Adaptive immune system

The adaptive immune system, also known as the acquired immune system 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 pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates (the other being the innate immune system). Acquired immunity creates immunological memory after an initial response to a specific pathogen, and 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 acquired system includes both humoral immunity components and cell-mediated immunity components.

The term "adaptive" was first used by Robert Good in reference to antibody responses in frogs as a synonym for "acquired immune response" in 1964. Good acknowledged he used the terms as synonyms but explained only that he "preferred" to use the term "adaptive". He might have been thinking of the then not implausible theory of antibody formation in which antibodies were plastic and could adapt themselves to the molecular shape of antigens, and/or to the concept of "adaptive enzymes" as described by Monod in bacteria, that is, enzymes whose expression could be induced by their substrates. The phrase was used almost exclusively by Good and his students and a few other immunologists working with marginal organisms until the 1990's when it became widely used in tandem with the term "innate immunity" which became a popular subject after the discovery of the Toll receptor system in Drosophila, a previously marginal organism for the study of immunology. The term "adaptive" as used in immunology is problematic as acquired immune responses can be both adaptive and maladaptive in the physiological sense. Indeed, both acquired and innate immune responses can be both adaptive and maladaptive in the evolutionary sense. Most textbooks today, following the early use by Janeway, use "adaptive" almost exclusively and noting in glossaries that the term is synonymous with "acquired".

The classic sense of "acquired immunity" came to mean, since Tonegawas's discovery, "antigen-specific immunity mediated by somatic gene rearrangements that create clone-defining antigen receptors". In the last decade, the term "adaptive" has been increasingly applied to another class of immune response not so-far associated with somatic gene rearrangements. These include expansion of natural killer (NK) cells with so-far unexplained specificity for antigens, expansion of NK cells expressing germ-line encoded receptors, and activation of other innate immune cells to an activated state that confers a short-term "immune memory". In this sense, "adaptive immunity" more closely resembles the concept of "activated state" or "heterostasis", thus returning in sense to the physiological sense of "adaptation" to environmental changes.

Ngram acquired immunity vs. adaptive immunity
Google Ngram of "acquired immunity " vs. "adaptive immunity". The peak for "adaptive" in the 1960's reflects its introduction to immunology by Robert A. Good and use by colleagues; the explosive increase in the 1990's was correlated with the use of the phrase "innate immunity".

Unlike the innate immune system, the acquired immune system is highly specific to a particular pathogen. Acquired immunity can also provide long-lasting protection; for example, someone who recovers from measles is now protected against measles for their lifetime. In other cases it does not provide lifetime protection; for example, chickenpox. The acquired system response destroys invading pathogens and any toxic molecules they produce. Sometimes the acquired system is unable to distinguish harmful from harmless foreign molecules; the effects of this may be hayfever, asthma or any other allergy. Antigens are any substances that elicit the acquired immune response (whether adaptive or maladaptive to the organism).. The cells that carry out the acquired immune response are white blood cells known as lymphocytes. Two main broad classes—antibody responses and cell mediated immune response—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.[1]

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 called "adaptive" because it prepares the body's immune system for future challenges (though it can actually also be maladaptive when it results in autoimmunity).[n 1]

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. Since the gene rearrangement leads to an irreversible change in the DNA of each cell, all progeny (offspring) of that cell inherit genes that encode 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.

SEM Lymphocyte
A scanning electron microscope image of a single human lymphocyte


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.[2]

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.


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.[1]

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.[3]

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.[4] 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 (cells that have not matured), left the bone marrow or thymus, have entered the lymphatic system, but 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 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.[3] Some cells are specially equipped to present antigen, and to prime naive T cells. Dendritic cells, B-cells, and macrophages are equipped with special "co-stimulatory" ligands recognized by co-stimulatory receptors on T cells, and are termed professional antigen-presenting cells (APCs).

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 microbial 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.[2]

Exogenous antigens

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

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 displays these non-self antigens on its surface by coupling them to a 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+T helper cells.[2]

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.[2]

T lymphocytes

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.[2]

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.[2] Once activated, the CTL undergoes a process called clonal selection, in which it gains functions and divides rapidly to produce an army of “armed” effector cells. Activated CTL then travels throughout the body searching for cells that bear 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).[2]

On resolution of the infection, most effector cells die and phagocytes clear them away—but a few of these cells remain as memory cells.[3] On 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

T cell activation
The T lymphocyte activation pathway. T cells contribute to immune defenses in two major ways: some direct and regulate immune responses; others directly attack infected or cancerous cells.[5]

CD4+ lymphocytes, also called "helper" or "regulatory" T cells, are immune response mediators, and play an important role in establishing and maximizing the capabilities of the acquired immune response.[2] 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.[3]

Th1 and Th2: helper T cell responses

Classically, 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 triggers 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.[2]

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.[2] In general, Th1 responses are more effective against intracellular pathogens (viruses and bacteria that are inside host cells).

The Th2 response is characterized by the release of Interleukin 5, which induces eosinophils in the clearance of parasites.[6] Th2 also produce Interleukin 4, which facilitates B cell isotype switching.[2] In general, Th2 responses are more effective against extracellular bacteria, parasites including helminths and toxins.[2] Like cytotoxic T cells, most of the CD4+ helper cells die on resolution of infection, with a few remaining as CD4+ memory cells.

Increasingly, there is strong evidence from mouse and human-based scientific studies of a broader diversity in CD4+ effector T helper cell subsets. Regulatory T (Treg) cells, have been identified as important negative regulators of adaptive immunity as they limit and suppresses the immune system to control aberrant immune responses to self-antigens; an important mechanism in controlling the development of autoimmune diseases.[3] Follicular helper T (Tfh) cells are another distinct population of effector CD4+ T cells that develop from naive T cells post-antigen activation. Tfh cells are specialized in helping B cell humoral immunity as they are uniquely capable of migrating to follicular B cells in secondary lymphoid organs and provide them positive paracrine signals to enable the generation and recall production of high-quality affinity-matured antibodies. Similar to Tregs, Tfh cells also play a role in immunological tolerance as an abnormal expansion of Tfh cell numbers can lead to unrestricted autoreactive antibody production causing severe systemic autoimmune disorders.[7]

The relevance of CD4+ T helper cells is highlighted during an HIV infection. HIV is able to subvert the immune system by specifically attacking the CD4+ 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.[3]

Gamma delta T cells

Gamma delta T cells (γδ T 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 adaptive 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 respond to stressed epithelial cells.

B lymphocytes and antibody production

B cell activation
The B lymphocyte activation pathway. B cells function to protect the host by producing antibodies that identify and neutralize foreign objects like bacteria and viruses.[5]

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 recognize a unique antigen, and neutralizing specific pathogens.[2]

Antigen and antibody binding would cause five different protective mechanisms:

  • Agglutination: Reduces number of infectious units to be dealt with
  • Activation of complement: Cause inflammation and cell lysis
  • Opsonization: Coating antigen with antibody enhances phagocytosis
  • Antibody-dependent cell-mediate cytotoxicity: Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells
  • Neutralization: Blocks adhesion of bacteria and viruses to mucosa

Like the T cell, B cells express a unique B cell receptor (BCR), in this case, a membrane-bound 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,[2] whereas B cells recognize antigens in their native form.[2] 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.[2]

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.[2] About 10% of plasma cells survive to become long-lived antigen-specific memory B cells.[2] 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 adaptive 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.[8]

Adaptive-like immunity 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 thru 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.[9][10] Unlike in verterbrates 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.[11] It was also shown that it is possible to transfer the memory into offsprings. 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.[12] Other experimental model based on red flour beetle also showed pathogen specific primed memory transfer into offsprings from both mothers and fathers.[13]

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.[14] 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.[14]

Other mechanisms supporting the specificity of insect immunity is RNA interference (RNAi). RNAi is a form of antiviral immunity with high specificity.[15] 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.[16] Despite the research the exact mechanisms responsible for immune priming and specificity in insects are not well described.

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.[2] 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.[2]

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.


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.[3] 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.[3] 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.[1]

Most viral vaccines are based on live attenuated viruses, whereas many bacterial vaccines are based on acellular components of microorganisms, including harmless toxin components.[1] Many antigens derived from acellular vaccines do not strongly induce an adaptive response, and most bacterial vaccines require the addition of adjuvants that activate the antigen-presenting cells of the innate immune system to enhance immunogenicity.[3]

Immunological diversity

Antibody chains
An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.[5]

Most large molecules, including virtually all proteins and many polysaccharides, can serve as antigens.[2] 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.[2] 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 respond to each antigen.[3]

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,[1] 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 can produce more than 1 trillion different antibody molecules.[3] Millions of genes would be required to store the genetic information that produces these receptors, but, the entire human genome contains fewer than 25,000 genes.[17]

Myriad receptors are produced through a process known as clonal selection.[1][2] According to the clonal selection theory, at birth, an animal randomly generates a vast diversity of lymphocytes (each bearing a unique antigen receptor) from information encoded in a small family of genes. To generate each unique antigen receptor, these genes 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. This assembly process 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.[2] Throughout an animal's lifetime, lymphocytes that can react against the antigens an animal actually encounters are selected for action—directed against anything that expresses that antigen.

Note that the innate and acquired portions of the immune system work together, not in spite of each other. The acquired arm, B, and T cells couldn't function without the innate system' input. 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 adaptive 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.[2] The second is that the fetus itself may promote local immunosuppression in the mother, perhaps by a process of active nutrient depletion.[2] 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[18] to limit exchange of migratory cells between the developing embryo and the body of the mother (something an epithelium can't 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.[19]

The human genome project found several thousand ERVs classified into 24 families.[20]

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.[21] Cytokines produced during innate immune responses are among the activators of adaptive immune responses.[21] Antibodies exert additive or synergistic effects with mechanisms of innate immunity. Unstable HbS clusters Band-3, a major integral red cell protein;[22] 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.[23]

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.[24]

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,[21] 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.[25]


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.[26] 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).[27] 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.[28] Diversity is generated by a cytosine deaminase-mediated rearrangement of LRR-based DNA segments.[29] 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.[26] 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 diverse immune receptors with a functional dichotomy that parallels Ig and TCR molecules.[30] The innate immune system, which has an important role in AIS activation, is the most important defense system of invertebrates and plants.

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 crosses 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.
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.

See also

Notes and references

  1. ^ In the technical sense, both the innate and acquired immune systems are "adaptive" in the physiological and evolutionary sense of allowing the organism to adapt to changing external circumstances (and both can be maladaptive if overactive, causing pathological inflammation or autoimmunity). Furthermore, the pathogen-receptors of innate and acquired immune mechanisms are both specific: The specificities of innate immunity have evolved over evolutionary time in response to highly conserved molecular features of the microbial world, whereas the specificities of acquired immunity mature in each organism. For this reason, in general the term "acquired" is preferred to "adaptive" or "specific".
  1. ^ a b c d e f Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walters P (2002). Molecular Biology of the Cell (4th ed.). New York and London: Garland Science. ISBN 0-8153-3218-1.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z Janeway CA, Travers P, Walport M, Shlomchik MJ (2001). Immunobiology (5th ed.). New York and London: Garland Science. ISBN 0-8153-4101-6.
  3. ^ a b c d e f g h i j k Janeway CA, Travers P, Walport M, Shlomchik MJ (2005). Immunobiology (6th ed.). Garland Science. ISBN 0-443-07310-4.
  4. ^ "Microbiology and Immunology On-Line Textbook". University of South Carolina School of Medicine. Archived from the original on 2 September 2008.
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Adaptive NK cells

Adaptive natural killer (NK) cells is a sub-population of natural killer cells, a cell type of the innate immune system. Adaptive NK cells have been identified in both humans and mice.The term adaptive NK cells stems from their described immunological behaviour, which parallels functions of the adaptive immune system including dynamic expansions of defined subsets of cells and protective memory responses

Antigen-presenting cell

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen complexed with major histocompatibility complexes (MHCs) on their surfaces; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). These cells process antigens and present them to T-cells.

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

Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs. Antigen presentation allows for specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors. Some cancer therapies involve the creation of artificial APCs to prime the adaptive immune system to target malignant cells.


CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 (protein) on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. In total CD40L has three binding partners: CD40, α5β1 integrin and αIIbβ3. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (TFH cells). On TFH cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

Cell-mediated immunity

Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Historically, the immune system was separated into two branches: humoral immunity, for which the protective function of immunization could be found in the humor (cell-free bodily fluid or serum) and cellular immunity, for which the protective function of immunization was associated with cells. CD4 cells or helper T cells provide protection against different pathogens. Naive T cells, mature T cells that have yet to encounter an antigen, are converted into activated effector T cells after encountering antigen-presenting cells (APCs). These APCs, such as macrophages, dendritic cells, and B cells in some circumstances, load antigenic peptides onto the MHC of the cell, in turn presenting the peptide to receptors on T cells. The most important of these APCs are highly specialized dendritic cells; conceivably operating solely to ingest and present antigens. Activated Effector T cells can be placed into three functioning classes, detecting peptide antigens originating from various types of pathogen: The first class being Cytotoxic T cells, which kill infected target cells by apoptosis without using cytokines, the second class being TH1 cells, which primarily function to activate macrophages, and the third class being TH2 cells, which primarily function to stimulate B cells into producing antibodies.The innate immune system and the adaptive immune system each comprise both humoral and cell-mediated components.

Cellular immunity protects the body through:

T-cell mediated immunity or T-cell immunity: activating antigen-specific cytotoxic T cells that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;

Macrophage and natural killer cell action: enabling the destruction of pathogens via recognition and secretion of cytotoxic granules (for natural killer cells) and phagocytosis (for macrophages); and

Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection.


Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.

Complement component 1q

The complement component 1q (or simply C1q) is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.

Antibodies of the adaptive immune system can bind antigen, forming an antigen-antibody complex. When C1q binds antigen-antibody complexes, the C1 complex becomes activated. Activation of the C1 complex initiates the classical complement pathway of the complement system. The antibodies IgM and all IgG subclasses except IgG4 are able to initiate the complement system.


Cruzipain is a cysteine protease expressed by Trypanosoma cruzi.It is classified under EC

Cruzipain is a sulfated glycoprotein which plays a role in the parasitic disease known as Chagas disease. It is found to aid the parasite in entering the host cell and in evading an immune response.Cruzipain can help parasites escape the response from the adaptive immune system by interfering with the functions of immunoglobulins from the immunoglobin G subclasses. These immunoglobulins are bound to receptors and cruzipain interacts with these immunoglobulins by cleaving their hinges.During smooth muscle cell invasion, cruzipain may cause receptors on endothelin, a vasoconstrictor, to move around, which may interfer with the vasoconstrictor's ability to cause the blood vessels to become narrower.

Gabriel Victora

Gabriel D. Victora is an immunologist who is a recipient of the 2017 MacArthur Genius Grant for his research on the adaptive immune system and the processes by which it adjusts its reactions to infections. He is the Laurie and Peter Grauer Assistant Professor at Rockefeller University, where he heads the Laboratory of Lymphocyte Dynamics.Victora earned his PhD in 2011 from New York University Medical School. From 2012 to 2016, he was a fellow at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology. In 2012, he earned the NIH Director’s Early Independence Award for his work using two-photon microscopy to understand the changes over time of the level of diversity of antibodies in germinal centers.

Genetic recombination

Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be passed on from the parents to the offspring. Most recombination is naturally occurring.

During meiosis in eukaryotes, genetic recombination involves the pairing of homologous chromosomes. This may be followed by information transfer between the chromosomes. The information transfer may occur without physical exchange (a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed) (see SDSA pathway in Figure); or by the breaking and rejoining of DNA strands, which forms new molecules of DNA (see DHJ pathway in Figure).

Recombination may also occur during mitosis in eukaryotes where it ordinarily involves the two sister chromosomes formed after chromosomal replication. In this case, new combinations of alleles are not produced since the sister chromosomes are usually identical. In meiosis and mitosis, recombination occurs between similar molecules of DNA (homologous sequences). In meiosis, non-sister homologous chromosomes pair with each other so that recombination characteristically occurs between non-sister homologues. In both meiotic and mitotic cells, recombination between homologous chromosomes is a common mechanism used in DNA repair.

Gene conversion - the process during which homologous sequences are made identical also falls under genetic recombination.

Genetic recombination and recombinational DNA repair also occurs in bacteria and archaea, which use asexual reproduction.

Recombination can be artificially induced in laboratory (in vitro) settings, producing recombinant DNA for purposes including vaccine development.

V(D)J recombination in organisms with an adaptive immune system is a type of site-specific genetic recombination that helps immune cells rapidly diversify to recognize and adapt to new pathogens.


Gnathostomata are the jawed vertebrates. The term derives from Greek: γνάθος (gnathos) "jaw" + στόμα (stoma) "mouth". Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all living vertebrates. In addition to opposing jaws, living gnathostomes have teeth, paired appendages, and a horizontal semicircular canal of the inner ear, along with physiological and cellular anatomical characters such as the myelin sheathes of neurons. Another is an adaptive immune system that uses V(D)J recombination to create antigen recognition sites, rather than using genetic recombination in the variable lymphocyte receptor gene.It is now assumed that Gnathostomata evolved from ancestors that already possessed a pair of both pectoral and pelvic fins. In addition to this, some placoderms were shown to have a third pair of paired appendages, that in males had been modified to claspers and basal plates in females, a pattern not seen in any other vertebrate group.The Osteostraci are generally considered the sister taxon of Gnathostomata.It is believed that the jaws evolved from anterior gill support arches that had acquired a new role, being modified to pump water over the gills by opening and closing the mouth more effectively – the buccal pump mechanism. The mouth could then grow bigger and wider, making it possible to capture larger prey. This close and open mechanism would, with time, become stronger and tougher, being transformed into real jaws.

Newer research suggests that a branch of Placoderms was most likely the ancestor of present-day gnathostomes. A 419-million-year-old fossil of a placoderm named Entelognathus had a bony skeleton and anatomical details associated with cartilaginous and bony fish, demonstrating that the absence of a bony skeleton in Chondrichthyes is a derived trait. The fossil findings of primitive bony fishes such as Guiyu oneiros and Psarolepis, which lived contemporaneously with Entelognathus and had pelvic girdles more in common with placoderms than with other bony fish, show that it was a relative rather than a direct ancestor of the extant gnathostomes. It also indicates that spiny sharks and Chondrichthyes represent a single sister group to the bony fishes. Fossils findings of juvenile placoderms, which had true teeth that grew on the surface of the jawbone and had no roots, making it impossible to replace or regrow as they broke or wore down as they grew older, proves the common ancestor of all gnathostomes had teeth and place the origin of teeth along with, or soon after, the evolution of jaws.Late Ordovician-aged microfossils of what have been identified as scales of either acanthodians or "shark-like fishes", may mark Gnathostomata's first appearance in the fossil record. Undeniably unambiguous gnathostome fossils, mostly of primitive acanthodians, begin appearing by the early Silurian, and become abundant by the start of the Devonian.

Humoral immunity

Humoral immunity or humoural immunity is the aspect of immunity that is mediated by macromolecules found in extracellular fluids such as secreted antibodies, complement proteins, and certain antimicrobial peptides. Humoral immunity is so named because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Its aspects involving antibodies are often called antibody-mediated immunity.

The study of the molecular and cellular components that form the immune system, including their function and interaction, is the central science of immunology. The immune system is divided into a more primitive innate immune system, and acquired or adaptive immune system of vertebrates, each of which contains humoral and cellular components.

Humoral immunity refers to antibody production and the accessory processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

Immune system

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Pathogens can rapidly evolve and adapt, and thereby avoid detection and neutralization by the immune system; however, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and invertebrates. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.

Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.

Innate immune system

The innate immune system is one of the two main immunity strategies found in vertebrates (the other being the adaptive immune system). The innate immune system is an older evolutionary defense strategy, relatively speaking, and it is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.The major functions of the vertebrate innate immune system include:

Recruiting immune cells to sites of infection through the production of chemical factors, including specialized chemical mediators called cytokines

Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells

Identification and removal of foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells

Activation of the adaptive immune system through a process known as antigen presentation

Acting as a physical and chemical barrier to infectious agents; via physical measures like skin or tree bark and chemical measures like clotting factors in blood or sap from a tree, which are released following a contusion or other injury that breaks through the first-line physical barrier (not to be confused with a second-line physical or chemical barrier, such as the blood-brain barrier, which protects the extremely vital and highly sensitive nervous system from pathogens that have already gained access to the host's body).


An Isograft is a graft of tissue between two individuals who are genetically identical (i.e. monozygotic twins). Transplant rejection between two such individuals virtually never occurs, making isografts particularly relevant to organ transplanations; patients with organs from their identical twins are incredibly likely to receive the organs favorably and survive. Monozygotic twins have the same major histocompatibility complex, leading to the low instances of tissue rejection by the adaptive immune system. Furthermore, there is virtually no incidence of graft-versus-host disease.

In 1993 a research article demonstrated that islet isografts were being transplanted into young diabetic mice [STZ induced diabetic NOD mice] and the mice survived at least about 22 days post transplantation.

Myeloid tissue

Myeloid tissue, in the bone marrow sense of the word myeloid (myelo- + -oid), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (myelo- + -genous) is any tissue of, or arising from, bone marrow; in these senses the terms are usually used synonymously, as for example with chronic myeloid/myelogenous leukemia.

In hematopoiesis, myeloid or myelogenous cells are blood cells that arise from a progenitor cell for granulocytes, monocytes, erythrocytes, or platelets (the common myeloid progenitor, that is, CMP or CFU-GEMM), or in a narrower sense also often used, specifically from the lineage of the myeloblast (the myelocytes, monocytes, and their daughter types). Thus, although all blood cells, even lymphocytes, are normally born in the bone marrow in adults, myeloid cells in the narrowest sense of the term can be distinguished from lymphoid cells, that is, lymphocytes, which come from common lymphoid progenitor cells that give rise to B cells and T cells. Those cells' differentiation (that is, lymphopoiesis) is not complete until they migrate to lymphatic organs such as the spleen and thymus for programming by antigen challenge. Thus, among leukocytes, the term myeloid is associated with the innate immune system, in contrast to lymphoid, which is associated with the adaptive immune system. Similarly, myelogenous usually refers to nonlymphocytic white blood cells, and erythroid can often be used to distinguish "erythrocyte-related" from that sense of myeloid and from lymphoid.The word myelopoiesis has several senses in a way that parallels those of myeloid, and myelopoiesis in the narrower sense is the regulated formation specifically of myeloid leukocytes (myelocytes), allowing that sense of myelopoiesis to be contradistinguished from erythropoiesis and lymphopoiesis (even though all blood cells are normally produced in the marrow in adults).

Myeloid neoplasms always concern bone marrow cell lineage and are related to hematopoietic cells. Myeloid tissue can also be present in the liver and spleen in fetuses, and sometimes even in adults as well, which leads to extramedullary hematopoiesis.

There is one other sense of myeloid that means "pertaining to the spinal cord", but it is much less commonly used. Myeloid should not be confused with myelin, referring to an insulating layer covering the axons of many neurons.


Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif . This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.

Periodic fever syndrome

Periodic fever syndromes (also known as autoinflammatory diseases or autoinflammatory syndromes) are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, patients with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system.The syndromes are diverse, but tend to cause episodes of fever, joint pains, skin rashes, abdominal pains and may lead to chronic complications such as amyloidosis.Most autoinflammatory diseases are genetic and present during childhood. The most common genetic autoinflammatory syndrome is familial Mediterranean fever, which causes short episodes of fever, abdominal pain, serositis, lasting less than 72 hours. It is caused by mutations in the MEFV gene, which codes for the protein pyrin.

Pyrin is a protein normally present in the inflammasome. The mutated pyrin protein is thought to cause inappropriate activation of the inflammasome, leading to release of the pro-inflammatory cytokine IL-1β. Most other autoinflammatory diseases also cause disease by inappropriate release of IL-1β. Thus, IL-1β has become a common therapeutic target, and medications such as anakinra, rilonacept, and canakinumab have revolutionized the treatment of autoinflammatory diseases.

However, there are some autoinflammatory diseases that are not known to have a clear genetic cause. This includes PFAPA, which is the most common autoinflammatory disease seen in children, characterized by episodes of fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Other autoinflammatory diseases that do not have clear genetic causes include adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, Schnitzler syndrome, and chronic recurrent multifocal osteomyelitis. It is likely that these diseases are multifactorial, with genes that make people susceptible to these diseases, but they require an additional environmental factor to trigger the disease.

Receptor editing

Receptor editing is a process that occurs during the maturation of B cells, which are part of the adaptive immune system. This process forms part of central tolerance to attempt to change the specificity of the antigen receptor of self reactive immature B-cells, in order to rescue them from programmed cell death, called apoptosis. It is thought that 20-50% of all peripheral naive B cells have undergone receptor editing making it the most common method of removing self reactive B cells.During maturation in the bone marrow, B cells are tested for interaction with self antigens, which is called negative selection. If the maturing B cells strongly interact with these self antigens, they undergo death by apoptosis. Negative selection is important to avoid the production of B cells that could cause autoimmune diseases. They can avoid apoptosis by modifying the sequence of light chain V and J genes (components of the antigen receptor) so that it has a different specificity and may not recognize self antigens anymore. This process of changing the specificity of the immature B cell receptor is called receptor editing.

Recombination-activating gene

The recombination-activating genes (RAGs) encode enzymes that play an important role in the rearrangement and recombination of the genes of immunoglobulin and T cell receptor molecules, however there is no evidence to suggest the developing T cells can undergo receptor editing in the same way that B cells do. There are two recombination-activating gene products known as RAG-1 and RAG-2, whose cellular expression is restricted to lymphocytes during their developmental stages. RAG-1 and RAG-2 are essential to the generation of mature B and T lymphocytes, two cell types that are crucial components of the adaptive immune system.

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