular lineage (called
asymmetric division).
 HSCs are maintained within specialized microscopic anatomic niches in the
bone marrow. In these locations, nonhematopoietic stromal cells provide
contact-dependent signals and soluble factors required for continuous
cycling of the HSCs.
 HSCs give rise to two kinds of multipotent progenitor cells, one that
generates lymphoid and some myeloid cells and another that produces
more myeloid cells, erythrocytes, and platelets.

Bone Marrow
 The common myeloid-lymphoid progenitor gives rise to committed
precursors of T cell, B cell, as well as to some myeloid cells. The common
myeloid-megakaryocyte-erythroid progenitors give rise to committed
precursors of the erythroid, megakaryocytic, granulocytic, and monocytic
lineages, which give rise, respectively, to mature red blood cells, platelets,
granulocytes (neutrophils, eosinophils, basophils), and monocytes. Most
dendritic cells arise from a branch of the monocytic lineage.
 In addition to self-renewing stem cells and their differentiating progeny, the
marrow contains numerous long-lived antibody-secreting plasma cells.
These cells are generated in peripheral lymphoid tissues as a consequence
of antigenic stimulation of B cells and then migrate to the bone marrow.

Thymus
 The thymus is the site of T cell maturation. The thymus is a bilobed organ
situated in the anterior mediastinum. Each lobe is divided into multiple lobules by
fibrous septa, and each lobule consists of an outer cortex and an inner medulla.
 The cortex contains a dense collection of T lymphocytes, and the lighter-staining
medulla is more sparsely populated with lymphocytes. Bone marrow–derived
macrophages and dendritic cells are found almost exclusively in the medulla.
Scattered throughout the thymus are nonlymphoid epithelial cells, which have
abundant cytoplasm.
 Thymic cortical epithelial cells produce IL-7, which is required early in T cell
development. A different subset of epithelial cells found only in the medulla, called
medullary thymic epithelial cells (MTEC), plays a special role in presenting self
antigens to developing T cells and causing their deletion. This is one mechanism of
ensuring that the immune system remains tolerant to self antigens.

Thymus
 In the medulla there are structures called Hassall’s corpuscles, which are
composed of tightly packed whorls of epithelial cells that may be remnants
of degenerating cells.
 The lymphocytes in the thymus, also called thymocytes, are T lymphocytes
at various stages of maturation. The most immature cells enter the thymus,
and their maturation begins in the cortex.
 As thymocytes mature, they migrate toward the medulla, so that the
medulla contains mostly mature T cells. Only mature naïve T cells exit the
thymus and enter the blood and peripheral lymphoid tissues.

FIG: Morphology of the thymus.
A, Low-power light micrograph of a lobe of
the thymus showing the cortex and
medulla. The darker blue-stained outer
cortex and paler blue inner medulla are
apparent.
B, High-power light micrograph of the
thymic medulla. The numerous small blue-
staining cells are developing T cells called
thymocytes, and the larger pink structure
is Hassall’s corpuscle, uniquely
characteristic of the thymic medulla but
whose function is poorly understood.
C, Schematic diagram of the thymus
illustrating a portion of a lobe divided into
multiple lobules by fibrous trabeculae.

Peripheral Lymphoid Organs
 The peripheral lymphoid organs, which consist of the lymph nodes, the spleen, and
the mucosal and cutaneous immune systems, are organized in a way that promotes
the development of adaptive immune responses. T and B lymphocytes must locate
microbes that enter at any site in the body, then respond to these microbes and eliminate
them.
 The anatomic organization of peripheral lymphoid organs enables APCs to concentrate
antigens in these organs and lymphocytes to locate and respond to the antigens. This
organization is complemented by a remarkable ability of lymphocytes to circulate
throughout the body in such a way that naive lymphocytes preferentially go to the
specialized organs in which antigen is concentrated, and effector cells go to sites of
infection where microbes must be eliminated.
 Migration of effector lymphocytes to sites of infection is most relevant for T cells, because
effector T cells have to locate and eliminate microbes at these sites. By contrast, plasma
cells do not need to migrate to sites of infection; instead, they secrete antibodies, and the
antibodies enter the blood, where they may bind blood-borne pathogens or toxins.

Lymph Nodes
 Lymph nodes are encapsulated nodular aggregates of lymphoid tissues located
along lymphatic channels throughout the body. Fluid constantly leaks out of blood
vessels in all epithelia and connective tissues and most parenchymal organs.
 This fluid, called lymph, is drained by lymphatic vessels from the tissues to the
lymph nodes and eventually back into the blood circulation. Therefore, the lymph
contains a mixture of substances absorbed from epithelia and tissues. As the
lymph passes through lymph nodes, APCs in the nodes are able to sample the
antigens of microbes that may enter through epithelia into tissues.
 In addition, dendritic cells pick up antigens of microbes from epithelia and other
tissues and transport these antigens to the lymph nodes. The net result of these
processes of antigen capture and transport is that the antigens of microbes
entering through epithelia or colonizing tissues become concentrated in draining
lymph nodes.

FIG: Morphology of a lymph node.
Schematic diagram of a lymph node illustrating
the T cell–rich and B cell–rich zones and the
routes of entry of lymphocytes and antigen
(shown captured by a dendritic cell).
FIG: Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs.
A, Schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas
of a lymph node. Naive B and T lymphocytes enter through a high endothelial venule (HEV), shown in
cross section, and are drawn to different areas of the node by chemokines that are produced in these
areas and bind selectively to either cell type. Also shown is the migration of dendritic cells, which pick up
antigens from epithelia, enter through afferent lymphatic vessels, and migrate to the T cell–rich areas of
the node. B, In this histologic section of a lymph node, the B lymphocytes, located in the follicles, are
stained green, and the T cells, in the parafollicular cortex, are stained red using immunofluorescence. In
this technique, a section of the tissue is stained with antibodies specific for T or B cells coupled to
fluorochromes that emit different colors when excited at the appropriate wavelengths. The anatomic
segregation of T and B cells also occurs in the spleen (not shown).

Lymph Nodes
 There are about 500 lymph nodes in the human body. A lymph node is
surrounded by a fibrous capsule, beneath which is a sinus system lined by
reticular cells, cross-bridged by fibrils of collagen and other extracellular
matrix proteins and filled with lymph, macrophages, dendritic cells, and
other cell types.
 Afferent lymphatics empty into the subcapsular (marginal) sinus, and
lymph may drain from there directly into the connected medullary sinus
and then out of the lymph node through the efferent lymphatics. Beneath
the inner floor of the subcapsular sinus is the lymphocyte-rich cortex.
 The outer cortex contains aggregates of cells called follicles. Some follicles
contain central areas called germinal centers.

Lymph Nodes
 Each germinal center consists of a dark zone packed with proliferating B
cells called centroblasts, and a light zone containing cells called centrocytes
that have stopped proliferating and are being selected to survive and
differentiate further.
 Follicles without germinal centers are called primary follicles, and those
with germinal centers are called secondary follicles. The cortex around the
follicles is called the parafollicular cortex or paracortex and is organized
into cords, which are regions with a complex microanatomy of matrix
proteins, fibers, lymphocytes, dendritic cells, and mononuclear phagocytes.

Lymph Nodes
 B and T lymphocytes are sequestered in distinct regions of the cortex of
lymph nodes.
 Follicles are the B cell zones. They are located in the lymph node cortex and
are organized around FDCs, which have processes that interdigitate to form
a dense reticular network.
 Primary follicles contain mostly mature, naive B lymphocytes. Germinal
centers develop in response to antigenic stimulation. They are sites of
remarkable B cell proliferation, selection of B cells producing high-affinity
antibodies, and generation of memory B cells and long-lived plasma cells.

Lymph Nodes
 The T lymphocytes are located mainly beneath and more central to the follicles, in
the paracortical cords.
 These T cell–rich zones, often called the paracortex, contain a network of
fibroblastic reticular cells (FRCs), many of which form the outer layer of tube-
like structures called FRC that contain organized arrays of extracellular matrix
molecules. These conduits begin at the subcapsular sinus and extend to both
medullary sinus lymphatic vessels and cortical blood vessels, called high
endothelial venules (HEVs).
 Naive T cells enter the T cell zones through the HEVs. T cells are densely packed
around the conduits in the lymph node cortex. Most (∼70%) of the cortical T cells
are CD4+ helper T cells, intermingled with relativsely sparse CD8+ cells. These
proportions can change dramatically during the course of an infection. For
example, during a viral infection, there may be a marked increase in CD8+ T cells.

Lymph Nodes
 The anatomic segregation of B and T cells ensures that each lymphocyte
population is in close contact with the appropriate APCs, that is, B cells with
FDCs and T cells with dendritic cells.
 Activated T cells either migrate toward follicles to help B cells or exit the node and
enter the circulation. Activated B cells migrate into germinal centers and, after
differentiation into plasma cells, may home to the bone marrow.
 In the lymph node, if a T cell specifically recognizes an antigen on a dendritic cell,
that T cell forms stable conjugates with the dendritic cell and is activated. Such an
encounter between an antigen and a specific lymphocyte is likely to be a random
event, but most T cells in the body circulate through some lymph nodes at least
once a day. Naive cells that have not encountered specific antigens leave the lymph
nodes and reenter the circulation.

FIG: Migration of T lymphocytes. Naive T lymphocytes migrate from the blood through high
endothelial venules into the T cell zones of lymph nodes, where the cells are activated by antigens.
Activated T cells exit the nodes, enter the bloodstream, and migrate preferentially to peripheral
tissues at sites of infection and inflammation.

Lymph Nodes
 The effector cells that are generated upon T cell activation preferentially
migrate into the tissues infected by microbes, where the T lymphocytes
perform their function of eradicating the infection.
 B lymphocytes that recognize and respond to antigen in lymph node
follicles differentiate into antibody-secreting cells, which either remain in
the lymph nodes or migrate to the bone marrow.

Spleen
 The spleen is a highly vascularized organ whose major functions are to
remove aging and damaged blood cells and particles (such as immune
complexes and opsonized microbes) from the circulation and to initiate
adaptive immune responses to blood-borne antigens.
 The spleen weighs about 150g in adults and is located in the left upper
quadrant of the abdomen. The splenic parenchyma is anatomically and
functionally divided into red pulp, which is composed mainly of blood-filled
vascular sinusoids, and lymphocyte-rich white pulp. Blood enters the
spleen through a single splenic artery that pierces the capsule at the hilum
and divides into progressively smaller branches that remain surrounded by
protective and supporting fibrous trabeculae.

Spleen
 The red pulp macrophages serve as an important filter for the blood, removing
microbes, damaged cells, and antibody-coated (opsonized) cells and microbes.
Individuals lacking a spleen are susceptible to disseminated infections with
encapsulated bacteria such as pneumococci and meningococci. This may be
because such organisms are normally cleared by opsonization and phagocytosis,
and this function is defective in the absence of the spleen.
 The white pulp contains the cells that mediate adaptive immune responses to
blood-borne antigens. In the white pulp are many collections of densely packed
lymphocytes, which appear as white nodules against the background of the red
pulp. The white pulp is organized around central arteries, which are branches of
the splenic artery distinct from the branches that form the vascular sinusoids.
Several smaller branches of each central artery pass through the lymphocyte-rich
area and drain into a marginal sinus.

Spleen
 A region of specialized cells surrounding
the marginal sinus, called the marginal
zone, forms the boundary between the
red pulp and white pulp. The
architecture of the white pulp is
analogous to the organization of lymph
nodes, with segregated T cell and B cell
zones.
 The anatomic arrangements of the APCs,
B cells, and T cells in the splenic white
pulp promote the interactions required
for the efficient development of humoral
immune response.
FIG: Morphology of the
spleen. A, Schematic
diagram shows a splenic
arteriole surrounded by
the periarteriolar
lymphoid sheath (PALS)
and attached follicle
containing a prominent
germinal center. The
PALS and lymphoid
follicles together
constitute the white pulp.
B, Light micrograph of a
section of spleen shows
an arteriole with the
PALS and a follicle with a
germinal center. These
are surrounded by the
red pulp, which is rich in
vascular sinusoids.

Cutaneous and Mucosal Immune System
 The cutaneous immune system and mucosal immune system are specialized collections
of lymphoid tissues and APCs located in and under the epithelia of the skin and the
gastrointestinal and respiratory tracts, respectively. Although most of the immune cells in
these tissues are diffusely scattered beneath the epithelial barriers, there are discrete
collections of lymphocytes and APCs organized in a similar way as in lymph nodes. For
example, tonsils in the pharynx and Peyer’s patches in the intestine are two anatomically
defined mucosal lymphoid tissues.
 At any time, at least a quarter of the body’s lymphocytes are in the mucosal tissues and skin
(reflecting the large size of these tissues), and many of these are memory cells. Cutaneous
and mucosal lymphoid tissues are sites of immune responses to antigens that breach
epithelia. A remarkable property of the cutaneous and mucosal immune systems is that
they are able to respond to pathogens but do not react to the enormous numbers of usually
harmless commensal microbes present at the epithelial barriers. This is accomplished by
several mechanisms, including the action of regulatory T cells and other cells that suppress
rather than activate T lymphocytes.

FIG: Mucosal immune system. Schematic diagram of the mucosal immune system uses the small bowel as an example. Many commensal
bacteria are present in the lumen. The mucus-secreting epithelium provides an innate barrier to microbial invasion. Specialized epithelial cells, such
as M cells, promote the transport of antigens from the lumen into underlying tissues. Cells in the lamina propria, including dendritic cells, T
lymphocytes, and macrophages, provide innate and adaptive immune defense against invading microbes; some of these cells are organized into
specialized structures, such as Peyer’s patches in the small intestine. Immunoglobulin A (IgA) is a type of antibody abundantly produced in mucosal
tissues that is transported into the lumen, where it binds and neutralizes microbes.

Overview of Immune Response to Microbes
The Early Innate Immune Response to Microbes
 The innate immune system blocks the entry of microbes and eliminates or
limits the growth of many microbes that are able to colonize tissues. The
main sites of interaction between individuals and their environment— the
skin, lungs, and gastrointestinal and respiratory tracts—are lined by
continuous epithelia, which serve as barriers to prevent the entry of
microbes from the external environment. If microbes successfully breach
the epithelial barriers, they encounter other cells of innate immunity.
 The cellular innate immune response to microbes consists of two main
types of reactions—inflammation and antiviral defense.

 Inflammation is the process of recruitment of leukocytes and plasma proteins
from the blood, their accumulation in tissues, and their activation to destroy the
microbes. The major leukocytes that are recruited in inflammation are the
phagocytes, neutrophils (which have short life spans in tissues) and monocytes
(which develop into tissue macrophages). Phagocytes ingest microbes and dead
cells and destroy these in intracellular vesicles.
 Antiviral defense consists of a cytokine-mediated reaction in which cells acquire
resistance to viral infection and killing of virus infected cells by specialized cells of
the innate immune system, natural killer (NK) cells.
 The reactions of innate immunity are effective at controlling and even eradicating
infections. However, as mentioned earlier, many pathogenic microbes have evolved
to resist innate immunity. Defense against these pathogens requires the more
powerful and specialized mechanisms of adaptive immunity.

The Adaptive Immune Response
 The adaptive immune system uses three main strategies to combat most microbes.
 Antibodies: Secreted antibodies bind to extracellular microbes, block their ability
to infect host cells, and promote their ingestion and subsequent destruction by
phagocytes.
 Phagocytosis: Phagocytes ingest microbes and kill them, and antibodies and
helper T cells enhance the microbicidal abilities of the phagocytes.
 Cell killing: Cytotoxic T lymphocytes (CTLs) destroy cells infected by microbes
that are inaccessible to anti bodies and phagocytic destruction.
 All adaptive immune responses develop in sequential steps, each of which
corresponds to particular reactions of lymphocytes

FIG: Phases of adaptive immune response.
An adaptive immune response consists of
distinct phases; the first three are recognition
of antigen, activation of lymphocytes, and
elimination of antigen (effector phase). The
response declines as antigen-stimulated
lymphocytes die by apoptosis, restoring the
baseline steady state called homeostasis, and
the antigen-specific cells that survive are
responsible for memory. The duration of each
phase may vary in different immune
responses. These principles apply to both
humoral immunity (mediated by B
lymphocytes) and cell-mediated immunity
(mediated by T lymphocytes).

Capture and Display of Microbial Antigens:
 Microbes that enter through epithelia, as well as their protein antigens, are
captured by dendritic cells residing in these epithelia, and the cell-bound antigens
are transported to draining lymph nodes. Microbial protein antigens are processed
in the dendritic cells to generate peptides that are displayed on the cell surface
bound to MHC molecules. Naive T cells recognize these peptide-MHC complexes,
and this is the first step in the initiation of T cell responses. Dendritic cells also
display microbial peptides in the spleen.
 Intact microbes or microbial antigens that enter lymph nodes and spleen are
recognized in unprocessed (native) form by specific B lymphocytes. Antigens may
also be displayed to B lymphocytes by certain APCs in lymphoid organs.

Antigen Recognition by Lymphocytes:
 Lymphocytes specific for a large number of antigens exist before exposure to the
antigen, and when an antigen enters a secondary lymphoid organ, it binds to
(selects) the antigen-specific cells and activates them. This fundamental concept is
called the clonal selection hypothesis.
 A characteristic of the immune system is that a very large number of clones is
generated during the maturation of lymphocytes, thus maximizing the potential
for recognizing diverse microbes. A clone refers to a lymphocyte of one specificity
and its progeny.
 Because T cell receptors are specific for MHC-associated peptides, these
lymphocytes can interact only with cell-associated antigens (because MHC
molecules are cell surface proteins) and not with free antigen.

 To respond, the T cells need to recognize not only antigens but also other
molecules, called costimulators, which are induced on the APCs by
microbes.
 B lymphocytes use their antigen receptors (membrane bound antibody
molecules) to recognize antigens of many different chemical types.
 Engagement of antigen receptors and other signals trigger lymphocyte
proliferation and differentiation. The reactions and functions of T and B
lymphocytes differ in important ways and are best considered separately.

Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of
Cell-Associated Microbes
 Activated CD4+ helper T lymphocytes proliferate and differentiate into
effector cells whose functions are mediated largely by secreted cytokines.
When naïve CD4+ T cells are activated by antigen, they secrete the cytokine
interleukin-2 (IL-2), which is a growth factor that stimulates the
proliferation (clonal expansion) of the antigen-specific T cells.
 Some of the effector T cells generated in the lymphoid organ may migrate
back into the blood and then into any site where the antigen (or microbe) is
present. These effector cells are reactivated by antigen at sites of infection
and perform the functions responsible for elimination of the microbes.

 Some CD4+ helper T cells secrete cytokines that recruit leukocytes and
stimulate production of microbicidal substances in phagocytes. Thus, these
T cells help phagocytes to kill the infectious pathogens. Other CD4+ helper T
cells secrete cytokines that help B cells produce a type of antibody called
immunoglobulin E (IgE) and activate leukocytes called eosinophils, which
are able to kill parasites that may be too large to be phagocytosed.
 Activated CD8+ lymphocytes proliferate and differentiate into CTLs that kill
cells harboring microbes in the cytoplasm. These microbes may be viruses
that infect many cell types or bacteria that are ingested by macrophages but
escape from phagocytic vesicles into the cytoplasm. By destroying the
infected cells, CTLs eliminate the reservoirs of infection.

Humoral Immunity: Activation of B Lymphocytes and Elimination of
Extracellular Microbes
 On activation by antigen, B lymphocytes proliferate and differentiate into cells that
secrete different classes of antibodies with distinct functions. The response of B
cells to protein antigens requires activating signals (help) from CD4+ T cells (which
is the historical reason for calling these T cells helper cells). B cells can respond to
many nonprotein antigens without the participation of helper T cells.
 Some of the progeny of the expanded B cell clones differentiate into antibody-
secreting plasma cells. Each plasma cell secretes antibodies that have the same
antigen binding site as the cell surface antibodies (B cell receptors) that first
recognized the antigen. Polysaccharides and lipids stimulate secretion mainly of
the antibody class called IgM. Protein antigens induce the production of antibodies
of functionally different classes (IgG, IgA, IgE) from a single clone of B cells.

 The humoral immune response combats microbes in many ways.
 Antibodies bind to microbes and prevent them from infecting cells, thus
neutralizing the microbes.
 IgG antibodies coat microbes and target them for phagocytosis because
phagocytes (neutrophils and macrophages) express receptors for parts of IgG
molecules.
 IgG and IgM activate the complement system, and complement products promote
phagocytosis and destruction of microbes. Some antibodies serve special roles at
particular anatomic sites.
 IgA is secreted from mucosal epithelia and neutralizes microbes in the lumens of
mucosal tissues, such as the respiratory and gastrointestinal tracts.
 Maternal IgG is actively transported across the placenta and protects the newborn
until the baby’s immune system becomes mature.

Decline of Immune Responses and Immunologic Memory:
 The majority of effector lymphocytes induced by an infectious pathogen die
by apoptosis after the microbe is eliminated, thus returning the immune
system to its basal resting state, called homeostasis. This occurs because
microbes provide essential stimuli for lymphocyte survival and activation,
and effector cells are short-lived. Therefore, as the stimuli are eliminated,
the activated lymphocytes are no longer kept alive.
 The initial activation of lymphocytes generates long-lived memory cells,
which may survive for years after the infection and mount rapid and robust
responses to a repeat encounter with the antigen.

Overview of immune response

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