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Try free for 5 days Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer. Hypersensitivity reactions. Summary Hypersensitivity reactions occur when the normally protective immune system responds abnormally, potentially harming the body. Hypersensitivity classification [1] [2] Summary of pathophysiology Examples Type I : immediate Preformed IgE antibodies coating mast cells and basophils are crosslinked by contact with free antigen.
Cell degranulatio n results in the release of histamine and other inflammatory mediators. Allergic or anaphylactic transfusion reactions e. Complement system activation and lysis or phagocytosis of cells Antibody -dependent cell-mediated cytotoxicity e. References Mandallaz et al.. Bird-egg syndrome. Cross-reactivity between bird antigens and egg-yolk livetins in IgE-mediated hypersensitivity. International Archives of Allergy and Applied Immunology.
Relationship of Dust Mites and Crustaceans. Updated: July 13, Accessed: April 17, Urticaria and angioedema. Allergy Asthma Clin Immunol. Numerous cells are involved in the innate immune response such as phagocytes macrophages and neutrophils , dendritic cells, mast cells, basophils, eosinophils, natural killer NK cells and lymphocytes T cells.
Phagocytes are sub-divided into two main cell types: neutrophils and macrophages. Both of these cells share a similar function: to engulf phagocytose microbes. In addition to their phagocytic properties, neutrophils contain granules that, when released, assist in the elimination of pathogenic microbes. Unlike neutrophils which are short-lived cells , macrophages are long-lived cells that not only play a role in phagocytosis, but are also involved in antigen presentation to T cells.
Macrophages are named according to the tissue in which they reside. For example, macrophages present in the liver are called Kupffer cells while those present in the connective tissue are termed histiocytes see Figure 1 [ 1 ].
Characteristics and function of cells involved in innate immunity [ 1 , 3 , 4 ]. Dendritic cells also phagocytose and function as antigen-presenting cells APCs and act as important messengers between innate and adaptive immunity. Mast cells and basophils share many salient features with each other and both are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. Unlike mast cells, which generally reside in the connective tissue surrounding blood vessels, basophils reside in the circulation.
Eosinophils are granulocytes that possess phagocytic properties and play an important role in the destruction of parasites that are too large to be phagocytosed. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma.
NK cells also known as large granular lymphocytes [LGLs] play a major role in the rejection of tumours and the destruction of cells infected by viruses. Destruction of infected cells is achieved through the release of perforins and granzymes from NK-cell granules which induce apoptosis programmed cell death [ 4 ]. The main characteristics and functions of the cells involved in the innate immune response are summarized in Figure 1.
Innate immunity can be viewed as comprising four types of defensive barriers: anatomic skin and mucous membrane , physiologic temperature, low pH and chemical mediators , endocytic and phagocytic, and inflammatory. Table 1 summarizes the non-specific host-defense mechanisms for each of these barriers.
Adaptive immunity develops when innate immunity is ineffective in eliminating infectious agents and the infection is established. The cells of the adaptive immune system include: T cells, which are activated through the action of antigen presenting cells APCs , and B cells.
T cells derive from hematopoietic stem cells in bone marrow and, following migration, mature in the thymus. These cells express a unique antigen-binding receptor on their membrane, known as the T-cell receptor TCR , and as previously mentioned, require the action of APCs usually dendritic cells, but also macrophages, B cells, fibroblasts and epithelial cells to recognize a specific antigen. Class I MHC molecules present endogenous intracellular peptides while class II molecules present exogenous extracellular peptides.
The MHC protein displays fragments of antigens peptides when a cell is infected with a pathogen or has phagocytosed foreign proteins [ 2 , 3 ]. T cells are activated when they encounter an APC that has digested an antigen and is displaying antigen fragments bound to its MHC molecules. Cytotoxic T cells are primarily involved in the destruction of cells infected by foreign agents.
Clonal expansion of cytotoxic T cells produce effector cells which release perforin and granzyme proteins that causes lysis of target cells and granulysin a substance that induces apoptosis of target cells. Upon resolution of the infection, most effector cells die and are cleared by phagocytes. However, a few of these cells are retained as memory cells that can quickly differentiate into effector cells upon subsequent encounters with the same antigen [ 2 , 3 ].
Adaptive immunity: T-cell and B-cell activation and function. T helper Th cells play an important role in establishing and maximizing the immune response.
These cells have no cytotoxic or phagocytic activity, and cannot kill infected cells or clear pathogens. However, they "mediate" the immune response by directing other cells to perform these tasks. Once activated, Th cells release cytokines that influence the activity of many cell types, including the APCs that activate them. As mentioned earlier, mast cells and eosinophils are instrumental in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. IgE antibodies are also associated with allergic reactions see Table 2.
Therefore, an imbalance of Th2 cytokine production is associated with the development of atopic allergic conditions. Like cytotoxic T cells, most Th cells will die upon resolution of infection, with a few remaining as Th memory cells [ 2 , 3 ]. A third type of T cell, known as the regulatory T cell T reg , also plays a role in the immune response.
T reg cells limit and suppress the immune system and, thereby, may function to control aberrant immune responses to self-antigens and the development of autoimmune disease. B cells arise from hematopoietic stem cells in the bone marrow and, following maturation, leave the marrow expressing a unique antigen-binding receptor on their membrane.
The principal function of B cells is the production of antibodies against foreign antigens [ 2 , 3 ]. When activated by foreign antigens, B cells undergo proliferation and differentiate into antibody-secreting plasma cells or memory B cells see Figure 2. These cells can be called upon to respond quickly and eliminate an antigen upon re-exposure. Plasma cells, on the other hand, do not express antigen-binding receptors. These are short-lived cells that undergo apoptosis when the inciting agent that induced the immune response is eliminated.
Given their function in antibody production, B cells play a major role in the humoral or antibody-mediated immune response as opposed to the cell-mediated immune response, which is governed primarily by T cells [ 2 , 3 ]. Antibody-mediated immunity is the branch of the acquired immune system that is mediated by B-cell antibody production. This, in turn, attracts the assistance of Th cells which secrete cytokines that help the B cell multiply and mature into antibody-secreting plasma cells.
The secreted antibodies bind to antigens on the surface of pathogens, flagging them for destruction through pathogen and toxin neutralization, classical complement activation, opsonin promotion of phagocytosis and pathogen elimination. Upon elimination of the pathogen, the antigen-antibody complexes are cleared by the complement cascade see Figure 2 [ 2 ].
Each of these antibodies has differing biological functions and recognize and neutralize specific pathogens. Table 2 summarizes the various functions of the five Ig antibodies [ 5 ]. Antibodies play an important role in containing virus proliferation during the acute phase of infection. However, they are not generally capable of eliminating a virus once infection has occurred.
Once an infection is established, cell-mediated immune mechanisms are most important in host defense. Cell-mediated immunity does not involve antibodies, but rather protects an organism through [ 2 ]:. Adaptive immunity is an antigen-specific response which is relatively slow, since it requires a genetic rearrangement [ 1 ]. The main objective of the immune system is the defense against pathogens through these innate and adaptive mechanisms [ 2 , 3 ].
However, dysfunction or deficiency of the immune system can lead to tissue injuries and diseases. On the one hand, there are hypersensitivity diseases, which are characterized by excessive and undesirable reactions, produced by the immune system [ 4 ]. On the other hand, autoimmune diseases refer to the failure of the immunological tolerance mechanisms, causing reactions against own cells and tissues [ 5 ]. The innate immune system is the first line of defense against invading pathogens.
It has a double role to provide initial control of the infection and initiate an adaptive immune response. The innate immune system consists of physical barriers such as epithelial layers and mucus, soluble factors such as the complement system, soluble mediators, cytokines and cells such as neutrophils, macrophages and dendritic cells [ 6 ].
These immune cells detected pathogens based on their molecules or pathogen-associated molecular patterns PAMPs that are recognized by multiple classes of pattern-recognition receptors PRRs that initiate inflammatory responses [ 7 ]. PRRs can also recognize host molecules containing damage-associated molecular patterns DAMPs , molecules that are released from cells damaged [ 8 ]. Then, these PRRs respond by producing several soluble mediators such as the complement system and proinflammatory cytokines to kill microbes or infected cells [ 1 ].
The cells of the innate immune system have several functions that are essential for the defense of the organism. These cells respond by producing inflammatory cytokines and some of them are responsible for removing foreign substances, pathogens or infected cells.
Some of the innate immune cells include macrophages, dendritic cells, neutrophils, mast cells, basophils and eosinophils. Macrophages function as cells that capture and degrade agents that are not recognized as belonging to the organism, in addition to being antigen-presenting cells; therefore, they are essential in both types of immunity innate and adaptive [ 9 ].
Macrophages are formed in the bone marrow from myeloid progenitor cells, which when stimulated by the granulocyte-macrophage colony-stimulating factor GM-CSF are converted into monocytes, immature cells that are released into the bloodstream. Monocytes mature when stimulated by chemotactic substances, making them migrate to tissues as mature cells, establishing themselves for a lifetime of weeks to months.
This cell type is directly related to the inflammatory response, since phagocytosis uses harmful substances that can cause acute cell injury and promote apoptosis, including reactive oxygen species ROS , high amounts of nitric oxide and halogenating radicals.
Then, the macrophages can be divided into two general classes, depending on their phenotype, M1 that promote inflammation and M2 that release anti-inflammatory and pro-regenerative cytokines [ 12 , 13 ]. The process of formation of dendritic cells DCs is like macrophages, being monocytes in their more immature stage.
However, these cells are directed to epithelia even as immature cells and remain there for long periods weeks or months. When they capture microorganisms or antigenic agents, they eliminate them by phagocytosis, going through the lymph to the lymph nodes, where they will perform their specialized function as antigen-presenting cells [ 14 ]. The DCs present antigens to the T lymphocytes; however, it has been proven that they are also capable of activating B lymphocytes, natural killer NK cells, macrophages and eosinophils.
DCs participate in innate immunity; however, they regulate the adaptive immune response and are fundamental for the development of immunological memory and tolerance [ 15 ]. There are mainly two DCs subpopulations: classical and plasmacytoid DCs. On the one hand, classical DCs are specialized cells in the antigen processing and presentation, which have both high phagocytic activity and capacity for cytokine production [ 16 ].
On the other hand, plasmacytoid DCs are long-lived cells [ 17 ], which are present in the bone marrow and in all peripheral organs and are specialized to respond to viral infection with mass production of type I interferons IFN. However, these DCs can also act as antigen-presenting cells and control the responses of T cells [ 18 ]. Neutrophils are phagocytes that are derived from myeloid cells as well as monocytes and dendritic cells. Its morphology is very characteristic, since they present nuclear lobes of different morphologies and they are known as polymorphonuclear PMN.
They are the first cells of the immune system to reach the focus of infection and their function is practically phagocytosis. Although its short life has been identified that neutrophils are also involved in adaptive immunity, previously, it was known that neutrophils participated in the elimination of foreign agents by phagocytosis, dying in their function; however, it has been found that neutrophils have the ability to return to the bloodstream as antigen-presenting cells, interacting with dendritic cells, NK cells, T and B lymphocytes [ 19 , 20 ].
Mast cells are derived from mesenchymal precursor cells MCPs in bone marrow but mature in peripheral tissues.
They are distributed mainly in tissues close to the external environment such as the skin, mucous membranes, digestive tract and respiratory tract. Activation of mast cells causes the activation of phospholipase A2 and breaks down membrane lipids to produce arachidonic acid, which can be metabolized in two ways: 1 the cyclooxygenase COX pathway, producing prostaglandins and 2 the lipoxygenase pathway LOX , producing leukotrienes. Both prostaglandins and leukotrienes have pro-inflammatory effects, increasing vascular permeability.
The mast cells boost the immune response, increasing the recruitment of specific cells against pathogens, activating different types of immune cells such as macrophages, eosinophils and lymphocytes that eliminate bacteria, fungi, some parasites and cells infected by viruses. Basophils are granulocytes derived from myeloid cells.
They are the least abundant 0. They have many granules containing histamine, heparin, serotonin and high amounts of leukotrienes. Like mast cells, they contain histamine in their granules, being responsible for most of the early symptoms of IgE-dependent and non-dependent allergy sneezing, pruritus, bronchospasm and edema.
Basophils migrate to the site of inflammation and secrete proteases and various inflammatory mediators such as IL-4 to activate cells such as macrophages, innate lymphoid cells, fibroblasts and endothelial cells, aggravating the allergic inflammatory response [ 23 , 24 ]. Eosinophils play an important role in hypersensitivity since they are stimulated by IL-5 produced by mast cells and Th2 cells.
Also, fibroblasts when stimulated by IL-4, release eotaxins, molecules that stimulate the function of eosinophils [ 27 ]. Innate immune cells are capable of recognizing pathogens and endogenous molecules of proteins known as PRRs. PRRs dictate the initiation of an adequate and effective innate immune response, as well as the activation of the adaptive immune response to infection or inflammation [ 28 ].
The TLRs family, was originally identified in Drosophila, as important genes for its ontogeny and the innate immune response in Drosophila adults [ 30 ].
The TLRs family consists of 10 highly conserved transmembrane glycoproteins in humans, which recognize a wide range of pathogens [ 31 ]. They are expressed in a wide variety of cells such as innate immune cells, T and B cells, epithelial cells, fibroblasts, and endothelial cells; however, not all cell types express every TLR [ 34 ].
For example, TLR2 recognizes lipoarabinomannan from mycobacteria [ 36 ]. Further, TLR4 is also involved in antiviral innate immunity [ 42 , 43 ]. TLR5 is highly expressed DCs and detects bacterial flagellin [ 44 , 45 ]. TLR10 has been implicated in the recognition of Helicobacter pylori by gastric epithelial cells and may act as a heterodimer with TLR2 [ 47 , 48 ].
The NLR family comprises 22 members in humans. Most NLRs share common structural characteristics including a C-terminal leucine-rich repeat LRR domain, often involved in ligand recognition, a central NOD, and a variable N-terminal effector domain [ 49 ].
The most well-defined sensors of peptidoglycan are the cytosolic NOD-like receptors NLRs , NOD1 and NOD2, which are expressed by diverse cell types, including myeloid phagocytes and epithelial cells [ 51 ], which recognize specific ligands from various pathogens.
This family is involved in increasing the proinflammatory events caused by cell death and several more proinflammatory processes [ 52 ]. They act as sensors for viral replication within human host cells necessary to mediate antiviral responses [ 53 ]. Cytokines are secreted proteins that can be delineated as a distinct class of signaling molecules from hormones based on two key factors. First, the kinetics of cytokine secretion rapid and dramatic induction following specific extracellular stimuli , which is often prolonged at less dramatic concentrations to affect physiological changes.
Second, cytokines can be signaling autocrine, paracrine and endocrine fashions [ 54 , 55 ]. Cytokines are involved in regulating the homeostasis of the organism, but when its production or its signaling pathway in the cell is not regulated, this homeostasis is altered, which can trigger in a pathology [ 56 , 57 ].
The interleukin-1 superfamily members are closely linked to damaging inflammation; however, the same members also function to increase nonspecific resistance to infection and the development of an immune response to foreign antigens [ 60 ]. This family plays a pivotal role in immunity, inflammation and controlling cell cycle proliferation, differentiation and apoptosis [ 62 ].
ILrelated cytokines play key roles in defense against extracellular pathogen, autoimmunity. In addition, there is evidence that indicates that some of these molecules are involved in the amplification and perpetuation of pathological processes in many inflammatory diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis and allergy. However, the same cytokines can exert anti-inflammatory effects in specific settings and play key role in the control of immune homeostasis [ 63 , 64 ].
This cytokine family shows some redundant but not uniformly identical biological activity. IL-6 exerts pleiotropic effects on inflammation, immune response and hematopoiesis [ 66 , 67 ]. IL-6 is produced at the inflammation site by infection or tissue damage, which induces production of acute phase proteins such as C-reactive protein CRP , serum amyloid A, fibrinogen and hepcidin in liver.
But, dysregulated excessive or persistent production of IL-6 plays a pathological role in various kinds of diseases [ 65 ]. Inflammation is a protective response to infection, tissue stress and injury [ 71 ]. This inflammatory response is characterized by its clinical signs such as redness, heat, swelling, pain and dysfunction [ 72 ].
The inflammatory response is triggered by inducers such as PAMPs derived from bacteria, viruses, fungi and parasites; and DAMPs derived from cell damage, as well as toxic cellular components or any other harmful conditions [ 73 ]. Subsequently, the PRRs induced the synthesis and release of soluble mediators such as cytokines [ 75 ]. Cytokines, as optimal protection against pathogens, provide the necessary signals to initiate an inflammatory response, through the differentiation and proliferation of the immune system cells, adapting their effector functions as necessary to promote protective immunity, and once the inducers are eliminated, they suppress the inflammatory response, promoting tissue repair and return to homeostasis [ 54 ].
The inflammatory response is characterized by successive phases [ 76 ]: 1 silent phase, where cells reside in the damaged tissue releases in the first inflammatory mediators; 2 vascular phase, where vasodilation and increased vascular permeability occur; 3 cellular phase, which is characterized by the infiltration of leukocytes to the site of injury; and 4 resolution of inflammation, which is the process to return tissues to homeostasis [ 77 , 78 , 79 ].
Phagocytosis is the physiological process carried out by phagocytic cells to identify, digest and eliminate foreign substances or pathogens Figure 1. Infection with pathogens is the most common cause to trigger this immune mechanism.
The pathogens proliferate releasing small peptides with chemotactic activity, dispersing in the areas of underlying tissue and blood vessels. Endothelial cells initiate the synthesis of cell adhesion proteins, as do phagocytes found in the blood.
The adhesion proteins allow the phagocytes of the blood to bind to the endothelial cells, causing them to roll on the surface until finding an exit between the cell junctions, migrating to the extravascular space by a process known as diapedesis. The phagocytes that were close to the area of infection and those that migrated from the blood move toward the focus of infection attracted by the chemotactic peptides.
The interaction of these surface molecules causes the invagination of the cell membrane and the formation of cellular prolongations that end up involving the foreign pathogens in a phagocytic vacuole or phagosome.
The chemical interaction of the molecules on the membrane surface of microorganisms and phagocytes activates diverse receptors, including those of Gq proteins that activate phospholipase C, an enzyme that degrades membrane phospholipids to produce inositol triphosphate IP3 and diacylglycerol DAG.
The IP3, among many of its functions, is responsible for regulating cell movement by the cytoskeleton through the release of calcium ions by the endoplasmic reticulum. The ROS react with the biomolecules that make up the structures of the microorganisms lipids, polysaccharides, proteins and nucleic acids , causing their death.
Simultaneously, the phagocytes fuse lysosomes to the vacuole in which the microorganism is internalized, forming the phagosome, also releasing many hydrolytic enzymes that favor the digestion of the microorganism components [ 82 ]. In addition, ROS are released that contribute to the degradation of biomolecules. Lysosomes contain myeloperoxidase, an enzyme that hydrolyzes hydrogen peroxide for the formation of halogenating radicals such as hypochlorous acid, hypochlorite and hypoiodite, which increase the damage to microorganisms.
Finally, cell debris has two purposes: 1 to be eliminated by exocytosis, debris are evacuated into the bloodstream to be eliminated by renal route ; and 2 to transport certain antigenic components to the cell membrane to be presented to T and B cells and be able to give the process of acquired immunity mainly in the case of dendritic cells and macrophages [ 82 ].
The adaptive immune system has the capacity to generate a wide range of specific antigen receptors, through somatic mechanisms of gene rearrangement. These mechanisms create a random repertoire of receptors that are clonally distributed in T and B lymphocytes. This gives it the advantage of having a wide repertoire of specific antigen receptors, which can be recognized, without these having to be encoded in the host genome, allowing the recognition of almost any antigenic structure.
The activation of lymphocytes requires two types of signals: 1 a signal induced by the antigen receptor itself when recognizing its related antigen, and a costimulatory signal by professional antigen-presenting cells APCs. Therefore, the innate immune system, as already explained earlier, determines the origin of the antigens by means of a non-clonal system of receptors, PRRs, encoded in the germ line, which controls the expression of costimulatory molecules and effector cytokines, while the adaptive immune system does it through antigenic receptors [ 83 , 84 ].
During the hematopoiesis that is generated in the bone marrow, it gives rise to the precursors of all the lineages and states of differentiation of the T cells. These precursors, called thymocytes, travel through the peripheral blood and reach the thymus, where they mature in T lymphocytes. Once they are differentiated, they travel through the blood circulation until they are activated by means of the surface receptor they present, when they encounter a specific antigen. This receptor, known as T cell receptor TCR , binds to the major histocompatibility complex MHC , a complex expressed by antigen-presenting cells, in which the antigen is presented in the form of peptides.
T lymphocytes are responsible for cellular adaptive immunity. As the case of macrophages, B lymphocytes and other T lymphocytes, through costimulatory molecules and the release of cytokines, this causes a powerful cellular activation and therefore an effective immune response. Mediated by the secretion of cytokines, they can be differentiated into Th1, Th2, Th9, Th17 and Th22 types [ 86 ].
In addition, memory T lymphocytes have a long life, functionally inactive but respond to new exposures of the same antigen quickly and efficiently.
There is another population of T lymphocytes, the regulatory T lymphocytes [ 86 ]. This cellular population is responsible for eliminating autoreactive T cells that escaped the process of negative selection or central tolerance; with the purpose, to avoid the development of an autoimmune response [ 87 ]. In addition, they recognize complete proteins without needing to be processed to be presented through the MHC molecules [ 88 ].
The B lymphocytes are originated from the same precursor that gives origin to the T lymphocytes and the NK cells.
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