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Theinnate immune system ornonspecific immune system[1] is one of the two main immunity strategies invertebrates (the other being theadaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune system response found inplants,fungi,prokaryotes, andinvertebrates (see§ Beyond vertebrates).[2]
The major functions of the innate immune system are to:
Anatomical barriers include physical, chemical and biological barriers. The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line of defense against invading organisms.[3]Desquamation (shedding) of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surface. Lack of blood vessels, the inability of the epidermis to retain moisture, and the presence ofsebaceous glands in the dermis, produces an environment unsuitable for the survival ofmicrobes.[3] In the gastrointestinal andrespiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious agents.[3] Also,mucus traps infectious agents.[3]Gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or cell surface attachment sites.[3] The flushing action of tears and saliva helps prevent infection of the eyes and mouth.[3]
| Anatomical barrier | Additional defense mechanisms |
|---|---|
| Skin | Sweat (includingdermcidin),cathelicidin, desquamation, flushing,[3] organic acids,[3]skin flora |
| Gastrointestinal tract | Peristalsis,gastric acid,bile acids,digestive enzyme, flushing,thiocyanate,[3]defensins,[3]gut flora,[3]lysozymes |
| Respiratory airways andlungs | Mucociliary escalator,[4]surfactant,[3]defensins[3] |
| Nasopharynx | Mucus, saliva,lysozyme[3] |
| Eyes | Tears[3] |
| Blood–brain barrier | endothelial cells (via passivediffusion/osmosis & active selection).P-glycoprotein (mechanism by whichactive transportation is mediated) |
Theepithelial barrier hypothesis (also known as theepithelial barrier theory) is a medical concept suggesting that dysfunction of epithelial barriers, induced by environmental toxic substances such as air pollutants, detergents, food additives, microplastics, and nanoparticles, contributes to the development of chronic diseases. Barrier impairment occurs in the skin, respiratory tract, and intestines, and is often accompanied by microbial dysbiosis, bacterial translocation, tissue and systemic inflammation, and immune dysregulation. These processes have been proposed as contributing factors to allergic, autoimmune, metabolic, and neuropsychiatric disorders.[5][6] The hypothesis was initially framed in the early 2020s by immunologistCezmi A. Akdis and has since been discussed in independent peer-reviewed reviews in the fields of immunology, allergy, dermatology, and nutrition.[7][8] Akdis introduced the concept to explain the rising prevalence of chronic inflammatory diseases in industrialized societies. It builds on earlier frameworks such as thehygiene hypothesis and incorporates findings frommicrobiome research.[9]
Proposed mechanisms include:
Disease contexts include:
Critics of the theory argue that many associations remain correlative and emphasize the need for longitudinal human studies and standardized methods to assess epithelial barrier integrity.[14][15]
Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells. It establishes a physical barrier against the spread of infection and promotes healing of any damaged tissue following pathogen clearance.[16]
The process of acute inflammation is initiated by cells already present in all tissues, mainly residentmacrophages,dendritic cells,histiocytes,Kupffer cells, andmast cells. These cells present receptors contained on the surface or within the cell, namedpattern recognition receptors (PRRs), which recognize molecules that are broadly shared bypathogens but distinguishable from host molecules, collectively referred to aspathogen-associated molecular patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRRs recognizes a PAMP) and releaseinflammatory mediators, like cytokines and chemokines, which are responsible for the clinical signs of inflammation. PRR activation and its cellular consequences have been well-characterized as methods of inflammatory cell death, which includepyroptosis,necroptosis, andPANoptosis. These cell death pathways help clear infected or aberrant cells and release cellular contents and inflammatory mediators.
Chemical factors produced during inflammation (histamine,bradykinin,serotonin,leukotrienes, andprostaglandins) sensitizepain receptors, cause localvasodilation of theblood vessels, and attract phagocytes, especially neutrophils.[16] Neutrophils then trigger other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes.Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response. These cytokines includeTNF,HMGB1, andIL-1.[17]
The inflammatory response is characterized by the following symptoms:
Thecomplement system is abiochemical cascade of the immune system that helps, or "complements", the ability of antibodies to clear pathogens or mark them for destruction by other cells. The cascade is composed of many plasma proteins, synthesized in theliver, primarily byhepatocytes. The proteins work together to:
The three different complement systems are classical, alternative and lectin.
Elements of the complement cascade can be found in many non-mammalian species includingplants,birds,fish, and some species ofinvertebrates.[18]
White blood cells (WBCs) are also known asleukocytes. Most leukocytes differ from other cells of the body in that they are not tightly associated with a particular organ or tissue; thus, their function is similar to that of independent, single-cell organisms. Most leukocytes are able to move freely and interact with and capture cellular debris, foreign particles, and invading microorganisms (althoughmacrophages,mast cells, anddendritic cells are less mobile). Unlike many other cells, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of multipotenthematopoietic stem cells present inbone marrow.[19][20]
The innate leukocytes include:natural killer cells, mast cells,eosinophils,basophils; and thephagocytic cells includemacrophages,neutrophils, and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.[2]
Mast cells are a type of innate immune cell that resides in connective tissue and in mucous membranes. They are intimately associated with wound healing and defense against pathogens, but are also often associated withallergy andanaphylaxis.[16] When activated, mast cells rapidly release characteristic granules, rich inhistamine andheparin, along with various hormonal mediators andchemokines, or chemotacticcytokines into the environment. Histamine dilatesblood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.[16]
The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or 'phagocytose', pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of itsplasma membrane, wrapping the membrane around the particle until it is enveloped (i.e., the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside aphagosome, which merges with alysosome.[2] The lysosome contains enzymes and acids that kill and digest the particle or organism. In general, phagocytes patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, calledcytokines. The phagocytic cells of the immune system include macrophages,neutrophils, and dendritic cells.
Phagocytosis of the hosts' own cells is common as part of regular tissue development and maintenance. When host cells die, either byapoptosis or by cell injury due to an infection, phagocytic cells are responsible for their removal from the affected site.[20] By helping to remove dead cells preceding growth and development of new healthy cells, phagocytosis is an important part of the healing process following tissue injury.
Macrophages, from the Greek, meaning "large eaters", are large phagocytic leukocytes, which are able to move beyond the vascular system by migrating through the walls ofcapillary vessels and entering the areas between cells in pursuit of invading pathogens. In tissues, organ-specific macrophages are differentiated from phagocytic cells present in the blood calledmonocytes. Macrophages are the most efficient phagocytes and can phagocytose substantial numbers of bacteria or other cells or microbes.[2] The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a "respiratory burst", causing the release ofreactive oxygen species. Pathogens also stimulate the macrophage to produce chemokines, which summon other cells to the site of infection.[2] There are also resident macrophages in many tissues including mucous membranes, liver, lungs, and skin (where they are often calledLangerhans cells).
Neutrophils, along witheosinophils andbasophils, are known asgranulocytes due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobednuclei. Neutrophil granules contain a variety of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to macrophages, neutrophils attack pathogens by activating arespiratory burst. The main products of the neutrophil respiratory burst are strongoxidizing agents includinghydrogen peroxide,free oxygen radicals andhypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50–60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection.[16] The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day duringacute inflammation.[16]
Dendritic cells (DCs) are phagocytic cells present in tissues that are in contact with the external environment, mainly theskin and the inner mucosal lining of thenose,lungs,stomach, andintestines.[20] They are named for their resemblance toneuronaldendrites, but dendritic cells are not connected to thenervous system. Dendritic cells are very important in the process ofantigen presentation, and serve as a link between the innate andadaptive immune systems.
Basophils and eosinophils are cells related to the neutrophil. When activated by a pathogen encounter,histamine-releasing basophils are important in the defense againstparasites and play a role inallergic reactions, such asasthma.[2] Upon activation, eosinophils secrete a range of highlytoxic proteins and free radicals that are highly effective in killing parasites, but may also damage tissue during an allergic reaction. Activation and release of toxins by eosinophils are, therefore, tightly regulated to prevent any inappropriate tissue destruction.[16]
Natural killer cells (NK cells) do not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such astumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self". This term describes cells with abnormally low levels of a cell-surface marker called MHC I (major histocompatibility complex) - a situation that can arise in viral infections of host cells.[21] They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self". The MHC makeup on the surface of damaged cells is altered and the NK cells become activated by recognizing this. 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 cellimmunoglobulin receptors (KIR) that slow the reaction of NK cells. TheNK-92 cell line does not express KIR and is developed for tumor therapy.[22][23][24][25]
Like other 'unconventional' T cell subsets bearing invariantT cell receptors (TCRs), such asCD1d-restrictedNatural Killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. γδ T cells may be considered a component ofadaptive immunity in that theyrearrange TCR genes to produce junctional diversity and develop a memoryphenotype. The various subsets may be considered part of the innate immune system where a restricted TCR or NK receptors may be used as apattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours tocommon molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells.
Thecoagulation system overlaps with the immune system. Some products of the coagulation system can contribute to non-specific defenses via their ability to increasevascular permeability and act aschemotactic agents forphagocytic cells. In addition, some of the products of the coagulation system are directlyantimicrobial. For example,beta-lysine, a protein produced by platelets duringcoagulation, can causelysis of manyGram-positive bacteria by acting as a cationic detergent.[3] Manyacute-phase proteins ofinflammation are involved in the coagulation system.
Increased levels oflactoferrin andtransferrin inhibit bacterial growth by binding iron, an essential bacterial nutrient.[3]
The innate immune response to infectious and sterile injury is modulated by neural circuits that control cytokine production period. Theinflammatory reflex is a prototypical neural circuit that controls cytokine production in thespleen.[26] Action potentials transmitted via thevagus nerve to the spleen mediate the release ofacetylcholine, theneurotransmitter that inhibits cytokine release by interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokine-producing cells.[27] The motor arc of theinflammatory reflex is termed thecholinergic anti-inflammatory pathway.
The parts of the innate immune system display specificity for different pathogens.
| Pathogen | Main examples[28] | Phagocytosis[28] | complement[28] | NK cells[28] |
|---|---|---|---|---|
| Intracellular and cytoplasmicvirus | yes | yes[29] | yes | |
| Intracellularbacteria | yes (specificallyneutrophils) | yes[30] | yes | |
| no | yes | yes | ||
| Extracellularbacteria | yes | yes | no | |
| Intracellularprotozoa | no | no | yes | |
| Extracellularprotozoa | yes | yes | no/yes | |
| Extracellularfungi | yes[31] | yes | yes[32] |
Innate immune system cells prevent free growth of microorganisms within the body, but many pathogens have evolved mechanisms to evade it.[33][34]
One strategy is intracellular replication, as practised byMycobacterium tuberculosis, or wearing a protective capsule, which prevents lysis by complement and by phagocytes, as inSalmonella.[35]Bacteroides species are normallymutualistic bacteria, making up a substantial portion of the mammaliangastrointestinal flora.[36] Species such asB. fragilis areopportunistic pathogens, causing infections of theperitoneal cavity. They inhibit phagocytosis by affecting the phagocytes receptors used to engulf bacteria. They may also mimic host cells so the immune system does not recognize them as foreign.Staphylococcus aureus inhibits the ability of the phagocyte to respond to chemokine signals.M. tuberculosis,Streptococcus pyogenes, andBacillus anthracis utilize mechanisms that directly kill the phagocyte.[37][citation needed]
Bacteria and fungi may form complexbiofilms, protecting them from immune cells and proteins; biofilms are present in the chronicPseudomonas aeruginosa andBurkholderia cenocepacia infections characteristic ofcystic fibrosis.[38]
Type Iinterferons (IFN), secreted mainly bydendritic cells,[39] play a central role in antiviral host defense and a cell's antiviral state.[40] Viral components are recognized by different receptors:Toll-like receptors are located in the endosomal membrane and recognize double-strandedRNA (dsRNA), MDA5 and RIG-I receptors are located in the cytoplasm and recognize long dsRNA and phosphate-containing dsRNA respectively.[41] When thecytoplasmic receptorsMDA5 andRIG-I recognize a virus the conformation between thecaspase-recruitment domain (CARD) and the CARD-containing adaptor MAVS changes. In parallel, when TLRs in the endocytic compartments recognize a virus the activation of the adaptor proteinTRIF is induced. Both pathways converge in the recruitment and activation of the IKKε/TBK-1 complex, inducingdimerization oftranscription factorsIRF3 andIRF7, which are translocated in the nucleus, where they induce IFN production with the presence of a particular transcription factor and activate transcription factor 2. IFN is secreted through secretoryvesicles, where it can activate receptors on both the cell it was released from (autocrine) or nearby cells (paracrine). This induces hundreds of interferon-stimulated genes to be expressed. This leads toantiviral protein production, such asprotein kinase R, which inhibits viral protein synthesis, or the2′,5′-oligoadenylate synthetase family, which degrades viral RNA.[40]
Some viruses evade this by producing molecules that interfere with IFN production. For example, theInfluenza A virus producesNS1 protein, which can bind to host and viral RNA, interact with immune signaling proteins or block their activation byubiquitination, thus inhibiting type I IFN production.[42] Influenza A also blocks protein kinase R activation and establishment of the antiviral state.[43] The dengue virus also inhibits type I IFN production by blockingIRF3phosphorylation using NS2B3protease complex.[44]
Bacteria (and perhaps otherprokaryotic organisms), utilize a unique defense mechanism, called therestriction modification system to protect themselves from pathogens, such asbacteriophages. In this system, bacteria produceenzymes, calledrestriction endonucleases, that attack and destroy specific regions of the viralDNA of invading bacteriophages.Methylation of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases.[45] Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes.[46]
Invertebrates do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates.[47] Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity.Pattern recognition receptors (PRRs) are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. TLRs are a major class of pattern recognition receptor, that exists in allcoelomates (animals with a body-cavity), including humans.[48] Thecomplement system exists in most life forms. Some invertebrates, including various insects,crabs, andworms utilize a modified form of the complement response known as theprophenoloxidase (proPO) system.[47]
Antimicrobial peptides are an evolutionarilyconserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemicimmunity. Several species ofinsect produce antimicrobial peptides known asdefensins andcecropins.
In invertebrates, PRRs triggerproteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—includinghemolymph coagulation andmelanization. Proteolytic cascades are important components of the invertebrate immune system because they are turned on more rapidly than other innate immune reactions because they do not rely on gene changes. Proteolytic cascades function in both vertebrate and invertebrates, even though different proteins are used throughout the cascades.[49]
In the hemolymph, which makes up the fluid in the circulatory system ofarthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. Various proteins and mechanisms are involved in invertebrate clotting. In crustaceans,transglutaminase from blood cells and mobile plasma proteins make up the clotting system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein. On the other hand, in thehorseshoe crab clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, likelipopolysaccharides enter.[49]
Members of every class of pathogen that infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes, and insects can all causeplant disease. As with animals, plants attacked by insects or other pathogens use a set of complexmetabolic responses that lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and otherherbivores.[50] (see:plant defense against herbivory).
Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that few animals can. Walling off or discarding a part of a plant helps stop infection spread.[50]
Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use PRRs to recognize conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved microbial signatures were identified in rice (XA21, 1995)[51][52] and inArabidopsis (FLS2, 2000).[53] Plants also carry immune receptors that recognize variable pathogen effectors. These include the NBS-LRR class of proteins. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specificelicitors, the plant produces a localizedhypersensitive response (HR), in which cells at the site of infection undergo rapid apoptosis to prevent spread to other parts of the plant. HR has some similarities to animalpyroptosis, such as a requirement ofcaspase-1-like proteolytic activity ofVPEγ, acysteine protease that regulates cell disassembly during cell death.[54]
"Resistance" (R) proteins, encoded byR genes, are widely present in plants and detect pathogens. These proteins contain domains similar to theNOD Like Receptors and TLRs.Systemic acquired resistance (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents.[55] SAR involves the production ofchemical messengers, such assalicylic acid orjasmonic acid. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves.[56] Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role forjasmonates in transmission of the signal to distal portions of the plant.RNA silencing mechanisms are important in the plant systemic response, as they can block virus replication.[57] Thejasmonic acid response is stimulated in leaves damaged by insects, and involves the production ofmethyl jasmonate.[50]
{{cite journal}}: CS1 maint: DOI inactive as of September 2025 (link)database of proteins and their interactions in innate immunesystem
