Innate immune system

See also: Immune system and Adaptive immune system

Innate immune system

The innate immune system, also known as non-specific immune system and secondary line of defence,^[1] comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.^[2] Innate immune systems provide immediate defense against infection, and are found in all classes of plant and animal life.

The innate immune system is thought to constitute an evolutionarily older defense strategy, and is the dominant immune system found in plants, fungi, insects, and in primitive multicellular organisms.^[3]

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 to promote clearance of dead cells or antibody complexes.
• The identification and removal of foreign substances present in organs, tissues, the 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

Anatomical barriers

Anatomical barrier	Additional defense mechanisms
Skin	Sweat, desquamation, flushing,[4] organic acids[4]
Gastrointestinal tract	Peristalsis, gastric acid, bile acids, digestive enzyme, flushing, thiocyanate,[4] defensins,[4] gut flora[4]
Respiratory airways and lungs	Mucociliary elevator, surfactant,[4] defensins[4]
Nasopharynx	Mucus, saliva, lysozyme[4]
Eyes	Tears[4]

The epithelial surfaces form a physical barrier that is very impermeable to most infectious agents, acting as the first line of defense against invading organisms.^[4] Desquamation of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces.^[4] In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia helps removing infectious agents.^[4] Also, mucus traps infectious agents.^[4] The gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.^[4] The flushing action of tears and saliva helps prevent infection of the eyes and mouth.^[4]

Inflammation

Main article: Inflammation

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 and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.^[5]

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mastocytes. These cells present on their surfaces certain receptors named pattern recognition receptors (PRRs), which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRR recognize a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation.

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes also prostaglandins) sensitize pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagocytes, especially neutrophils.^[5] Neutrophils then trigger other parts of the immune system by releasing factors that summon other leukocytes and lymphocytes. Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response. These cytokines include TNF, HMGB1, and IL-1.^[6]

The inflammatory response is characterized by the following symptom: redness, heat, swelling, pain, and possible dysfunction of the organs or tissues involved.

Complement system

Main article: Complement system

The complement system is a biochemical 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 the liver, primarily by hepatocytes. The proteins work together to:

• trigger the recruitment of inflammatory cells.
• "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen.
• forming holes in the plasma membrane of the pathogen, resulting in cytolysis of the pathogen cell, causing the death of the pathogen.
• rid the body of neutralized antigen-antibody complexes.

Elements of the complement cascade can be found in many nonmammalian species including plants, birds, fish and some species of invertebrates.^[7]

Cells of the innate immune response

Main article: Leukocyte

A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

All white blood cells (WBC) are known as leukocytes. Leukocytes are different from other cells of the body in that they are not tightly associated with a particular organ or tissue; thus, they function similar to independent, single-celled organisms. Leukocytes are able to move freely and interact with and capture cellular debris, foreign particles, or invading microorganisms. Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of multipotent hematopoietic stem cells present in the bone marrow.^[2]

The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells including macrophages, neutrophils and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.^[3]

Mast cells

Main article: Mast cell

Mast cells are a type of innate immune cell that reside in connective tissue and in the mucous membranes. They are intimately associated with defense against pathogens and wound healing, but are also often associated with allergy and anaphylaxis.^[5] When activated, mast cells rapidly release characteristic granules, rich in histamine and heparin, along with various hormonal mediators, and chemokines, or chemotactic cytokines into the environment. Histamine dilates blood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.^[5]

Phagocytes

Main article: Phagocytosis

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, i.e. phagocytose, pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its plasma 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 an endosome which merges with a lysosome.^[3] The lysosome contains enzymes and acids that kill and digest the particle or organism. Phagocytes generally patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. 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 internally induced by processes involving programmed cell death (also called apoptosis), or caused by cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal from the affected site.^[2] 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.

A macrophage

Macrophages

Main article: Macrophages

Macrophages, from the Greek, meaning "large eaters," are large phagocytic leukocytes, which are able to move outside of the vascular system by moving across the cell membrane of capillary 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 called monocytes. Macrophages are the most efficient phagocytes, and can phagocytose substantial numbers of bacteria or other cells or microbes.^[3] 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 of reactive oxygen species. Pathogens also stimulate the macrophage to produce chemokines, which summons other cells to the site of infection.^[3]

Neutrophils

Main article: Neutrophils

A neutrophil

Neutrophils, along with two other cell types; eosinophils and basophils (see below), are known as granulocytes due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobed nuclei. 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 a respiratory burst. The main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50 to 60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection.^[5] 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 during acute inflammation.^[5]

Dendritic cells

Main article: Dendritic cell

Dendritic cells (DC) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), and the inner mucosal lining of the nose, lungs, stomach and intestines.^[2] They are named for their resemblance to neuronal dendrites, but dendritic cells are not connected to the nervous system. Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive immune systems.

An eosinophil

Basophils and eosinophils

Main articles: Basophil granulocyte and Eosinophil granulocyte

Basophils and eosinophils are cells related to the neutrophil (see above). When activated by a pathogen encounter, basophils releasing histamine are important in defense against parasites, and play a role in allergic reactions (such as asthma).^[3] Upon activation, eosinophils secrete a range of highly toxic proteins and free radicals that are highly effective in killing bacteria and parasites, but are also responsible for tissue damage occurring during allergic reactions. Activation and toxin release by eosinophils is therefore tightly regulated to prevent any inappropriate tissue destruction.^[5]

Natural killer cells

Main article: Natural killer cell

Natural killer cells, or NK cells, are a component of the innate immune system which does not directly attack invading microbes. 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.^[7] 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."

γδ T cells

Main article: gamma/delta T cells

Like other 'unconventional' T cell subsets bearing invariant T cell receptors (TCRs), such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. 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 will respond to stressed epithelial cells.

Other vertebrate mechanisms

The coagulation system overlaps with the immune system. Some products of the coagulation system can contribute to the non-specific defenses by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, a protein produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent.^[4] Many acute-phase proteins of inflammation are involved in the coagulation system.

Also increased levels of lactoferrin and transferrin inhibit bacterial growth by binding iron, an essential nutrient for bacteria.^[4]

Neural regulation of innate immunity

The innate immune response to infectious and sterile injury is modulated by neural circuits that control cytokine production. The Inflammatory Reflex is a prototypical neural circuit that controls cytokine production in spleen.^[8] Action potentials transmitted via the vagus nerve to spleen mediate the release of acetylcholine, the neurotransmitter which inhibits cytokine release by interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokine-producing cells.^[9] The motor arc of the inflammatory reflex is termed the cholinergic anti-inflammatory pathway.

Pathogen-specificity

The parts of the innate immune system have different specificity for different pathogens.

Pathogen	Main examples [10]	Phagocytosis [10]	complement[10]	NK cells[10]
Intracellular and cytoplasmic virus	influenza mumps measles rhinovirus	yes	no	yes
Intracellular bacteria	Listeria monocytogenes Legionella Mycobacterium Rickettsia	yes (specifically neutrophils, no for rickettsia)	no	yes (no for rickettsia)
Extracellular bacteria	Staphylococcus Streptococcus Neisseria Salmonella typhi	yes	yes	no
Intracellular protozoa	Plasmodium malariae Leishmania donovani	no	no	no
Extracellular protozoa	Entamoeba histolytica Giardia lamblia	yes	yes	no
Extracellular fungi	Candida Histoplasma Cryptococcus	no	yes	no

Innate immune evasion

Cells of the innate immune system effectively prevent free growth of bacteria within the body; however, many pathogens have evolved mechanisms allowing them to evade the innate immune system.^[11][12]

Evasion strategies that circumvent the innate immune system include intracellular replication, such as in Salmonella, or a protective capsule that prevents lysis by complement and by phagocytes, as in Mycobacterium tuberculosis.^[13] Bacteroides species are normally mutualistic bacteria, making up a substantial portion of the mammalian gastrointestinal flora.^[14] Some species (B. fragilis, for example) are opportunistic pathogens, causing infections of the peritoneal cavity. These species evade the immune system through inhibition of phagocytosis by affecting the receptors that phagocytes use to engulf bacteria or by mimicking host cells so that the immune system does not recognize them as foreign. Staphylococcus aureus inhibits the ability of the phagocyte to respond to chemokine signals. Other organisms such as M. tuberculosis, Streptococcus pyogenes and Bacillus anthracis utilize mechanisms that directly kill the phagocyte.

Bacteria and fungi may also form complex biofilms, providing protection from the cells and proteins of the immune system; recent studies indicate that such biofilms are present in many successful infections, including the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.^[15]

Innate immunity in other species

Host defense in prokaryotes

Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism, called the restriction modification system to protect themselves from pathogens, such as bacteriophages. In this system, bacteria produce enzymes, called restriction endonucleases, that attack and destroy specific regions of the viral DNA of invading bacteriophages. Methylation of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases.^[16] Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes.

Host defense in invertebrates

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.^[17] Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists in all coelomates (animals with a body-cavity), including humans.^[18] The complement system, as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, crabs, and worms utilize a modified form of the complement response known as the prophenoloxidase (proPO) system.^[17]

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic immunity. Several species of insect produce antimicrobial peptides known as defensins and cecropins.

Proteolytic cascades

In invertebrates, pattern recognition proteins (PRPs) trigger proteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—including hemolymph coagulation and melanization. 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 have been found to function the same in both vertebrate and invertebrates, even though different proteins are used throughout the cascades.^[19]

Clotting mechanisms

In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are various different proteins and mechanisms that 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 the horseshoe crab species clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, like lipopolysaccharides enter.^[19]

Host defense in plants

Members of every class of pathogen which infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes and insects can all cause plant disease. As with animals, plants attacked by insects or other pathogens use a set of complex metabolic responses that lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other herbivores.^[20] (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 very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection.^[20]

Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to identify pathogens and to start a basal response, which produces chemical signals that aid in warding off infection. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specific elicitors, the plant produces a localized hypersensitive response (HR), in which cells at the site of infection undergo rapid programmed cell death to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic activity of VPEγ, a cysteine protease that regulates cell disassembly during cell death.^[21]

"Resistance" (R) proteins, encoded by R genes, are widely present in plants and detect pathogens. These proteins contain domains similar to the NOD Like Receptors and Toll-like receptors utilized in animal innate immunity. Systemic acquired resistance (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents.^[22] SAR involves the production of chemical messengers, such as salicylic acid or jasmonic acid. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves.^[23] Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role for jasmonates in transmission of the signal to distal portions of the plant. RNA silencing mechanisms are also important in the plant systemic response, as they can block virus replication.^[24] The jasmonic acid response, is stimulated in leaves damaged by insects, and involves the production of methyl jasmonate.^[20]

See also

• Apoptosis
• Toll-like receptor

External links

• The Center for Modeling Immunity to Enteric Pathogens (MIEP)

References

1. ^ Paul Grasso. "Essentials of Pathology for Toxicologists". CRC Press. http://books.google.com/books?id=QwPuKwriPHcC&pg=PA28&dq=innate+immunity+non-sepcific+immunity&hl=en&ei=4_RcTsucG-nx0gHfyriQAw&sa=X&oi=book_result&ct=result&resnum=1&ved=0CDIQ6AEwAA#v=onepage&q&f=false. Retrieved 30 August 2011. "Our immune system is therefore crucial to our survival. It is currently divided into two categories which are innate (non-specific) immunity and acquired (specific) immunity." 
2. ^ ^{a b c d} Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walters (2002). Molecular Biology of the Cell; Fourth Edition. New York and London: Garland Science. ISBN 0-8153-3218-1. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2. 
3. ^ ^{a b c d e f} Janeway, Charles; Paul Travers, Mark Walport, and Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10. .
4. ^ ^{a b c d e f g h i j k l m n o p q} IMMUNOLOGY - CHAPTER ONE > INNATE (NON-SPECIFIC) IMMUNITY Gene Mayer, Ph.D. Immunology Section of Microbiology and Immunology On-line. University of South Carolina
5. ^ ^{a b c d e f g} Stvrtinová, Viera; Ján Jakubovský and Ivan Hulín (1995). Inflammation and Fever from Pathophysiology: Principles of Disease. Computing Centre, Slovak Academy of Sciences: Academic Electronic Press. http://nic.sav.sk/logos/books/scientific. 
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8. ^ Tracey, KJ (2007). "Physiology and immunology of the cholinergic antiinflammatory pathway". The Journal of clinical investigation 117 (2): 289–96. doi:10.1172/JCI30555. PMC 1783813. PMID 17273548. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1783813. 
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10. ^ ^{a b c d} Unless else specified in boxes, then ref is: Lippincott's Illustrated Reviews: Immunology. Paperback: 384 pages. Publisher: Lippincott Williams & Wilkins; (July 1, 2007). Language: English. ISBN 0781795435. ISBN 978-0781795432. Page 172
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13. ^ Finlay B, Falkow S (1997). "Common themes in microbial pathogenicity revisited". Microbiol Mol Biol Rev 61 (2): 136–69. PMC 232605. PMID 9184008. http://mmbr.asm.org/cgi/reprint/61/2/136.pdf. 
14. ^ Dorland WAN (editor) (2003). Dorland's Illustrated Medical Dictionary (30th ed.). W.B. Saunders. ISBN 0-7216-0146-4. 
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17. ^ ^{a b} Beck, Gregory and Habicht, Gail S. Immunity and the Invertebrates Scientific American. November 1996:60-66.
18. ^ Imler, JL; Hoffmann, JA (2001). "Toll receptors in innate immunity". Trends in cell biology 11 (7): 304–11. doi:10.1016/S0962-8924(01)02004-9. PMID 11413042. 
19. ^ ^{a b} Cerenius L, Kawabata S, Lee BL, Nonaka M, Söderhäll K (October 2010). "Proteolytic cascades and their involvement in invertebrate immunity". Trends Biochem. Sci. 35 (10): 575–83. doi:10.1016/j.tibs.2010.04.006. PMID 20541942. 
20. ^ ^{a b c} Schneider, David (2005) Plant immune responses Stanford University Department of Microbiology and Immunology.
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