The adaptive immune system, also known as the acquired immune or, more rarely, as the specific immune system,
is a subsystem of the overall immune system that is composed of highly specialized, systemic cells and processes that
eliminate or prevent pathogen growth. The adaptive immune system is one of the two main immunity strategies found in
vertebrates (the other being the innate immune system). Adaptive immunity creates immunological memory after an
initial response to a specific pathogen, leads to an enhanced response to subsequent encounters with that pathogen.
This process of acquired immunity is the basis of vaccination. Like the innate system, the adaptive system includes
both humoral immunity components and cell-mediated immunity components.
Unlike the innate immune system, the adaptive immune system is highly specific to a specific pathogen. Adaptive immunity
can also provide long-lasting protection: for example; someone who recovers from measles is now protected against measles
for their lifetime but in other cases it does not provide lifetime protection: for example; chickenpox. The
adaptive system response destroys invading pathogens and any toxic molecules they produce. Sometimes the adaptive system is
unable to distinguish foreign molecules, the effects of this may be high fever, asthma or any other allergies.
Antigens are any substances that elicit the adaptive immune response. The cells that carry out the adaptive immune response
are white blood cells known as lymphocytes. There are two main broad classes - antibody responses and cell-mediated immune
response which are also carried by two different lymphocytes (B cells and T cells). In antibody responses, B cells
are activated to secrete antibodies, which are proteins also known as immunoglobulins. Antibodies travel through the
bloodstream and bind to the foreign antigen causing it to inactivate, which does not allow the antigen to bind to the host.
In acquired immunity, pathogen-specific receptors are "acquired" during the lifetime of the organism
(whereas in innate immunity pathogen-specific receptors are already encoded in the germline). The acquired response is said
to be "adaptive" because it prepares the body's immune system for future challenges (though it can actually also
be maladaptive when it results in autoimmunity).
The system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations),
and V(D)J recombination (an irreversible genetic recombination of antigen receptor gene segments). This mechanism allows
a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each
individual lymphocyte. Because the gene rearrangement leads to an irreversible change in the DNA of each cell,
all of the progeny (offspring) of that cell will then inherit genes encoding the same receptor specificity,
including the Memory B cells and Memory T cells that are the keys to long-lived specific immunity.
A theoretical framework explaining the workings of the acquired immune system is provided by
immune network theory.
This theory, which builds on established concepts of clonal selection, is being applied in the search for an HIV vaccine.
[Additional detailed explanation from Wikipedia covers the following:]
- Functions
- Lymphocytes
- Antigen presentation
- Exogenous antigens
- Endogenous antigens
- T lymphocytes
- CD8+ T lymphocytes and cytotoxicity
- Helper T-cells
- Th1 and Th2: helper T cell responses
- something wrong here
- γδ T cells
- B lymphocytes and antibody production
- Alternative acquired immune system
- Immunological memory
- Passive memory
- Active memory
- Immunization
- Immunological diversity
- Acquired immunity during pregnancy
- Immune network theory
- Stimulation of adaptive immunity
- Evolution
Functions
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Acquired immunity is triggered in vertebrates when a pathogen evades the innate immune system and (1) generates a threshold
level of antigen and (2) generates "stranger" or "danger" signals activating dendritic cells.
The major functions of the acquired immune system include:
- Recognition of specific "non-self" antigens in the presence of "self", during the process of antigen presentation
- Generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells
- Development of immunological memory, in which pathogens are "remembered" through memory cells
Lymphocytes
The cells of the acquired immune system are T and B lymphocytes; lymphocytes are a subset of leukocyte. B cells and T cells
are the major types of lymphocytes. The human body has about 2 trillion lymphocytes, constituting 20–40% of white blood cells
(WBCs); their total mass is about the same as the brain or liver. The peripheral blood contains 2% of circulating lymphocytes;
the rest move within the tissues and lymphatic system.
B cells and T cells are derived from the same multipotent hematopoietic stem cells, and are morphologically indistinguishable
from one another until after they are activated. B cells play a large role in the humoral immune response, whereas T cells
are intimately involved in cell-mediated immune responses. In all vertebrates except Agnatha, B cells and T cells are
produced by stem cells in the bone marrow. T progenitors migrate from the bone marrow to the thymus where they are called
thymocytes and where they develop into T cells. In humans, approximately 1–2% of the lymphocyte pool recirculates each
hour to optimize the opportunities for antigen-specific lymphocytes to find their specific antigen within the secondary lymphoid tissues.
In an adult animal, the peripheral lymphoid organs contain a mixture of B and T cells in at least three stages of differentiation:
- naive cells that have not matured, left the bone marrow or thymus, have entered the lymphatic system, but that
have yet to encounter their cognate antigen
- effector cells that have been activated by their cognate antigen, and are actively involved in eliminating a pathogen
- memory cells – the long-lived survivors of past infections
Antigen presentation
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Acquired immunity relies on the capacity of immune cells to distinguish between the body's own cells and unwanted invaders. The
host's cells express "self" antigens. These antigens are different from those on the surface of bacteria or on the surface
of virus-infected host cells ("non-self" or "foreign" antigens). The acquired immune response is triggered by recognizing
foreign antigen in the cellular context of a danger-activated dendritic cell.
With the exception of non-nucleated cells (including erythrocytes), all cells are capable of presenting antigen through the
function of major histocompatibility complex (MHC) molecules. Some cells are specially equipped to present antigen,
and to prime naive T cells. Dendritic cells and B-cells (and to a lesser extent macrophages) are equipped with special
"co-stimulatory" ligands recognized by co-stimulatory receptors on T cells, and are termed
professional antigen-presenting cells (APC).
Several T cells subgroups can be activated by professional APCs, and each type of T cell is specially equipped to deal with each
unique toxin or bacterial and viral pathogen. The type of T cell activated, and the type of response generated, depends,
in part, on the context in which the APC first encountered the antigen.
Exogenous antigens
Dendritic cells engulf exogenous pathogens, such as bacteria, parasites or toxins in the tissues and then migrate,
via chemotactic signals, to the T cell-enriched lymph nodes. During migration, dendritic cells undergo a process of
maturation in which they lose most of their ability to engulf other pathogens and develop an ability to communicate with T-cells.
The dendritic cell uses enzymes to chop the pathogen into smaller pieces, called antigens. In the lymph node, the
dendritic cell will display these "non-self" antigens on its surface by coupling them to a "self"-receptor called the
Major histocompatibility complex, or MHC (also known in humans as Human leukocyte antigen (HLA)).
This MHC:antigen complex is recognized by T-cells passing through the lymph node. Exogenous antigens are usually displayed on
MHC class II molecules, which activate CD4+ helper T-cells.
Endogenous antigens
Endogenous antigens are produced by intracellular bacteria and viruses replicating within a host cell. The host cell uses enzymes
to digest virally associated proteins, and displays these pieces on its surface to T-cells by coupling them to MHC.
Endogenous antigens are typically displayed on MHC class I molecules, and activate CD8+ cytotoxic T-cells. With the
exception of non-nucleated cells (including erythrocytes), MHC class I is expressed by all host cells.
T lymphocytes
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CD8+ T lymphocytes and cytotoxicity
Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a sub-group of
T cells that induce the death of cells that are infected with viruses (and other pathogens), or are otherwise damaged
or dysfunctional.
Naive cytotoxic T cells are activated when their T-cell receptor (TCR) strongly interacts with a peptide-bound
MHC class I molecule. This affinity depends on the type and orientation of the antigen/MHC complex, and is what keeps
the CTL and infected cell bound together. Once activated, the CTL undergoes a process called clonal expansion in which
it gains functionality, and divides rapidly, to produce an army of “armed”-effector cells. Activated CTL
will then travel throughout the body in search of cells bearing that unique MHC Class I + peptide.
When exposed to these infected or dysfunctional somatic cells, effector CTL release perforin and granulysin: cytotoxins
that form pores in the target cell's plasma membrane, allowing ions and water to flow into the infected cell, and causing
it to burst or lyse. CTL release granzyme, a serine protease that enters cells via pores to induce apoptosis
(cell death). To limit extensive tissue damage during an infection, CTL activation is tightly controlled and in general
requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T-cells
(see below).
Upon resolution of the infection, most of the effector cells will die and be cleared away by phagocytes, but a few of these
cells will be retained as memory cells. Upon a later encounter with the same antigen, these memory cells quickly differentiate
into effector cells, dramatically shortening the time required to mount an effective response.
Helper T-cells
CD4+ lymphocytes, or helper T cells, are immune response mediators, and play an important role in establishing and
maximizing the capabilities of the acquired immune response. These cells have no cytotoxic or phagocytic activity; and cannot
kill infected cells or clear pathogens, but, in essence "manage" the immune response, by directing other
cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The activation of
a naive helper T-cell causes it to release cytokines, which influences the activity of many cell types, including the APC
(Antigen-Presenting Cell) that activated it. Helper T-cells require a much milder activation stimulus than cytotoxic T cells.
Helper T cells can provide extra signals that "help" activate cytotoxic cells.
Th1 and Th2: helper T cell responses
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Two types of effector CD4+ T helper cell responses can be induced by a professional APC, designated Th1 and Th2, each designed
to eliminate different types of pathogens. The factors that dictate whether an infection will trigger a Th1 or Th2 type response are
not fully understood, but the response generated does play an important role in the clearance of different pathogens.
The Th1 response is characterized by the production of Interferon-gamma, which activates the bactericidal activities of macrophages,
and induces B cells to make opsonizing (coating) and complement-fixing antibodies, and leads to "cell-mediated immunity".
The Th2 response is characterized by the release of Interleukin 4, which results in the activation of B cells to make neutralizing
non-cytolytic antibodies, leading to "humoral immunity". In general, Th1 responses are more effective against intracellular
pathogens (viruses and bacteria that are inside host cells), whereas Th2 responses are more effective against extracellular
bacteria, parasites including helminths and toxins. Like cytotoxic T cells, most of the CD4+ helper cells will die upon
resolution of infection, with a few remaining as CD4+ memory cells.
HIV is able to subvert the immune system by attacking the CD4+ T cells, precisely the cells that could drive the destruction of the
virus, but also the cells that drive immunity against all other pathogens encountered during an organism's lifetime.
A third type of T lymphocyte, the regulatory T cells (Treg), limits and suppresses the immune system, and may control
aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases.
γδ T cells
γδ T cells (gamma delta cells) possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ αβ T cells
and share characteristics of helper T cells, cytotoxic T cells and natural killer cells. Like other 'unconventional'
T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit characteristics that
place them at the border between innate and acquired immunity. On one hand, γδ T cells may be considered a component of acquired
immunity in that they rearrange TCR genes via V(D)J recombination, which also produces junctional diversity, and develop a memory
phenotype. On the other hand, however, the various subsets may also be considered part of the innate immune system where
a restricted TCR or NK receptors may be used as a pattern recognition receptor. For example, according to this paradigm,
large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial
Vδ1 T cells will respond to stressed epithelial cells.
B lymphocytes and antibody production
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B Cells are the major cells involved in the creation of antibodies that circulate in blood plasma and lymph, known as humoral immunity.
Antibodies (also known as immunoglobulin, Ig), are large Y-shaped proteins used by the immune system to identify and neutralize
foreign objects. In mammals, there are five types of antibody: IgA, IgD, IgE, IgG, and IgM,
differing in biological properties; each has evolved to handle different kinds of antigens. Upon activation, B cells
produce antibodies, each of which recognizing a unique antigen, and neutralizing specific pathogens.
Like the T cell, B cells express a unique B cell receptor (BCR), in this case, an immobilized antibody molecule.
All the BCR of any one clone of B cells recognizes and binds to only one particular antigen. A critical difference between B cells and
T cells is how each cell "sees" an antigen. T cells recognize their cognate antigen in a processed form – as a peptide in
the context of an MHC molecule, whereas B cells recognize antigens in their native form. Once a B cell encounters its cognate
(or specific) antigen (and receives additional signals from a helper T cell (predominately Th2 type)), it further
differentiates into an effector cell, known as a plasma cell.
Plasma cells are short-lived cells (2–3 days) that secrete antibodies. These antibodies bind to antigens, making them
easier targets for phagocytes, and trigger the complement cascade. About 10% of plasma cells will survive to become long-lived
antigen-specific memory B cells. Already primed to produce specific antibodies, these cells can be called upon to respond quickly
if the same pathogen re-infects the host, while the host experiences few, if any, symptoms.
Alternative acquired immune system
Although the classical molecules of the acquired immune system (e.g., antibodies and T cell receptors) exist only
in jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the
lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors (VLRs for short) that,
like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes.
These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.
Immunological memory
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When B cells and T cells are activated some will become memory cells. Throughout the lifetime of an animal these memory cells form a
database of effective B and T lymphocytes. Upon interaction with a previously encountered antigen, the appropriate memory cells
are selected and activated. In this manner, the second and subsequent exposures to an antigen produce a stronger and
faster immune response. This is "adaptive" because the body's immune system prepares itself for future challenges,
but is "maladaptive" of course if the receptors are autoimmune. Immunological memory can be in the form of either passive
short-term memory or active long-term memory.
Passive memory
Passive memory is usually short-term, lasting between a few days and several months. Newborn infants have had no prior exposure
to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother.
In utero, maternal IgG is transported directly across the placenta, so that, at birth, human babies have high levels
of antibodies, with the same range of antigen specificities as their mother. Breast milk contains antibodies (mainly IgA)
that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize
its own antibodies.
This is passive immunity because the fetus does not actually make any memory cells or antibodies: It only borrows them.
Short-term passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.
Active memory
In general, active immunity is long-term and can be acquired by infection followed by B cells and T cells activation, or
artificially acquired by vaccines, in a process called immunization.
Immunization
Historically, infectious disease has been the leading cause of death in the human population. Over the last century,
two important factors have been developed to combat their spread: sanitation and immunization. Immunization (commonly
referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective
manipulation of the immune system that scientists have developed. Immunizations are successful because they utilize the
immune system's natural specificity as well as its inducibility.
The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the
immune system to develop protective immunity against that organism, but that does not itself cause the pathogenic effects of that
organism. An antigen (short for antibody generator), is defined as any substance that binds to a specific antibody
and elicits an adaptive immune response.
Most viral vaccines are based on live attenuated viruses, whereas many bacterial vaccines are based on acellular components of
microorganisms, including harmless toxin components. Many antigens derived from acellular vaccines do not strongly induce
an acquired response, and most bacterial vaccines require the addition of adjuvants that activate the antigen-presenting cells
of the innate immune system to enhance immunogenicity.
Immunological diversity
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Most large molecules, including virtually all proteins and many polysaccharides, can serve as antigens. The parts of
an antigen that interact with an antibody molecule or a lymphocyte receptor, are called epitopes, or antigenic determinants.
Most antigens contain a variety of epitopes and can stimulate the production of antibodies, specific T cell responses, or both.
A very small proportion (less than 0.01%) of the total lymphocytes are able to bind to a particular antigen, which suggests
that only a few cells will respond to each antigen.
For the acquired response to "remember" and eliminate a large number of pathogens the immune system must be able to distinguish
between many different antigens, and the receptors that recognize antigens must be produced in a huge variety of configurations,
in essence one receptor (at least) for each different pathogen that might ever be encountered. Even in the absence of
antigen stimulation, a human is capable of producing more than 1 trillion different antibody molecules. Millions of genes
would be required to store the genetic information used to produce these receptors, but, the entire human genome contains
fewer than 25,000 genes.
Myriad receptors are produced through a process known as clonal selection. According to the clonal selection theory, at birth,
an animal will randomly generate a vast diversity of lymphocytes (each bearing a unique antigen receptor) from information encoded
in a small family of genes. In order to generate each unique antigen receptor, these genes will have undergone a process called
V(D)J recombination, or combinatorial diversification, in which one gene segment recombines with other gene segments to form a
single unique gene. It is this assembly process that generates the enormous diversity of receptors and antibodies, before the
body ever encounters antigens, and enables the immune system to respond to an almost unlimited diversity of antigens. Throughout
the lifetime of an animal, those lymphocytes that can react against the antigens an animal actually encounters, will be selected
for action, directed against anything that expresses that antigen.
It is important to note that the innate and acquired portions of the immune system work together and not in spite of each other.
The acquired arm, B and T cells, would be unable to function without the input of the innate system. T cells are useless
without antigen-presenting cells to activate them, and B cells are crippled without T cell help. On the other hand,
the innate system would likely be overrun with pathogens without the specialized action of the acquired immune response.
Acquired immunity during pregnancy
The cornerstone of the immune system is the recognition of "self" versus "non-self". Therefore, the mechanisms
that protect the human fetus (which is considered "non-self") from attack by the immune system, are particularly interesting.
Although no comprehensive explanation has emerged to explain this mysterious, and often repeated, lack of rejection, two
classical reasons may explain how the fetus is tolerated. The first is that the fetus occupies a portion of the body protected by a
non-immunological barrier, the uterus, which the immune system does not routinely patrol. The second is that the fetus
itself may promote local immunosuppression in the mother, perhaps by a process of active nutrient depletion. A more modern
explanation for this induction of tolerance is that specific glycoproteins expressed in the uterus during pregnancy suppress the uterine
immune response (see eu-FEDS).
During pregnancy in viviparous mammals (all mammals except Monotremes), endogenous retroviruses (ERVs) are activated
and produced in high quantities during the implantation of the embryo. They are currently known to possess immunosuppressive properties,
suggesting a role in protecting the embryo from its mother's immune system. Also viral fusion proteins cause the formation of the
placental syncytium in order to limit the exchange of migratory cells between the developing embryo and the body of the mother
(something an epithelium will not do sufficiently, as certain blood cells are specialized to be able to insert themselves between
adjacent epithelial cells). The immunodepressive action was the initial normal behavior of the virus, similar to HIV. The fusion
proteins were a way to spread the infection to other cells by simply merging them with the infected one (HIV does this too).
It is believed that the ancestors of modern viviparous mammals evolved after an infection by this virus, enabling the fetus to survive
the immune system of the mother.
The human genome project found several thousand ERVs classified into 24 families.
Immune network theory
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A theoretical framework explaining the workings of the acquired immune system is provided by immune network theory, based on interactions
between idiotypes (unique molecular features of one clonotype, i.e. the unique set of antigenic determinants of the variable portion
of an antibody) and 'anti-idiotypes' (antigen receptors that react with the idiotype as if it were a foreign antigen).
This theory, which builds on the existing clonal selection hypothesis and since 1974 has been developed mainly by Niels Jerne and
Geoffrey W. Hoffmann, is seen as being relevant to the understanding of the HIV pathogenesis and the search for an HIV vaccine.
Stimulation of adaptive immunity
One of the most interesting developments in biomedical science during the past few decades has been elucidation of mechanisms mediating
innate immunity. One set of innate immune mechanisms is humoral, such as complement activation. Another set comprises
pattern recognition receptors such as Toll-like receptors, which induce the production of interferons and other cytokines increasing
resistance of cells such as monocytes to infections. Cytokines produced during innate immune responses are among the activators of
adaptive immune responses. Antibodies exert additive or synergistic effects with mechanisms of innate immunity. Unstable HbS
clusters Band-3, a major integral red cell protein; antibodies recognize these clusters and accelerate their removal by
phagocytic cells. Clustered Band 3 proteins with attached antibodies activate complement, and complement C3 fragments are
opsonins recognized by the CR1 complement receptor on phagocytic cells.
A population study has shown that the protective effect of the sickle-cell trait against falciparum malaria involves the augmentation of
adaptive as well as innate immune responses to the malaria parasite, illustrating the expected transition from innate to adaptive immunity.
Repeated malaria infections strengthen adaptive immunity and broaden its effects against parasites expressing different surface antigens.
By school age most children have developed efficacious adaptive immunity against malaria. These observations raise questions about
mechanisms that favor the survival of most children in Africa while allowing some to develop potentially lethal infections.
In malaria, as in other infections, innate immune responses lead into, and stimulate, adaptive immune responses.
The genetic control of innate and adaptive immunity is now a large and flourishing discipline.
Humoral and cell-mediated immune responses limit malaria parasite multiplication, and many cytokines contribute to the pathogenesis of
malaria as well as to the resolution of infections.
Evolution
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The adaptive immune system, which has been best-studied in mammals, originated in a jawed fish approximately 500 million years ago.
Most of the molecules, cells, tissues, and associated mechanisms of this system of defense are found in cartilaginous fishes.
Lymphocyte receptors, Ig and TCR, are found in all jawed vertebrates. The most ancient Ig class, IgM, is
membrane-bound and then secreted upon stimulation of cartilaginous fish B cells. Another isotype, shark IgW, is related to
mammalian IgD. TCRs, both α/β and γ/δ, are found in all animals from gnathostomes to mammals. The organization of gene
segments that undergo gene rearrangement differs in cartilaginous fishes, which have a cluster form as compared to the translocon form
in bony fish to mammals. Like TCR and Ig, the MHC is found only in jawed vertebrates. Genes involved in antigen processing
and presentation, as well as the class I and class II genes, are closely linked within the MHC of almost all studied species.
Lymphoid cells can be identified in some pre-vertebrate deuterostomes (i.e., sea urchins). These bind antigen with pattern
recognition receptors (PRRs) of the innate immune system. In jawless fishes, two subsets of lymphocytes use variable
lymphocyte receptors (VLRs) for antigen binding. Diversity is generated by a cytosine deaminase-mediated rearrangement of
LRR-based DNA segments. There is no evidence for the recombination-activating genes (RAGs) that rearrange Ig and TCR gene
segments in jawed vertebrates.
The evolution of the AIS, based on Ig, TCR, and MHC molecules, is thought to have arisen from two major
evolutionary events: the transfer of the RAG transposon (possibly of viral origin) and two whole genome duplications.
Though the molecules of the AIS are well-conserved, they are also rapidly evolving. Yet, a comparative approach finds that
many features are quite uniform across taxa. All the major features of the AIS arose early and quickly. Jawless fishes have a
different AIS that relies on gene rearrangement to generate diversity but has little else in common with the jawed vertebrate AIS.
The innate immune system, which has an important role in AIS activation, is the most important defense system of invertebrates
and plants.
[End of Wikipedia section]
