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The "immune system" is a network of biological processes that protects an organism against disease. It detects and responds to a wide variety of pathogens, from viruses to parasitic worm, as well as cancer cells and distinguishing them from the organism's own healthy tissue. Many species have two major subsystems namely innate and adaptive immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive (acquired) immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Adaptive immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination. Dysfunction of the immune system can cause immunodeficiency, autoimmune disease, and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. 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. Some treatments have been available such us immunotherapy for cancer, and monoclonal antibody-based medicine for autoimmune disease.

Introduction[edit | edit source]

The immune system is a host defense system that includes many biological structures and processes within an organism that protects against disease. In many species, the immune system can be classified into subsystems, such as the innate immune system and the adaptive immune system. Important immune systems have evolved and exist in their modern offspring in ancient plants and animals. These processes include phagocytosis, complement system, and the synthesis of antimicrobial peptides. Jawed vertebrates, including humans, have much more complex defense mechanisms, including the ability to adapt to more accurately recognize pathogens.

The immune system protects its host with a variety of layered protections. Pathogens such as bacteria and viruses are stopped from entering the body by physical barriers.[1] In vertebrates, pathogens that cross these barriers would be overcome by an innate immune system. Therefore as pathogens effectively resist an innate response, the adaptive immune system is triggered to provide stronger response.[2] During an infection, the immune system adapts its response to enhance its identification of the pathogen. This enhanced response is then maintained after the pathogen has been eliminated, in the form of immunological memory, which helps the adaptive immune system to launch faster and stronger attacks each time the pathogen is encountered.[3][4]

Innate immune system[edit | edit source]

Microorganisms or toxins that successfully enter the body encounter the cells of the innate immune system. The innate response is typically activated when microbes are identified by receptors that recognize molecules that are conserved among broad groups of microorganisms,[5] or molecules that released from damaged cells.[6]

Surface barriers[edit | edit source]

The organisms cannot be completely sealed from their surroundings, thus the mechanisms act to protect the openings of the body, such as the lungs, intestines, and the genitourinary tract. Several barriers, including mechanical, chemical, and biological barriers, protect organism from infection. Surface barriers are part of mucosal immunity, which formed in the mucosal area by the mucosal ecosystem. The mucosal area covers a much larger body surface compared to the skin area. Each mucosal area is consists of slightly different immune components that affect their primary mechanism of response toward pathogen invasion.[7]

The mucosal immune system components are the physical barrier, humoral component, cellular component, and gut microbiota. The physical barrier includes the mucosal layer and epithelial layer, especially the tight junction and acidic pH of the gastric.[8] The main function of the physical barrier is to limit microbial access to tissue physically and biologically. The humoral component is antimicrobial peptides such as the β-defensins[9] and sIgA. Antimicrobial peptides have direct bactericidal activity, whereas sIgA acts by blocking the attachment of bacteria to epithelial cells, agglutination, or directly affecting bacterial virulence.

A cellular component is comprising a broad type of lymphoid and non-lymphoid cells. Non-lymphoid includes mucosal epithelial and M cells. Mucosal epithelial comprises a variety of cells with a specific function. Goblet cells, for example, responsible for producing mucus. Goblet cells abundantly present in the lower gastrointestinal tract and correlate with the mucosa layer's thickness.[10] Another unique cell in the mucosal area is M cells, which are crucial to transfer the antigen or pathogen from intestinal lumen to lamina propria, where other immune cells' recognition occurs. Therefore, many dendritic cells in the lamina propria side are ready to capture antigen or pathogen transferred by M cells. The dendritic cell will present the antigen to lymphocytes in the inductive site of mucosal immune site, where lymphocytes resident in the mucosal area. In the small intestine, the immune cell is relatively more heterogeneous compared to the colon. Here also exist intraepithelial lymphoid cells. It can directly release cytokine and killing the infected cells.[11]

One component of the mucosal immune system that does not belong to the human structure is commensal bacteria located in the mucosal area, but mostly in the gastrointestinal tract.[12] The commensal bacteria are able to protect our body by direct and indirect mechanism. The direct mechanism include nutrient competition, i.e., competition for sialic acid and fucose. Another direct mechanism is by releasing molecules that induce toxicity, i.e., bacteriocins. The indirect mechanism of protection involves metabolic production (i.e., bile salts and short-chain fatty acids) and the immune system's induction to release antibacterial molecule, i.e., defensins.[13]

Immune sensing[edit | edit source]

Cells in the innate immune system employ receptors to identify molecular structures formed by pathogens.[14] These receptors called as pathogen recognition receptors (PRRs), a class of germ line-encoded receptors, that recognize two classes of molecules: pathogen-associated molecular patterns (PAMPs) which frequently found in pathogens, and damage-associated molecular patterns (DAMPs), which released by damage or death cells.[15] Currently, known PRR families are the toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the NOD–like receptors (NLRs), the RIG (retinoic acid-inducible gene)-like receptors (RLRs), and the AIM2-like receptor (ALR).[16] Toll-like receptors were first discovered in Drosophila, triggering the synthesis and secretion of cytokines, and activating other host defense programs required for both innate and adaptive immune responses. To date, 13 TLRs have been identified in mammals, of which 10 are present in humans (TLR1–10).[17]

Innate immune cells[edit | edit source]

The innate immune cells include the phagocyte (macrophages and neutrophils). The other cells involved in the innate response include innate lymphoid cells, natural killer cells), mast cells, eosinophils, and basophils. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms.[18]

Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.[19] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.[20][21]

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.[22] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes.[23] During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils is the first cells to arrive at the site of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes and cytokines, while they can also act as scavengers that eliminate dying cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.[24]

Dendritic cells are located mainly in the skin, nose, lungs, stomach, and intestines. Dendritic cells serve as a link between the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.[25]

Granulocytes are caracterized by the presence of granules in their cytoplasm, that include mast cells, basophils, eosinophils, and neutrophils. Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.[26] Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions.[27]

Innate lymphoid cells (ILCs) are a group of innate immune system cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells are defined by absence of antigen specific B cell receptor or T cell receptor (TCR) because of the lack of recombination activating gene. ILCs do not express myeloid or dendritic cell markers.[28]

Natural killer cells (NK cells), an ILCs, are lymphocytes and a component of the innate immune system which does not directly attack invading microbes.[29] Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex)—a situation that can arise in viral infections of host cells.[30] Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors which essentially put the brakes on NK cells.[31]

A minor subtype lymphocytes are the γδ T cells that recognize intact antigen and unbound to MHC antigen.[32] .[33]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 the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted natural killer T cells, γδ T cells straddle the border between innate and adaptive immunity.[34] On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.[32]

Complement system[edit | edit source]

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response.[35][36]

In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response.[37] The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.[38] The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.[39]

Inflammatory response[edit | edit source]

Inflammasome structure

Inflammation is one of the first responses of the immune system to infection.[40] The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes).[41][42] Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as terminating protein synthesis in the host cell.[43] These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.[44]

The pattern-recognition receptors called inflammasomes are multiprotein complexes consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1. This structure forms in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.[45]

Antiviral response[edit | edit source]

Upon viral infection, its genetic material that enters the cell will trigger the type I interferon production through the endosomal toll-like receptor or RIG-like receptor pathway.[46] Initially, this interferon is synthesized by infected cells and dendritic cells and is essential to inhibit viral replication. Further, natural killer cells will kill virus-infected cells before adaptive immunity response to fight the virus is developed. Several viruses can shut off MHC class I-antigen presentation, thus escaping recognition by cytotoxic T lymphocytes (CTL). Antibodies are effective against the virus only during the virus's extracellular stage, mainly by neutralizing the virus. The primary antibody contributing to this process is secretory IgA that neutralizes viral particles in the respiratory or intestinal mucosal. In the adaptive immune system, CTL is the main cell to eliminate virus infection. This cell recognized the endogenous viral peptide presented by MHC class I and directly showed its antiviral activity by killing the infected cells.

Adaptive immune system[edit | edit source]

diagram showing the processes of activation, cell destruction and digestion, antibody production and proliferation, and response memory
Overview of the processes involved in the primary immune response

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen.[47] The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.[48]

Adaptive immune cells[edit | edit source]

The main player in adaptive immune system is lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.[30] The B cell antigen-specific receptor is an antibody molecule on the B cell surface and recognizes native (unprocessed) antigen without any need for antigen processing. Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule.[49] Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.[30] When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen.

Antigen presentation to T lymphocytes[edit | edit source]

Both B cells and T cells posses receptor molecules that recognize specific antigens. T cells recognize antigen, only after antigens have been processed into peptide and presented in combination with a major histocompatibility complex (MHC) molecule by APC.[50]

Cell mediated immunity[edit | edit source]

There are two major subtypes of T cells: the cytotoxic T cell and the helper T cell. In addition, there are regulatory T cells which have a role in modulating immune response.[51]

Cytotoxic T cells[edit | edit source]

Cytotoxic T cells are a sub-group of T cells that kill infected cells, as well as damaged or dysfunctional cells.[52] Cytotoxic T cells are activated when their T-cell receptor binds to the specific antigen in a complex with the MHC class I molecule of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.[53] T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).[53]

Helper T cells[edit | edit source]

Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen.[54][55] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.[56]

Helper T cells express T cell receptors that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (such as Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for cytotoxic T cells, meaning many receptors on the helper T cell must be bound by an MHC:antigen to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.[57] The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.[58] In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.[59]

Humoral immune response[edit | edit source]

diagram showing the Y-shaped antibody. The variable region, including the antigen-binding site, is the top part of the two upper light chains. The remainder is the constant region.
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.[60]

A B cell identifies pathogens when immunoglobulins on its surface bind to a specific foreign antigen.[61] This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases cytokine and activates the B cell.[62] Activated B cell then begins to divide and differentiate to plasma cells that secrete the antibody. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.[63]

Disorders of human immunity[edit | edit source]

Immunodeficiency[edit | edit source]

Immunodeficiency is the result of failure or lack of immune system components, including lymphocytes, phagocytes, and complement systems. These immunodeficiencies can be either primary (congenital), such as severe combined immunodeficiency (SCID), or secondary (acquired) as the one caused by HIV infection.[64]

Allergy[edit | edit source]

Allergy is a condition in which the body overreacts to exposure to a molecule. Allergy is type 1 hypersensitivity reactions mediated by activation of mast cells or basophils. This cellular activation results in the release of allergic mediators such as histamine and leukotrienes. These mediators play a role in clinical allergic responses, such as increased vascular permeability, bronchodilation, vasoconstriction, and the itch sensation. Mast cells can secrete histamine and other mediators after being activated by various types of molecules.

Autoimmunity[edit | edit source]

Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.[61]

Manipulation in medicine[edit | edit source]

Immunosupression[edit | edit source]

Immunosuppressive drugs are used to control autoimmune disorders and to prevent transplant rejection after an organ transplant.[65] Another drug class that often used for immunosuppresion is glucocorticoid. Glucocorticoid have antiinflammatory and immunosuppresive property[66]and often used in conjunction with cytotoxic or immunosuppressive in low doses. Cytotoxic such as azathioprine inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects.[65] Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.[67]

Vaccination[edit | edit source]

Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination is to introduce an antigen from a pathogen in order to stimulate the immune system and develop adaptive immune response against that particular pathogen without causing disease associated with that organism.[19] This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.[68]

Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components.[19] Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells and maximize immunogenicity.[69]

Tumor immunology[edit | edit source]

The immune system responds not only to pathogens but also to transformed cells. In the 1950s, Macfarlane Burnet proposed the cancer immune surveillance concept, that the immune system is able to identify and destroy transformed cell clones and to kill the cancer cells that have formed.[70] Cancer immunosurveillance appears to be an important host protection mechanism that reduces cancer rates by inhibiting carcinogenesis and maintaining normal cellular homeostasis.[71] The transformed cells express antigens encoded by mutated genes (neoantigens) that are absent on normal cells. Mostly, the neoantigens are the products of randomly mutated genes that are not involved in carcinogenesis, or less commonly, products of mutated genes involved in oncogenesis. Consequently, new MHC-binding peptides are generated and provoke adaptive immune system mediated by T cells. Some antigens are derived from oncogenic viruses such as human papillomavirus (HPV), which causes carcinoma of the uterine cervical, mouth, and throat. In addition, some tumor antigens are the products made by normal cells but produced in excessive amounts by tumors, since the genes that encode these proteins are amplified. For instance, one type of epidermal growth factor called Her2 is overexpressed in some breast cancers. Therefore, the trastuzumab monoclonal antibody against Her2 is used to treat patients whose tumors display a high expression of Her2.

Concluding remarks[edit | edit source]

Additional information[edit | edit source]

Acknowledgements[edit | edit source]

Any people, organisations, or funding sources that you would like to thank.

Competing interests[edit | edit source]

Any conflicts of interest that you would like to declare. Otherwise, a statement that the authors have no competing interest.

Ethics statement[edit | edit source]

An ethics statement, if appropriate, on any animal or human research performed should be included here or in the methods section.

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