Overview of immune response

Properties and Overview of Immune Response

Md. Murad KhanLecturerDept. of MicrobiologyJagannath 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.

Functional significance: 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.

Functional significance: 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.

Functional significance: 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.

Functional significance: 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.

Functional significance: 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.

Functional significance: 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.

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Overview of immune response