Adaptive immune system

thumb|right|A [[scanning electron microscope image of a single human lymphocyte]]

The adaptive immune system (AIS), also known as the acquired immune system or specific immune system, is a subsystem of the immune system that is composed of specialized cells, organs, and processes that eliminate pathogens specifically. The acquired immune system is one of the two main immunity strategies found in vertebrates (the other being the innate immune system).

Like the innate system, the adaptive immune system includes both humoral immunity components and cell-mediated immunity components and destroys invading pathogens. Unlike the innate immune system, which is pre-programmed to react to common broad categories of pathogen, the adaptive immune system is highly specific to each particular pathogen the body has encountered.

Adaptive immunity creates immunological memory after an initial response to a specific pathogen, and leads to an enhanced response to future encounters with that pathogen. Antibodies are a critical part of the adaptive immune system. Adaptive immunity can provide long-lasting protection, sometimes for the person's entire lifetime. For example, someone who recovers from measles is now protected against measles for their lifetime; in other cases it does not provide lifetime protection, as with chickenpox. This process of adaptive immunity is the basis of vaccination.

The cells that carry out the adaptive immune response are white blood cells known as lymphocytes. B cells and T cells, two different types of lymphocytes, carry out the main activities: antibody responses, and cell-mediated immune response. 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.

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 B cells and memory T cells.

In humans, it takes 4–7 days for the adaptive immune system to mount a significant response.

Lymphocytes

T and B lymphocytes are the cells of the adaptive immune system. The human body has about 2 trillion lymphocytes, which are 20–40% of white blood cells; their total mass is about the same as the brain or liver. The peripheral bloodstream contains only 2% of all circulating lymphocytes; the other 98% move within tissues and the lymphatic system, which includes the lymph nodes and spleen. In humans, approximately 1–2% of the lymphocyte pool recirculates each hour to increase the opportunity for the cells to encounter the specific pathogen and antigen that they react to.

B cells and T cells are derived from the same multipotent hematopoietic stem cells, and look identical to 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 cell progenitors then migrate from the bone marrow to the thymus, where they develop further.

In an adult animal, the peripheral lymphoid organs contain a mixture of B and T cells in at least three stages of differentiation:

Naive B and naive T cells, which have left the bone marrow or thymus and entered the lymphatic system, but have yet to encounter their matching antigen
Effector cells that have been activated by their matching antigen, and are actively involved in eliminating a pathogen
Memory cells, the survivors of past infections

Antigen presentation

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 an 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.]]

CD4+ lymphocytes, also called "helper" T cells, are immune response mediators, and play an important role in establishing and maximizing the capabilities of the acquired immune response. Th2 also produce Interleukin 4, which facilitates B cell isotype switching. Regulatory T (Treg) cells, have been identified as important negative regulators of adaptive immunity as they limit and suppress the immune system to control aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases.

The relevance of CD4<sup>+</sup> T helper cells is highlighted during an HIV infection. HIV is able to subvert the immune system by specifically attacking the CD4<sup>+</sup> T cells, precisely the cells that could drive the clearance of the virus, but also the cells that drive immunity against all other pathogens encountered during an organism's lifetime. Instead of the classical antibodies and T cell receptors, 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.

In insects

For a long time it was thought that insects and other invertebrates possess only innate immune system. However, in recent years some of the basic hallmarks of adaptive immunity have been discovered in insects. Those traits are immune memory and specificity. Although the hallmarks are present the mechanisms are different from those in vertebrates.

Immune memory in insects was discovered through the phenomenon of priming. When insects are exposed to non-lethal dose or heat killed bacteria they are able to develop a memory of that infection that allows them to withstand otherwise lethal dose of the same bacteria they were exposed to before. Unlike in vertebrates, insects do not possess cells specific for adaptive immunity. Instead those mechanisms are mediated by hemocytes. Hemocytes function similarly to phagocytes and after priming they are able to more effectively recognize and engulf the pathogen. It was also shown that it is possible to transfer the memory into offspring. For example, in honeybees if the queen is infected with bacteria then the newly born workers have enhanced abilities in fighting with the same bacteria. Other experimental model based on red flour beetle also showed pathogen specific primed memory transfer into offspring from both mothers and fathers.

Most commonly accepted theory of the specificity is based on Dscam gene. Dscam gene also known as Down syndrome cell adhesive molecule is a gene that contains 3 variable Ig domains. Those domains can be alternatively spliced reaching high numbers of variations. It was shown that after exposure to different pathogens there are different splice forms of dscam produced. After the animals with different splice forms are exposed to the same pathogen only the individuals with the splice form specific for that pathogen survive. It has several different pathways that all end with the virus being unable to replicate. One of the pathways is siRNA in which long double stranded RNA is cut into pieces that serve as templates for protein complex Ago2-RISC that finds and degrades complementary RNA of the virus. MiRNA pathway in cytoplasm binds to Ago1-RISC complex and functions as a template for viral RNA degradation. Last one is piRNA where small RNA binds to the Piwi protein family and controls transposones and other mobile elements. Despite the research the exact mechanisms responsible for immune priming and specificity in insects are not well described.

In bacteria

thumb|Bacteria use CRISPR as part of their adaptive immune system to defend against [[bacteriophages.]]

CRISPR is a term in DNA research. It stands for clustered regularly-interspaced short palindromic repeats. These are part of the genetic code in prokaryotes: most bacteria and archaea have it. It is their defence against attack by viruses. Its structure and function was discovered in the 21st century.

CRISPR has a lot of short repeated sequences. These sequences are part of an adaptive immune system for prokaryotes. It allows them to remember and counter the bacteriophages which prey on them. They work as a kind of acquired immune system for bacteria.

Immunological memory

When B cells and T cells are activated some become memory B cells and some memory T 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" in the sense that 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.

Myriad receptors are produced through a process known as clonal selection. to limit exchange of migratory cells between the developing embryo and the body of the mother (something an epithelium cannot do sufficiently, as certain blood cells specialize 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

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. 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 acquired as well as innate immune responses to the malaria parasite, illustrating the expected transition from innate to acquired immunity.

Repeated malaria infections strengthen acquired 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 acquired 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

The acquired immune system evolved as an elaboration of the innate immune system. Lymphoid cells can be identified in some pre-vertebrate deuterostomes (i.e., sea urchins). Although not as prominently featured in the invertebrate innate immune system as the leucine-rich repeat (LRR) pattern recognition receptors, the immunoglobulin fold has also been involved in the recognition of self versus non-self since very early on in the evolution of animals, as exemplified by studies into the marine sponge.

The amphioxus is a chordate like all vertebrates. Its genome includes many building blocks of the adaptive immune system, but none of the true hallmarks such as somatic recombination. There is, however, considerable expansion in LRR genes and immunoglobulin-fold genes. There is high polymorphism among different individuals, an example of diversity in the innate immune system.

Jawed fish

The acquired immune system, which has been best-studied in mammals, originated in 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 jawed fish (cladistically including mammals).

Most elements of the jawed fish system are in place thanks to the second round of whole-genome duplication (2R) that the jawed fish have undergone, providing an expanded repertoire of immune-related genes. The immunoprotease 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. These systems, along with RAG, were set in place quickly after 2R had happened.

The RAG transposon likely invaded a "UrIg2" immunoglobin gene, which had an unsplit VJ, in an ancestor of all extant jawed fish. Splitting the V and J exons is adaptive, as it enables greater variation through changing the size of the CDR3 loop. This feature is inherited by all the descendants of UrIg2 such as Ig and TCR. use variable lymphocyte receptors (VLRs) for antigen binding. The VLRs are derived from pattern recognition receptors (PRRs) of the innate immune system. Diversity is generated by a cytosine deaminase-mediated rearrangement of LRR-based DNA segments.

The functional dichotomy between two of the lymphocyte subsets parallels Ig and TCR molecules.

Types of acquired immunity

Immunity can be acquired either actively or passively. Immunity is acquired actively when a person is exposed to foreign substances and the immune system responds. Passive immunity is when antibodies are transferred from one host to another. Both actively acquired and passively acquired immunity can be obtained by natural or artificial means.

Naturally Acquired Active Immunity – when a person is naturally exposed to antigens, becomes ill, then recovers.
Naturally Acquired Passive Immunity – involves a natural transfer of antibodies from a mother to her infant. The antibodies cross the woman's placenta to the fetus. Antibodies can also be transferred through breast milk with the secretions of colostrum.
Artificially Acquired Active Immunity – is done by vaccination (introducing dead or weakened antigen to the host's cell).
Artificially Acquired Passive Immunity – This involves the introduction of antibodies rather than antigens to the human body. These antibodies are from an animal or person who is already immune to the disease.

{| class="wikitable"

|-Adaptive immunity

! Naturally acquired !! Artificially acquired

| Active – Antigen enters the body naturally || Active – Antigens are introduced in vaccines.

| Passive – Antibodies pass from mother to fetus via placenta or infant via the mother's milk. || Passive – Preformed antibodies in immune serum are introduced by injection.

Notes and references

;Notes

;References