Immune system#Passive memory

The immune system protects its host from infection with layered defenses of increasing specificity. Physical barriers prevent pathogens such as bacteria and viruses from entering the organism.{{sfn | Sompayrac | 2019 | p=1}} If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all animals.{{cite journal | vauthors = Litman GW, Cannon JP, Dishaw LJ | title = Reconstructing immune phylogeny: new perspectives | journal = Nature Reviews. Immunology | volume = 5 | issue = 11 | pages = 866–79 | date = Nov 2005 | pmid = 16261174 | pmc = 3683834 | doi = 10.1038/nri1712 }} If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response.{{sfn | Sompayrac | 2019 | p=4}} Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.{{cite journal | vauthors = Restifo NP, Gattinoni L | title = Lineage relationship of effector and memory T cells | journal = Current Opinion in Immunology | volume = 25 | issue = 5 | pages = 556–63 | date = October 2013 | pmid = 24148236 | doi = 10.1016/j.coi.2013.09.003 | pmc=3858177}}{{cite journal | vauthors = Kurosaki T, Kometani K, Ise W | title = Memory B cells | journal = Nature Reviews. Immunology | volume = 15 | issue = 3 | pages = 149–59 | date = March 2015 | pmid = 25677494 | doi = 10.1038/nri3802 | s2cid = 20825732 }}

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are components of an organism's body that can be distinguished from foreign substances by the immune system.{{sfn | Sompayrac | 2019 | p=11}} Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (originally named for being antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.{{sfn | Sompayrac | 2019 | p=146}}

Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= sec. [https://www.ncbi.nlm.nih.gov/books/NBK26833/#A4639 "Pathogens Cross Protective Barriers to Colonize the Host"]}} Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.{{cite journal | vauthors = Boyton RJ, Openshaw PJ | title = Pulmonary defences to acute respiratory infection | journal = British Medical Bulletin | volume = 61 | issue = 1 | pages = 1–12 | year = 2002 | pmid = 11997295 | doi = 10.1093/bmb/61.1.1 | doi-access = free }}

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins.{{cite book | vauthors = Agerberth B, Gudmundsson GH | title = Antimicrobial Peptides and Human Disease | chapter = Host antimicrobial defence peptides in human disease | volume = 306 | pages = 67–90 | year = 2006 | pmid = 16909918 | doi = 10.1007/3-540-29916-5_3 | isbn = 978-3-540-29915-8 | series = Current Topics in Microbiology and Immunology }} Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials.{{cite journal|vauthors=Moreau JM, Girgis DO, Hume EB, Dajcs JJ, Austin MS, O'Callaghan RJ |title=Phospholipase A(2) in rabbit tears: a host defense against Staphylococcus aureus |journal=Investigative Ophthalmology & Visual Science |volume=42 |issue=10 |pages=2347–54 |date=Sep 2001 |pmid=11527949 |url=http://iovs.arvojournals.org/article.aspx?articleid=2200058}}{{cite journal | vauthors = Hankiewicz J, Swierczek E | title = Lysozyme in human body fluids | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 57 | issue = 3 | pages = 205–09 | date = Dec 1974 | pmid = 4434640 | doi = 10.1016/0009-8981(74)90398-2 }} Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens.{{cite journal | vauthors = Fair WR, Couch J, Wehner N | title = Prostatic antibacterial factor. Identity and significance | journal = Urology | volume = 7 | issue = 2 | pages = 169–77 | date = Feb 1976 | pmid = 54972 | doi = 10.1016/0090-4295(76)90305-8 }}{{cite journal | vauthors = Yenugu S, Hamil KG, Birse CE, Ruben SM, French FS, Hall SH | title = Antibacterial properties of the sperm-binding proteins and peptides of human epididymis 2 (HE2) family; salt sensitivity, structural dependence and their interaction with outer and cytoplasmic membranes of Escherichia coli | journal = The Biochemical Journal | volume = 372 | issue = Pt 2 | pages = 473–83 | date = Jun 2003 | pmid = 12628001 | pmc = 1223422 | doi = 10.1042/BJ20030225 }} In the stomach, gastric acid serves as a chemical defense against ingested pathogens.{{cite journal|vauthors=Smith JL|year=2003|title=The role of gastric acid in preventing foodborne disease and how bacteria overcome acid conditions|journal=J Food Prot|volume=66|issue=7|pages=1292–1303|pmid=12870767|doi=10.4315/0362-028X-66.7.1292|doi-access=free}}

Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, changing the conditions in their environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.{{cite journal | vauthors = Gorbach SL | title = Lactic acid bacteria and human health | journal = Annals of Medicine | volume = 22 | issue = 1 | pages = 37–41 | date = Feb 1990 | pmid = 2109988 | doi = 10.3109/07853899009147239 }}

{{further|Innate immune system}}

Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms,{{cite journal | vauthors = Medzhitov R | title = Recognition of microorganisms and activation of the immune response | journal = Nature | volume = 449 | issue = 7164 | pages = 819–26 | date = Oct 2007 | pmid = 17943118 | doi = 10.1038/nature06246 | bibcode = 2007Natur.449..819M | s2cid = 4392839 | doi-access = free }} or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens.{{cite journal | vauthors = Matzinger P | s2cid = 13615808 | title = The danger model: a renewed sense of self | journal = Science | volume = 296 | issue = 5566 | pages = 301–05 | date = Apr 2002 | pmid = 11951032 | doi = 10.1126/science.1071059 | bibcode = 2002Sci...296..301M | url = http://www.scs.carleton.ca/~soma/biosec/readings/matzinger-science.pdf }} Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= Chapter: [https://www.ncbi.nlm.nih.gov/books/NBK26846/ "Innate Immunity"] }} This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms, and the only one in plants.{{sfn | Iriti | 2019 | p=xi}}

Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens.{{cite journal | vauthors = Kumar H, Kawai T, Akira S | title = Pathogen recognition by the innate immune system | journal = International Reviews of Immunology | volume = 30 | issue = 1 | pages = 16–34 | date = February 2011 | pmid = 21235323 | doi = 10.3109/08830185.2010.529976 | s2cid = 42000671 }} They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells,{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc= Chapter: [https://www.ncbi.nlm.nih.gov/books/NBK26846/ "Innate Immunity"] }}{{cite journal | vauthors = Schroder K, Tschopp J | s2cid = 16916572 | title = The inflammasomes | journal = Cell | volume = 140 | issue = 6 | pages = 821–32 | date = March 2010 | pmid = 20303873 | doi = 10.1016/j.cell.2010.01.040 | doi-access = free }} to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death.{{sfn | Sompayrac | 2019 | p=20}}

Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs).{{cite journal | vauthors = Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K | s2cid = 20991617 | title = Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large | journal = Annual Review of Immunology | volume = 24 | pages = 353–89 | year = 2006 | pmid = 16551253 | doi = 10.1146/annurev.immunol.24.021605.090552 }} TLRs share a typical structural motif, the leucine rich repeats (LRRs), which give them a curved shape.{{cite journal | vauthors = Botos I, Segal DM, Davies DR | title = The structural biology of Toll-like receptors | journal = Structure | volume = 19 | issue = 4 | pages = 447–59 | date = April 2011 | pmid = 21481769 | pmc = 3075535 | doi = 10.1016/j.str.2011.02.004 }} Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Ten toll-like receptors have been described in humans.{{cite journal |vauthors=Vijay K |title=Toll-like receptors in immunity and inflammatory diseases: Past, present, and future |journal=Int Immunopharmacol |volume=59 |pages=391–412 |date=June 2018 |pmid=29730580 |pmc=7106078 |doi=10.1016/j.intimp.2018.03.002 }}

Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors.{{cite journal | vauthors = Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA | title = Pattern recognition receptors and the innate immune response to viral infection | journal = Viruses | volume = 3 | issue = 6 | pages = 920–40 | date = June 2011 | pmid = 21994762 | pmc = 3186011 | doi = 10.3390/v3060920 | doi-access = free }}

File:SEM blood cells.jpg image of normal circulating human blood. One can see red blood cells, several knobby white blood cells, including lymphocytes, a monocyte, and a neutrophil, and many small disc-shaped platelets.]]

Some leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the "professional" phagocytes (macrophages, neutrophils, and dendritic cells). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells.{{sfn| Sompayrac |2019 |pp= 1–4}}

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.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc=sec. [https://www.ncbi.nlm.nih.gov/books/NBK26846/#A4686 "Phagocytic Cells Seek, Engulf, and Destroy Pathogens"]}} 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.{{cite journal | vauthors = Ryter A | title = Relationship between ultrastructure and specific functions of macrophages | journal = Comparative Immunology, Microbiology and Infectious Diseases | volume = 8 | issue = 2 | pages = 119–33 | year = 1985 | pmid = 3910340 | doi = 10.1016/0147-9571(85)90039-6 }}{{cite journal | vauthors = Langermans JA, Hazenbos WL, van Furth R | title = Antimicrobial functions of mononuclear phagocytes | journal = Journal of Immunological Methods | volume = 174 | issue = 1–2 | pages = 185–94 | date = Sep 1994 | pmid = 8083520 | doi = 10.1016/0022-1759(94)90021-3 }} Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.{{cite journal | vauthors = May RC, Machesky LM | title = Phagocytosis and the actin cytoskeleton | journal = Journal of Cell Science | volume = 114 | issue = Pt 6 | pages = 1061–77 | date = Mar 2001 | doi = 10.1242/jcs.114.6.1061 | pmid = 11228151 | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11228151 | access-date = 6 November 2009 | archive-date = 31 March 2020 | archive-url = https://web.archive.org/web/20200331165444/https://jcs.biologists.org/content/114/6/1061.long | url-status = dead }} Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.{{cite journal | vauthors = Salzet M, Tasiemski A, Cooper E | s2cid = 28520695 | title = Innate immunity in lophotrochozoans: the annelids | journal = Current Pharmaceutical Design | volume = 12 | issue = 24 | pages = 3043–50 | year = 2006 | pmid = 16918433 | doi = 10.2174/138161206777947551 | url = https://pdfs.semanticscholar.org/da11/601b7ba0121f210136e0317729e3f367dd8c.pdf | archive-url = https://web.archive.org/web/20200331165454/https://pdfs.semanticscholar.org/da11/601b7ba0121f210136e0317729e3f367dd8c.pdf | url-status = dead | archive-date = 2020-03-31 }}

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.{{cite journal | vauthors = Zen K, Parkos CA | title = Leukocyte-epithelial interactions | journal = Current Opinion in Cell Biology | volume = 15 | issue = 5 | pages = 557–64 | date = Oct 2003 | pmid = 14519390 | doi = 10.1016/S0955-0674(03)00103-0 }} Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes.{{sfn|Stvrtinová | Jakubovský | Hulín |1995 |loc= Chapter: [https://web.archive.org/web/20010711220523/http://nic.savba.sk/logos/books/scientific/Inffever.html Inflammation and Fever]}} During the acute phase of inflammation, neutrophils migrate toward the site of inflammation in a process called chemotaxis and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, complement proteins, and cytokines. They can also act as scavengers that rid the body of worn-out cells and other debris and as antigen-presenting cells (APCs) that activate the adaptive immune system.{{cite journal | vauthors = Rua R, McGavern DB | title = Elucidation of monocyte/macrophage dynamics and function by intravital imaging | journal = Journal of Leukocyte Biology | volume = 98 | issue = 3 | pages = 319–32 | date = September 2015 | pmid = 26162402 | doi = 10.1189/jlb.4RI0115-006RR | pmc=4763596}}

Dendritic cells are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.{{cite journal | vauthors = Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S | title = Antigen presentation and T cell stimulation by dendritic cells | journal = Annual Review of Immunology | volume = 20 | issue = 1 | pages = 621–67 | year = 2002 | pmid = 11861614 | doi = 10.1146/annurev.immunol.20.100301.064828 }} They are named for their resemblance to neuronal dendrites, as both have many spine-like projections. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.

Granulocytes are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in connective tissues and mucous membranes and regulate the inflammatory response.{{sfn| Krishnaswamy | Ajitawi | Chi | 2006 | pp = 13–34}} They are most often associated with allergy and anaphylaxis.{{sfn|Stvrtinová | Jakubovský | Hulín |1995 |loc= Chapter: [https://web.archive.org/web/20010711220523/http://nic.savba.sk/logos/books/scientific/Inffever.html Inflammation and Fever]}} 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, such as asthma.{{cite journal | vauthors = Kariyawasam HH, Robinson DS | title = The eosinophil: the cell and its weapons, the cytokines, its locations | journal = Seminars in Respiratory and Critical Care Medicine | volume = 27 | issue = 2 | pages = 117–27 | date = Apr 2006 | pmid = 16612762 | doi = 10.1055/s-2006-939514 | s2cid = 260317790 }}

Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells are defined by the absence of antigen-specific B- or T-cell receptor (TCR) because of the lack of recombination activating gene. ILCs do not express myeloid or dendritic cell markers.{{cite journal | vauthors = Spits H, Cupedo T | title = Innate lymphoid cells: emerging insights in development, lineage relationships, and function | journal = Annual Review of Immunology | volume = 30 | pages = 647–75 | year = 2012 | pmid = 22224763 | doi = 10.1146/annurev-immunol-020711-075053 }}

Natural killer cells (NK cells) are lymphocytes and a component of the innate immune system that does not directly attack invading microbes.{{cite journal |vauthors=Gabrielli S, Ortolani C, Del Zotto G, Luchetti F, Canonico B, Buccella F, Artico M, Papa S, Zamai L |title=The Memories of NK Cells: Innate-Adaptive Immune Intrinsic Crosstalk |journal=Journal of Immunology Research |volume=2016 |pages=1376595 |year=2016 |pmid=28078307 |pmc=5204097 |doi=10.1155/2016/1376595 |doi-access=free }} 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.{{sfn|Bertok|Chow|2005|p= [https://books.google.com/books?id=DW3V2Uc-m8EC&q=%22missing+self%22+immunity+immune&pg=PA17 17]}} 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.{{sfn| Rajalingam |2012|loc= Chapter: Overview of the killer cell immunoglobulin-like receptor system}}

{{further|Inflammation}}

Inflammation is one of the first responses of the immune system to infection.{{cite journal | vauthors = Kawai T, Akira S | title = Innate immune recognition of viral infection | journal = Nature Immunology | volume = 7 | issue = 2 | pages = 131–37 | date = Feb 2006 | pmid = 16424890 | doi = 10.1038/ni1303 | s2cid = 9567407 | doi-access = free }} The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation and leukotrienes that attract certain white blood cells (leukocytes).{{cite journal | vauthors = Miller SB | title = Prostaglandins in health and disease: an overview | journal = Seminars in Arthritis and Rheumatism | volume = 36 | issue = 1 | pages = 37–49 | date = Aug 2006 | pmid = 16887467 | doi = 10.1016/j.semarthrit.2006.03.005 }}{{cite journal | vauthors = Ogawa Y, Calhoun WJ | title = The role of leukotrienes in airway inflammation | journal = The Journal of Allergy and Clinical Immunology | volume = 118 | issue = 4 | pages = 789–98; quiz 799–800 | date = Oct 2006 | pmid = 17030228 | doi = 10.1016/j.jaci.2006.08.009 | doi-access = free }} Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have antiviral effects, such as shutting down protein synthesis in the host cell.{{cite journal | vauthors = Le Y, Zhou Y, Iribarren P, Wang J | title = Chemokines and chemokine receptors: their manifold roles in homeostasis and disease | journal = Cellular & Molecular Immunology | volume = 1 | issue = 2 | pages = 95–104 | date = Apr 2004 | pmid = 16212895 | url = http://www.cmi.ustc.edu.cn/1/2/95.pdf }} Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote the healing of any damaged tissue following the removal of pathogens.{{cite journal | vauthors = Martin P, Leibovich SJ | title = Inflammatory cells during wound repair: the good, the bad and the ugly | journal = Trends in Cell Biology | volume = 15 | issue = 11 | pages = 599–607 | date = Nov 2005 | pmid = 16202600 | doi = 10.1016/j.tcb.2005.09.002 }} The pattern-recognition receptors called inflammasomes are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.{{cite journal | vauthors = Platnich JM, Muruve DA | title = NOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways | journal = Archives of Biochemistry and Biophysics | volume = 670 | pages = 4–14 | date = February 2019 | pmid = 30772258 | doi = 10.1016/j.abb.2019.02.008 | s2cid = 73464235 }}

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.{{cite journal | vauthors = Rus H, Cudrici C, Niculescu F | title = The role of the complement system in innate immunity | journal = Immunologic Research | volume = 33 | issue = 2 | pages = 103–12 | year = 2005 | pmid = 16234578 | doi = 10.1385/IR:33:2:103 | s2cid = 46096567 }}{{cite journal | vauthors = Degn SE, Thiel S | title = Humoral pattern recognition and the complement system | journal = Scandinavian Journal of Immunology | volume = 78 | issue = 2 | pages = 181–93 | date = August 2013 | pmid = 23672641 | doi = 10.1111/sji.12070 | doi-access = free }} Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.{{sfn|Bertok|Chow|2005|pp= [https://books.google.com/books?id=DW3V2Uc-m8EC&q=%22complement+system%22&pg=PA17 112–113]}} 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.{{cite book | vauthors = Liszewski MK, Farries TC, Lublin DM, Rooney IA, Atkinson JP | title = Control of the Complement System | volume = 61 | pages = 201–283 | year = 1996 | pmid = 8834497 | doi = 10.1016/S0065-2776(08)60868-8 | isbn = 978-0-12-022461-6 | series = Advances in Immunology | url-access = registration | url = https://archive.org/details/advancesinimmuno61dixo/page/201 }} 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, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.{{cite journal | vauthors = Sim RB, Tsiftsoglou SA | s2cid = 24505041 | title = Proteases of the complement system | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 1 | pages = 21–27 | date = Feb 2004 | pmid = 14748705 | doi = 10.1042/BST0320021 | url = http://pdfs.semanticscholar.org/9df4/e40fdcd4e1ba21a7047dca82ddf683c11d61.pdf | archive-url = https://web.archive.org/web/20190302045456/http://pdfs.semanticscholar.org/9df4/e40fdcd4e1ba21a7047dca82ddf683c11d61.pdf | url-status = dead | archive-date = 2019-03-02 }} 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 via the formation of a membrane attack complex.

{{further|Adaptive immune system}}

File:Primary immune response 1.png

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.{{cite journal | vauthors = Pancer Z, Cooper MD | title = The evolution of adaptive immunity | journal = Annual Review of Immunology | volume = 24 | issue = 1 | pages = 497–518 | year = 2006 | pmid = 16551257 | doi = 10.1146/annurev.immunol.24.021605.090542 }} 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.{{sfn | Sompayrac | 2019 | p=38}}

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.{{sfn| Janeway |2005 |p=}} B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.{{cite journal | vauthors = Holtmeier W, Kabelitz D | title = gammadelta T cells link innate and adaptive immune responses | volume = 86 | pages = 151–83 | year = 2005 | pmid = 15976493 | doi = 10.1159/000086659 | isbn = 3-8055-7862-8 | journal = Chemical Immunology and Allergy }} The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity.{{cite journal | vauthors = Venturi S, Venturi M | title = Iodine, thymus, and immunity | journal = Nutrition | volume = 25 | issue = 9 | pages = 977–79 | date = September 2009 | pmid = 19647627 | doi = 10.1016/j.nut.2009.06.002 }} In contrast, 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.{{sfn|Janeway|Travers|Walport|2001|loc= sec. [https://www.ncbi.nlm.nih.gov/books/NBK27112/#A1746 12-10]}} 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.{{sfn| Janeway |2005 |p=}} When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called clonal selection.{{sfn | Sompayrac | 2019 | pp= 5–6}}

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule.{{sfn | Sompayrac | 2019 | pp=51–53}}

{{Further|Cell-mediated immunity}}

There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are regulatory T cells which have a role in modulating immune response.{{sfn | Sompayrac | 2019 | pp=7–8}}

Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.{{cite journal | vauthors = Harty JT, Tvinnereim AR, White DW | title = CD8+ T cell effector mechanisms in resistance to infection | journal = Annual Review of Immunology | volume = 18 | issue = 1 | pages = 275–308 | year = 2000 | pmid = 10837060 | doi = 10.1146/annurev.immunol.18.1.275 }} As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T-cell receptor binds to this specific antigen in a complex with the MHC Class I receptor 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.{{cite journal | vauthors = Radoja S, Frey AB, Vukmanovic S | title = T-cell receptor signaling events triggering granule exocytosis | journal = Critical Reviews in Immunology | volume = 26 | issue = 3 | pages = 265–90 | year = 2006 | pmid = 16928189 | doi = 10.1615/CritRevImmunol.v26.i3.40 }} 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).

File:Activation of T and B cells.png

Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen.{{cite journal | vauthors = Abbas AK, Murphy KM, Sher A | title = Functional diversity of helper T lymphocytes | journal = Nature | volume = 383 | issue = 6603 | pages = 787–93 | date = Oct 1996 | pmid = 8893001 | doi = 10.1038/383787a0 | bibcode = 1996Natur.383..787A | s2cid = 4319699 }}{{cite book | vauthors = McHeyzer-Williams LJ, Malherbe LP, McHeyzer-Williams MG | title = From Innate Immunity to Immunological Memory | chapter = Helper T cell-regulated B cell immunity | volume = 311 | pages = 59–83 | year = 2006 | pmid = 17048705 | doi = 10.1007/3-540-32636-7_3 | isbn = 978-3-540-32635-9 | series = Current Topics in Microbiology and Immunology }} 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.{{sfn | Sompayrac | 2019 | p=8}}

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 killer T cells, meaning many receptors (around 200–300) 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.{{cite journal | vauthors = Kovacs B, Maus MV, Riley JL, Derimanov GS, Koretzky GA, June CH, Finkel TH | title = Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 23 | pages = 15006–11 | date = Nov 2002 | pmid = 12419850 | pmc = 137535 | doi = 10.1073/pnas.232058599 | bibcode = 2002PNAS...9915006K | doi-access = free }} 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.{{sfn|Alberts|Johnson|Lewis|Raff|2002|loc=Chapter. [https://www.ncbi.nlm.nih.gov/books/NBK26827/ "Helper T Cells and Lymphocyte Activation"]}} 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.{{cite journal | vauthors = Grewal IS, Flavell RA | title = CD40 and CD154 in cell-mediated immunity | journal = Annual Review of Immunology | volume = 16 | issue = 1 | pages = 111–35 | year = 1998 | pmid = 9597126 | doi = 10.1146/annurev.immunol.16.1.111 }}

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.{{cite journal | vauthors = Girardi M | title = Immunosurveillance and immunoregulation by gammadelta T cells | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 1 | pages = 25–31 | date = Jan 2006 | pmid = 16417214 | doi = 10.1038/sj.jid.5700003 | doi-access = free }} 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.

{{further|Humoral immunity}}

File:2220 Four Chain Structure of a Generic Antibody-IgG2 Structures.jpg (NIAID) |url=https://www.niaid.nih.gov/publications/immune/the_immune_system.pdf |access-date=1 January 2007 |url-status=dead |archive-url=https://web.archive.org/web/20070103005411/http://www.niaid.nih.gov/Publications/immune/the_immune_system.pdf |archive-date=3 January 2007 }}]]

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.{{cite journal | vauthors = Sproul TW, Cheng PC, Dykstra ML, Pierce SK | s2cid = 6550357 | title = A role for MHC class II antigen processing in B cell development | journal = International Reviews of Immunology | volume = 19 | issue = 2–3 | pages = 139–55 | year = 2000 | pmid = 10763706 | doi = 10.3109/08830180009088502 }} 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 lymphokines and activates the B cell.{{cite journal | vauthors = Parker DC | title = T cell-dependent B cell activation | journal = Annual Review of Immunology | volume = 11 | pages = 331–60 | date = 1993 | pmid = 8476565 | doi = 10.1146/annurev.iy.11.040193.001555 }} As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. 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.{{sfn| Murphy |Weaver |2016 |loc= Chapter 10: The Humoral Immune Response}}

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.{{cite journal | vauthors = Saji F, Samejima Y, Kamiura S, Koyama M | title = Dynamics of immunoglobulins at the feto-maternal interface | journal = Reviews of Reproduction | volume = 4 | issue = 2 | pages = 81–89 | date = May 1999 | pmid = 10357095 | doi = 10.1530/ror.0.0040081 | s2cid = 31099552 | url = http://pdfs.semanticscholar.org/ef69/261377c9d417b646679b850fc88a19128579.pdf | archive-url = https://web.archive.org/web/20210130212930/http://pdfs.semanticscholar.org/ef69/261377c9d417b646679b850fc88a19128579.pdf | url-status = dead | archive-date = 2021-01-30 }} Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.{{cite journal | vauthors = Van de Perre P | title = Transfer of antibody via mother's milk | journal = Vaccine | volume = 21 | issue = 24 | pages = 3374–76 | date = Jul 2003 | pmid = 12850343 | doi = 10.1016/S0264-410X(03)00336-0 }} This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another.{{cite journal | vauthors = Keller MA, Stiehm ER | title = Passive immunity in prevention and treatment of infectious diseases | journal = Clinical Microbiology Reviews | volume = 13 | issue = 4 | pages = 602–14 | date = Oct 2000 | pmid = 11023960 | pmc = 88952 | doi = 10.1128/CMR.13.4.602-614.2000 }}

{{further|Immunity (medical)}}

When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. T-cells recognize pathogens by small protein-based infection signals, called antigens, that bind directly to T-cell surface receptors.Sauls RS, McCausland C, Taylor BN. Histology, T-Cell Lymphocyte. In: StatPearls. StatPearls Publishing; 2023. Accessed November 15, 2023. http://www.ncbi.nlm.nih.gov/books/NBK535433/ B-cells use the protein, immunoglobulin, to recognize pathogens by their antigens. Althwaiqeb SA, Bordoni B. Histology, B Cell Lymphocyte. In: StatPearls. StatPearls Publishing; 2023. Accessed November 15, 2023. http://www.ncbi.nlm.nih.gov/books/NBK560905/ This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.{{sfn | Sompayrac | 2019 | p=98}}

File:Immune response2.svg

The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine{{cite journal | vauthors = Wick G, Hu Y, Schwarz S, Kroemer G | title = Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases | journal = Endocrine Reviews | volume = 14 | issue = 5 | pages = 539–63 | date = October 1993 | pmid = 8262005 | doi = 10.1210/edrv-14-5-539 }}{{cite journal | vauthors = Kroemer G, Brezinschek HP, Faessler R, Schauenstein K, Wick G | title = Physiology and pathology of an immunoendocrine feedback loop | journal = Immunology Today | volume = 9 | issue = 6 | pages = 163–5 | date = June 1988 | pmid = 3256322 | doi = 10.1016/0167-5699(88)91289-3 }} and the nervous{{cite journal | vauthors = Trakhtenberg EF, Goldberg JL | title = Immunology. Neuroimmune communication | journal = Science | volume = 334 | issue = 6052 | pages = 47–8 | date = October 2011 | pmid = 21980100 | doi = 10.1126/science.1213099 | bibcode = 2011Sci...334...47T | s2cid = 36504684 }}{{cite journal | vauthors = Veiga-Fernandes H, Mucida D | title = Neuro-Immune Interactions at Barrier Surfaces | journal = Cell | volume = 165 | issue = 4 | pages = 801–11 | date = May 2016 | pmid = 27153494 | pmc = 4871617 | doi = 10.1016/j.cell.2016.04.041 }}{{cite journal | title = Neuroimmune communication | journal = Nature Neuroscience | volume = 20 | issue = 2 | pages = 127 | date = February 2017 | pmid = 28092662 | doi = 10.1038/nn.4496 | doi-access = free }} systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.{{cite journal |vauthors=Wilcox SM, Arora H, Munro L, Xin J, Fenninger F, Johnson LA, Pfeifer CG, Choi KB, Hou J, Hoodless PA, Jefferies WA |title=The role of the innate immune response regulatory gene ABCF1 in mammalian embryogenesis and development |journal=PLOS ONE |volume=12 |issue=5 |pages=e0175918 |date=2017 |pmid=28542262 |pmc=5438103 |doi=10.1371/journal.pone.0175918 |bibcode=2017PLoSO..1275918W |doi-access=free }}

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive{{sfn| Wira |Crane-Godreau |Grant |2004 |loc= Chapter: Endocrine regulation of the mucosal immune system in the female reproductive tract}} and innate immune responses.{{cite journal | vauthors = Lang TJ | title = Estrogen as an immunomodulator | journal = Clinical Immunology | volume = 113 | issue = 3 | pages = 224–30 | date = Dec 2004 | pmid = 15507385 | doi = 10.1016/j.clim.2004.05.011 }}
{{cite journal | vauthors = Moriyama A, Shimoya K, Ogata I, Kimura T, Nakamura T, Wada H, Ohashi K, Azuma C, Saji F, Murata Y | title = Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle | journal = Molecular Human Reproduction | volume = 5 | issue = 7 | pages = 656–61 | date = Jul 1999 | pmid = 10381821 | doi = 10.1093/molehr/5.7.656 | doi-access = free }}
{{cite journal | vauthors = Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH | title = Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity | journal = Lupus | volume = 13 | issue = 9 | pages = 635–38 | year = 2004 | pmid = 15485092 | doi = 10.1191/0961203304lu1094oa | s2cid = 23941507 }}
{{cite journal | vauthors = King AE, Critchley HO, Kelly RW | title = Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role | journal = Molecular Human Reproduction | volume = 6 | issue = 2 | pages = 191–96 | date = Feb 2000 | pmid = 10655462 | doi = 10.1093/molehr/6.2.191 | doi-access = free }} Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive.{{cite journal | vauthors = Fimmel S, Zouboulis CC | title = Influence of physiological androgen levels on wound healing and immune status in men | journal = The Aging Male | volume = 8 | issue = 3–4 | pages = 166–74 | year = 2005 | pmid = 16390741 | doi = 10.1080/13685530500233847 | s2cid = 1021367 }} Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.{{cite journal | vauthors = Dorshkind K, Horseman ND | title = The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency | journal = Endocrine Reviews | volume = 21 | issue = 3 | pages = 292–312 | date = Jun 2000 | doi = 10.1210/edrv.21.3.0397 | pmid = 10857555 | doi-access = free }}{{cite journal | vauthors = Nagpal S, Na S, Rathnachalam R | title = Noncalcemic actions of vitamin D receptor ligands | journal = Endocrine Reviews | volume = 26 | issue = 5 | pages = 662–87 | date = Aug 2005 | pmid = 15798098 | doi = 10.1210/er.2004-0002 | doi-access = free }}

Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no clinical evidence to prove that vitamin D deficiency increases the risk for immune diseases or vitamin D supplementation lowers immune disease risk.{{cite web |title=Vitamin D - Fact Sheet for Health Professionals |url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |publisher=Office of Dietary Supplements, US National Institutes of Health |access-date=31 March 2022 |date=17 August 2021}} A 2011 United States Institute of Medicine report stated that "outcomes related to ... immune functioning and autoimmune disorders, and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting."{{cite book |author=Institute of Medicine |chapter=8, Implications and Special Concerns |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK56078/ |veditors=Ross AC, Taylor CL, Yaktine AL, Del Valle HB |title=Dietary Reference Intakes for Calcium and Vitamin D |publisher=National Academies Press |year=2011 |isbn=978-0-309-16394-1 |pmid=21796828 |doi=10.17226/13050 |url=https://www.ncbi.nlm.nih.gov/books/NBK56070/ |series=The National Academies Collection: Reports funded by the National Institutes of Health|s2cid=58721779 }}{{rp|5}}

The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function.{{cite journal | vauthors = Bryant PA, Trinder J, Curtis N | title = Sick and tired: Does sleep have a vital role in the immune system? | journal = Nature Reviews. Immunology | volume = 4 | issue = 6 | pages = 457–67 | date = Jun 2004 | pmid = 15173834 | doi = 10.1038/nri1369 | s2cid = 29318345 }} Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (NREM) sleep.{{cite journal | vauthors = Krueger JM, Majde JA | title = Humoral links between sleep and the immune system: research issues | journal = Annals of the New York Academy of Sciences | volume = 992 | issue = 1 | pages = 9–20 | date = May 2003 | pmid = 12794042 | doi = 10.1111/j.1749-6632.2003.tb03133.x | bibcode = 2003NYASA.992....9K | s2cid = 24508121 }} Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to rapid eye movement (REM) sleep.{{cite journal | vauthors = Majde JA, Krueger JM | title = Links between the innate immune system and sleep | journal = The Journal of Allergy and Clinical Immunology | volume = 116 | issue = 6 | pages = 1188–98 | date = Dec 2005 | pmid = 16337444 | doi = 10.1016/j.jaci.2005.08.005 | doi-access = free }}

In people with sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual.{{cite journal |vauthors=Taylor DJ, Kelly K, Kohut ML, Song KS |title=Is Insomnia a Risk Factor for Decreased Influenza Vaccine Response? |journal=Behavioral Sleep Medicine |volume=15 |issue=4 |pages=270–287 |date=2017 |pmid=27077395 |pmc=5554442 |doi=10.1080/15402002.2015.1126596}}{{Cite journal |last1=Rayatdoost |first1=Esmail |last2=Rahmanian |first2=Mohammad |last3=Sanie |first3=Mohammad Sadegh |last4=Rahmanian |first4=Jila |last5=Matin |first5=Sara |last6=Kalani |first6=Navid |last7=Kenarkoohi |first7=Azra |last8=Falahi |first8=Shahab |last9=Abdoli |first9=Amir |date=June 2022 |title=Sufficient Sleep, Time of Vaccination, and Vaccine Efficacy: A Systematic Review of the Current Evidence and a Proposal for COVID-19 Vaccination |journal=The Yale Journal of Biology and Medicine |volume=95 |issue=2 |pages=221–235 |issn=1551-4056 |pmc=9235253 |pmid=35782481}} Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.{{cite journal |vauthors=Krueger JM |title=The role of cytokines in sleep regulation |journal=Current Pharmaceutical Design |volume=14 |issue=32 |pages=3408–16 |date=2008 |pmid=19075717 |pmc=2692603 |doi=10.2174/138161208786549281}}

In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both innate and adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine causes increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cell activation, proliferation, and differentiation. During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the T_h1/T_h2 cytokine balance towards one that supports T_h1, an increase in overall T_h cell proliferation, and naïve T cell migration to lymph nodes. This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.{{cite journal | vauthors = Besedovsky L, Lange T, Born J | title = Sleep and immune function | journal = Pflügers Archiv | volume = 463 | issue = 1 | pages = 121–37 | date = Jan 2012 | pmid = 22071480 | doi = 10.1007/s00424-011-1044-0 | pmc=3256323}}

During wake periods, differentiated effector cells, such as cytotoxic natural killer cells and CD45RA+ cytotoxic T lymphocytes, peak in numbers. Anti-inflammatory molecules, such as cortisol and catecholamines, also peak during awake active times. Inflammation can cause oxidative stress and the presence of melatonin during sleep times could counteract free radical production during this time.{{cite web|url=http://www.webmd.com/sleep-disorders/excessive-sleepiness-10/immune-system-lack-of-sleep/ |title=Can Better Sleep Mean Catching fewer Colds? |access-date=28 April 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140509003219/http://www.webmd.com/sleep-disorders/excessive-sleepiness-10/immune-system-lack-of-sleep |archive-date=9 May 2014 }}

Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated.{{cite journal |vauthors=da Silveira MP, da Silva Fagundes KK, Bizuti MR, Starck É, Rossi RC, de Resende E, Silva DT |title=Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature |journal=Clinical and Experimental Medicine |volume=21 |issue=1 |pages=15–28 |date=February 2021 |pmid=32728975 |pmc=7387807 |doi=10.1007/s10238-020-00650-3}} Immediately after intense exercise there is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections,{{cite journal |vauthors=Peake JM, Neubauer O, Walsh NP, Simpson RJ |title=Recovery of the immune system after exercise |journal=Journal of Applied Physiology |volume=122 |issue=5 |pages=1077–1087 |date=May 2017 |pmid=27909225 |doi=10.1152/japplphysiol.00622.2016|s2cid=3521624 |url=https://researchonline.ljmu.ac.uk/id/eprint/16304/3/Recovery%20of%20the%20immune%20system%20after%20exercise.pdf }} but the evidence is inconclusive.{{cite journal |vauthors=Campbell JP, Turner JE |title=Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan |journal=Frontiers in Immunology |volume=9 |issue= |pages=648 |date=2018 |pmid=29713319 |pmc=5911985 |doi=10.3389/fimmu.2018.00648|doi-access=free }}{{cite journal |vauthors=Simpson RJ, Campbell JP, Gleeson M, Krüger K, Nieman DC, Pyne DB, Turner JE, Walsh NP |title=Can exercise affect immune function to increase susceptibility to infection? |journal=Exercise Immunology Review |volume=26 |issue= |pages=8–22 |date=2020 |pmid=32139352 |doi=}}

File:Neutrophils.jpg blood film]]

During exercise there is an increase in circulating white blood cells of all types. This is caused by the frictional force of blood flowing on the endothelial cell surface and catecholamines affecting β-adrenergic receptors (βARs). The number of neutrophils in the blood increases and remains raised for up to six hours and immature forms are present. Although the increase in neutrophils ("neutrophilia") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours.

The number of circulating lymphocytes (mainly natural killer cells) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of the cells die most migrate from the blood to the tissues, mainly the intestines and lungs, where pathogens are most likely to be encountered.

Some monocytes leave the blood circulation and migrate to the muscles where they differentiate and become macrophages. These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of stem cells and restorative macrophages, which are involved their maturing to muscle cells.{{cite journal |vauthors=Minari AL, Thomatieli-Santos RV |title=From skeletal muscle damage and regeneration to the hypertrophy induced by exercise: what is the role of different macrophage subsets? |journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume=322 |issue=1 |pages=R41–R54 |date=January 2022 |pmid=34786967 |doi=10.1152/ajpregu.00038.2021|s2cid=244369441 }}

{{main|Immune system contribution to regeneration}}

The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians such as in axolotl limb regeneration. According to one hypothesis, organisms that can regenerate (e.g., axolotls) could be less immunocompetent than organisms that cannot regenerate.{{cite journal | vauthors = Godwin JW, Pinto AR, Rosenthal NA | title = Chasing the recipe for a pro-regenerative immune system | journal = Seminars in Cell & Developmental Biology | volume = 61 | pages = 71–79 | date = January 2017 | pmid = 27521522 | pmc = 5338634 | doi = 10.1016/j.semcdb.2016.08.008 | series = Innate immune pathways in wound healing/Peromyscus as a model system }}

Failures of host defense occur and fall into three broad categories: immunodeficiencies,{{sfn | Sompayrac | 2019 | pp=120–24}} autoimmunity,{{sfn | Sompayrac | 2019 | pp=114–18}} and hypersensitivities.{{sfn | Sompayrac | 2019 | pp=111–14}}

{{further|Immunodeficiency}}

Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence.{{cite journal | vauthors = Aw D, Silva AB, Palmer DB | title = Immunosenescence: emerging challenges for an ageing population | journal = Immunology | volume = 120 | issue = 4 | pages = 435–46 | date = Apr 2007 | pmid = 17313487 | pmc = 2265901 | doi = 10.1111/j.1365-2567.2007.02555.x }}{{cite journal | vauthors = Chandra RK | title = Nutrition and the immune system: an introduction | journal = The American Journal of Clinical Nutrition | volume = 66 | issue = 2 | pages = 460S–63S | date = Aug 1997 | pmid = 9250133 | doi = 10.1093/ajcn/66.2.460S | doi-access = free }} In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function, while malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.{{cite journal | vauthors = Miller JF | title = The discovery of thymus function and of thymus-derived lymphocytes | journal = Immunological Reviews | volume = 185 | issue = 1 | pages = 7–14 | date = Jul 2002 | pmid = 12190917 | doi = 10.1034/j.1600-065X.2002.18502.x | s2cid = 12108587 }} Immunodeficiencies can also be inherited or 'acquired'.{{sfn | Reece | 2011 | p=967}} Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations.{{cite journal |vauthors=Burg M, Gennery AR |title=Educational paper: The expanding clinical and immunological spectrum of severe combined immunodeficiency |journal=Eur J Pediatr |volume= 170 |issue=5 |pages=561–571 |year=2011 |doi=10.1007/s00431-011-1452-3 |pmid=21479529 |pmc=3078321 }} Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.{{cite journal | vauthors = Joos L, Tamm M | title = Breakdown of pulmonary host defense in the immunocompromised host: cancer chemotherapy | journal = Proceedings of the American Thoracic Society | volume = 2 | issue = 5 | pages = 445–48 | year = 2005 | pmid = 16322598 | doi = 10.1513/pats.200508-097JS }}{{cite journal | vauthors = Copeland KF, Heeney JL | title = T helper cell activation and human retroviral pathogenesis | journal = Microbiological Reviews | volume = 60 | issue = 4 | pages = 722–42 | date = Dec 1996 | pmid = 8987361 | pmc = 239461 | doi = 10.1128/MMBR.60.4.722-742.1996 }}

{{further|Autoimmunity}}

File:Rheumatoid_Arthritis.JPG, an autoimmune disorder|alt=See caption]]

Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune diseases. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides.{{cite journal | vauthors = Miller JF | s2cid = 32476323 | title = Self-nonself discrimination and tolerance in T and B lymphocytes | journal = Immunologic Research | volume = 12 | issue = 2 | pages = 115–30 | year = 1993 | pmid = 8254222 | doi = 10.1007/BF02918299 }} 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. Common autoimmune diseases include Hashimoto's thyroiditis,{{citation-attribution|1={{cite web|title=Hashimoto's disease|url=https://www.womenshealth.gov/a-z-topics/hashimotos-disease|publisher=Office on Women's Health, U.S. Department of Health and Human Services|access-date=17 July 2017|date=12 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170728031758/https://www.womenshealth.gov/a-z-topics/hashimotos-disease|archive-date=28 July 2017}}}} rheumatoid arthritis,{{cite journal | vauthors = Smolen JS, Aletaha D, McInnes IB | s2cid = 37973054 | title = Rheumatoid arthritis | journal = Lancet | volume = 388 | issue = 10055 | pages = 2023–2038 | date = October 2016 | pmid = 27156434 | doi = 10.1016/S0140-6736(16)30173-8 | url = http://eprints.gla.ac.uk/131249/1/131249.pdf }} diabetes mellitus type 1,{{cite journal | vauthors = Farhy LS, McCall AL | title = Glucagon - the new 'insulin' in the pathophysiology of diabetes | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 18 | issue = 4 | pages = 407–14 | date = July 2015 | pmid = 26049639 | doi = 10.1097/mco.0000000000000192 | s2cid = 19872862 }} and systemic lupus erythematosus.{{cite web|title=Handout on Health: Systemic Lupus Erythematosus|url=http://www.niams.nih.gov/health_info/Lupus/default.asp|website=www.niams.nih.gov|access-date=12 June 2016|date=February 2015|url-status=live|archive-url=https://web.archive.org/web/20160617162703/http://www.niams.nih.gov/Health_Info/Lupus/default.asp|archive-date=17 June 2016}}

{{further|Hypersensitivity}}

Hypersensitivity is an immune response that damages the body's own tissues. It is divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen.{{cite web|url=http://www.microbiologybook.org/book/immunol-sta.htm|title=Immunology – Chapter Seventeen: Hypersensitivity States| vauthors = Ghaffar A |year=2006|publisher=University of South Carolina School of Medicine|work=Microbiology and Immunology On-line|access-date=29 May 2016}}

Type II hypersensitivity occurs when antibodies bind to antigens on the individual's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis. These reactions are mediated by T cells, monocytes, and macrophages.

{{further|Immune-mediated inflammatory diseases}}

Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause.

Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). 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 shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. 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.

File:Dexamethasone structure.svg dexamethasone]]

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.{{sfn | Sompayrac | 2019 | pp=83–85}}

Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent rejection after an organ transplant.{{sfn|Ciccone |2015 |loc = Chapter [https://books.google.com/books?id=Te1vCAAAQBAJ&q=%22immunosuppressive+drugs%22+autoimmune+tissue+damage&pg=PA625 37]}}{{cite journal | vauthors = Taylor AL, Watson CJ, Bradley JA | title = Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy | journal = Critical Reviews in Oncology/Hematology | volume = 56 | issue = 1 | pages = 23–46 | date = Oct 2005 | pmid = 16039869 | doi = 10.1016/j.critrevonc.2005.03.012 }}

Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs and can have many undesirable side effects, such as central obesity, hyperglycemia, and osteoporosis.{{cite journal | vauthors = Barnes PJ | title = Corticosteroids: the drugs to beat | journal = European Journal of Pharmacology | volume = 533 | issue = 1–3 | pages = 2–14 | date = Mar 2006 | pmid = 16436275 | doi = 10.1016/j.ejphar.2005.12.052 }} Their use is tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine.

Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. This killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.{{cite journal | vauthors = Masri MA | title = The mosaic of immunosuppressive drugs | journal = Molecular Immunology | volume = 39 | issue = 17–18 | pages = 1073–77 | date = Jul 2003 | pmid = 12835079 | doi = 10.1016/S0161-5890(03)00075-0 }}

{{Main|Immunostimulant|Immunotherapy|Vaccination}}

Claims made by marketers of various products and alternative health providers, such as chiropractors, homeopaths, and acupuncturists to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.{{cite magazine | vauthors = Hall H |author-link1 = Harriet Hall |date=July–August 2020 |title=How You Can Really Boost Your Immune System |url=https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |url-status= |magazine=Skeptical Inquirer |location=Amherst, New York |publisher=Center for Inquiry |archive-url=https://web.archive.org/web/20210121161902/https://skepticalinquirer.org/2020/06/how-you-can-really-boost-your-immune-system/ |archive-date=21 January 2021 |access-date=21 January 2021}}

{{Further|Vaccination}}

File:Polio Vaccination - Egypt (16868521330).jpg

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 (also called immunization) is to introduce an antigen from a pathogen to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism.{{sfn | Reece | 2011 | p=965}} 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.{{sfn| Janeway |2005 |p=}}[https://www.who.int/healthinfo/bod/en/index.html Death and DALY estimates for 2002 by cause for WHO Member States.] {{Webarchive|url=https://web.archive.org/web/20081021133659/http://www.who.int/healthinfo/bod/en/index.html |date=21 October 2008 }} World Health Organization. Retrieved on 1 January 2007.

Many vaccines are based on acellular components of micro-organisms, including harmless toxin components.{{sfn | Reece | 2011 | p=965}} 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 of the innate immune system and maximize immunogenicity.{{cite journal | vauthors = Singh M, O'Hagan D | title = Advances in vaccine adjuvants | journal = Nature Biotechnology | volume = 17 | issue = 11 | pages = 1075–81 | date = Nov 1999 | pmid = 10545912 | doi = 10.1038/15058 | s2cid = 21346647 | doi-access = free }}

{{Further|Cancer immunology}}

Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources;{{cite journal | vauthors = Andersen MH, Schrama D, Thor Straten P, Becker JC | title = Cytotoxic T cells | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 1 | pages = 32–41 | date = Jan 2006 | pmid = 16417215 | doi = 10.1038/sj.jid.5700001 | doi-access = free }} some are derived from oncogenic viruses like human papillomavirus, which causes cancer of the cervix,{{cite journal | vauthors = Boon T, van der Bruggen P | title = Human tumor antigens recognized by T lymphocytes | journal = The Journal of Experimental Medicine | volume = 183 | issue = 3 | pages = 725–29 | date = Mar 1996 | pmid = 8642276 | pmc = 2192342 | doi = 10.1084/jem.183.3.725 }} vulva, vagina, penis, anus, mouth, and throat,{{cite journal | vauthors = Ljubojevic S, Skerlev M | title = HPV-associated diseases | journal = Clinics in Dermatology | volume = 32 | issue = 2 | pages = 227–34 | year = 2014 | pmid = 24559558 | doi = 10.1016/j.clindermatol.2013.08.007 }} while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (for example, melanocytes) into tumors called melanomas.{{cite journal | vauthors = Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G | title = T-cell recognition of melanoma-associated antigens | journal = Journal of Cellular Physiology | volume = 182 | issue = 3 | pages = 323–31 | date = Mar 2000 | pmid = 10653598 | doi = 10.1002/(SICI)1097-4652(200003)182:3<323::AID-JCP2>3.0.CO;2-# | s2cid = 196590144 }}{{cite book | vauthors = Romero P, Cerottini JC, Speiser DE | title = The Human T Cell Response to Melanoma Antigens | volume = 92 | pages = 187–224 | year = 2006 | pmid = 17145305 | doi = 10.1016/S0065-2776(06)92005-7 | isbn = 978-0-12-373636-9 | series = Advances in Immunology }} A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.{{cite journal | vauthors = Guevara-Patiño JA, Turk MJ, Wolchok JD, Houghton AN | title = Immunity to cancer through immune recognition of altered self: studies with melanoma | volume = 90 | pages = 157–77 | year = 2003 | pmid = 14710950 | doi = 10.1016/S0065-230X(03)90005-4 | isbn = 978-0-12-006690-2 | journal = Advances in Cancer Research }}{{cite journal | vauthors = Renkvist N, Castelli C, Robbins PF, Parmiani G | title = A listing of human tumor antigens recognized by T cells | journal = Cancer Immunology, Immunotherapy | volume = 50 | issue = 1 | pages = 3–15 | date = Mar 2001 | pmid = 11315507 | doi = 10.1007/s002620000169 | s2cid = 42681479 | doi-access = free | pmc = 11036832 }}

File:Macs killing cancer cell.jpgs have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. Immunotherapy for the treatment of cancer is an active area of medical research.{{cite journal |vauthors=Morgan RA, Dudley ME, Wunderlich JR, etal |title=Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes |journal=Science |volume=314 |issue=5796 |pages=126–29 |date=October 2006 |pmid=16946036 |pmc=2267026 |doi=10.1126/science.1129003|bibcode = 2006Sci...314..126M }}]]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.{{cite journal | vauthors = Gerloni M, Zanetti M | s2cid = 25182066 | title = CD4 T cells in tumor immunity | journal = Springer Seminars in Immunopathology | volume = 27 | issue = 1 | pages = 37–48 | date = Jun 2005 | pmid = 15965712 | doi = 10.1007/s00281-004-0193-z | url = https://zenodo.org/record/1066157 }} Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.{{cite journal | vauthors = Seliger B, Ritz U, Ferrone S | title = Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation | journal = International Journal of Cancer | volume = 118 | issue = 1 | pages = 129–38 | date = Jan 2006 | pmid = 16003759 | doi = 10.1002/ijc.21312 | s2cid = 5655726 | doi-access = free }} NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.{{cite journal | vauthors = Hayakawa Y, Smyth MJ | title = Innate immune recognition and suppression of tumors | volume = 95 | pages = 293–322 | year = 2006 | pmid = 16860661 | doi = 10.1016/S0065-230X(06)95008-8 | isbn = 978-0-12-006695-7 | journal = Advances in Cancer Research }} Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.

Some tumors evade the immune system and go on to become cancers.{{cite journal | vauthors = Syn NL, Teng MW, Mok TS, Soo RA | title = De-novo and acquired resistance to immune checkpoint targeting | journal = The Lancet. Oncology | volume = 18 | issue = 12 | pages = e731–e741 | date = December 2017 | pmid = 29208439 | doi = 10.1016/s1470-2045(17)30607-1 }}{{cite journal | vauthors = Seliger B | title = Strategies of tumor immune evasion | journal = BioDrugs | volume = 19 | issue = 6 | pages = 347–54 | year = 2005 | pmid = 16392887 | doi = 10.2165/00063030-200519060-00002 | s2cid = 1838144 }} Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes.{{cite journal | vauthors = Frumento G, Piazza T, Di Carlo E, Ferrini S | title = Targeting tumor-related immunosuppression for cancer immunotherapy | journal = Endocrine, Metabolic & Immune Disorders Drug Targets | volume = 6 | issue = 3 | pages = 233–7 | date = September 2006 | pmid = 17017974 | doi = 10.2174/187153006778250019 }} In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.

Paradoxically, macrophages can promote tumor growth{{cite journal|vauthors=Stix G |title=A malignant flame. Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer |journal=Scientific American |volume=297 |issue=1 |pages=60–67 |date=Jul 2007 |pmid=17695843 |doi=10.1038/scientificamerican0707-60 |url=http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110716015048/http://podcast.sciam.com/daily/pdf/sa_d_podcast_070619.pdf |archive-date=16 July 2011 |bibcode=2007SciAm.297a..60S }} when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells. Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10.{{cite journal | vauthors = Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ | title = Tumor-induced Neurogenesis and Immune Evasion as Targets of Innovative Anti-Cancer Therapies | journal = Signal Transduct Target Ther | volume = 5 | issue = 1 | pages = 99 | date = 18 June 2020 | pmid = 32555170 | pmc = 7303203 | doi = 10.1038/s41392-020-0205-z }} Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumors.{{cite journal |vauthors=Yang Y |title=Cancer immunotherapy: harnessing the immune system to battle cancer |journal=The Journal of Clinical Investigation |volume=125 |issue=9 |pages=3335–7 |date=September 2015 |pmid=26325031 |pmc=4588312 |doi=10.1172/JCI83871 }}

Some drugs can cause a neutralizing immune response, meaning that the immune system produces neutralizing antibodies that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da).{{cite journal | vauthors = Baker MP, Reynolds HM, Lumicisi B, Bryson CJ | title = Immunogenicity of protein therapeutics: The key causes, consequences and challenges | journal = Self/Nonself | volume = 1 | issue = 4 | pages = 314–322 | date = October 2010 | pmid = 21487506 | pmc = 3062386 | doi = 10.4161/self.1.4.13904 }} In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;{{cite journal | vauthors = Welling GW, Weijer WJ, van der Zee R, Welling-Wester S | title = Prediction of sequential antigenic regions in proteins | journal = FEBS Letters | volume = 188 | issue = 2 | pages = 215–18 | date = Sep 1985 | pmid = 2411595 | doi = 10.1016/0014-5793(85)80374-4 | doi-access = free | bibcode = 1985FEBSL.188..215W }} however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.{{cite journal | vauthors = Söllner J, Mayer B | title = Machine learning approaches for prediction of linear B-cell epitopes on proteins | journal = Journal of Molecular Recognition | volume = 19 | issue = 3 | pages = 200–08 | year = 2006 | pmid = 16598694 | doi = 10.1002/jmr.771 | s2cid = 18197810 }} A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.{{cite journal | vauthors = Saha S, Bhasin M, Raghava GP | title = Bcipep: a database of B-cell epitopes | journal = BMC Genomics | volume = 6 | pages = 79 | year = 2005 | pmid = 15921533 | pmc = 1173103 | doi = 10.1186/1471-2164-6-79 | doi-access = free }} The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics.{{cite journal | vauthors = Flower DR, Doytchinova IA | title = Immunoinformatics and the prediction of immunogenicity | journal = Applied Bioinformatics | volume = 1 | issue = 4 | pages = 167–76 | year = 2002 | pmid = 15130835 }} Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.{{cite journal |vauthors=Kanduc D |title=From hepatitis C virus immunoproteomics to rheumatology via cross-reactivity in one table |journal=Current Opinion in Rheumatology |volume=31 |issue=5 |pages=488–492 |date=September 2019 |pmid=31356379 |doi=10.1097/BOR.0000000000000606|s2cid=198982175 }}

{{further|Innate immune system#Beyond vertebrates}}

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.{{cite journal |vauthors=Flajnik MF, Kasahara M |title=Origin and evolution of the adaptive immune system: genetic events and selective pressures |journal=Nature Reviews. Genetics |volume=11 |issue=1 |pages=47–59 |date=January 2010 |pmid=19997068 |pmc=3805090 |doi=10.1038/nrg2703 }} Immune systems evolved in deuterostomes as shown in the cladogram.

{{clade|style=font-size:95%;line-height:110%;

|label1=Deuterostomes

|sublabel1=innate immunity

|1={{clade

|1=Echinoderms, hemichordates, cephalochordates, urochordates

|label2=Vertebrates

|2={{clade

|sublabel1=VLR adaptive immunity

|1=Jawless fishes

|sublabel2=V(D)J adaptive immunity

|2=Jawed fishes and tetrapods

}}

}}

}}

Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally simplest forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages.{{cite journal | vauthors = Bickle TA, Krüger DH | title = Biology of DNA restriction | journal = Microbiological Reviews | volume = 57 | issue = 2 | pages = 434–50 | date = Jun 1993 | pmid = 8336674 | pmc = 372918 | doi = 10.1128/MMBR.57.2.434-450.1993 }} Prokaryotes (bacteria and archea) also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference.{{cite journal | vauthors = Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P | title = CRISPR provides acquired resistance against viruses in prokaryotes | journal = Science | volume = 315 | issue = 5819 | pages = 1709–12 | date = Mar 2007 | pmid = 17379808 | doi = 10.1126/science.1138140 | bibcode = 2007Sci...315.1709B | hdl = 20.500.11794/38902 | s2cid = 3888761 | hdl-access = free }}{{cite journal | vauthors = Brouns SJ, Jore MM, Lundgren M, Westra ER, Slijkhuis RJ, Snijders AP, Dickman MJ, Makarova KS, Koonin EV, van der Oost J | title = Small CRISPR RNAs guide antiviral defense in prokaryotes | journal = Science | volume = 321 | issue = 5891 | pages = 960–64 | date = Aug 2008 | pmid = 18703739 | pmc = 5898235 | doi = 10.1126/science.1159689 | bibcode = 2008Sci...321..960B }} Prokaryotes also possess other defense mechanisms.{{cite journal | vauthors = Hille F, Charpentier E | title = CRISPR-Cas: biology, mechanisms and relevance | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 371 | issue = 1707 | pages = 20150496 | date = November 2016 | pmid = 27672148 | pmc = 5052741 | doi = 10.1098/rstb.2015.0496 }}{{cite journal | vauthors = Koonin EV | title = Evolution of RNA- and DNA-guided antivirus defense systems in prokaryotes and eukaryotes: common ancestry vs convergence | journal = Biology Direct | volume = 12 | issue = 1 | pages = 5 | date = February 2017 | pmid = 28187792 | pmc = 5303251 | doi = 10.1186/s13062-017-0177-2 | doi-access = free }} Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.{{cite journal | vauthors = Bayne CJ | year = 2003 | title = Origins and evolutionary relationships between the innate and adaptive arms of immune systems | journal = Integr. Comp. Biol. | volume = 43 | issue = 2| pages = 293–99 | pmid = 21680436 | doi=10.1093/icb/43.2.293| doi-access = free }}

Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.{{cite journal | vauthors = Stram Y, Kuzntzova L | title = Inhibition of viruses by RNA interference | journal = Virus Genes | volume = 32 | issue = 3 | pages = 299–306 | date = Jun 2006 | pmid = 16732482 | doi = 10.1007/s11262-005-6914-0 | pmc = 7088519 }}

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant.{{cite web | vauthors = Schneider D |title=Innate Immunity – Lecture 4: Plant immune responses| publisher = Stanford University Department of Microbiology and Immunology |url=https://web.stanford.edu/class/mi104/Plant%20immunity.pdf | access-date = 1 January 2007}} Individual plant cells respond to molecules associated with pathogens known as pathogen-associated molecular patterns or PAMPs.{{cite journal | vauthors = Jones JD, Dangl JL | title = The plant immune system | journal = Nature | volume = 444 | issue = 7117 | pages = 323–29 | date = Nov 2006 | pmid = 17108957 | doi = 10.1038/nature05286 | bibcode = 2006Natur.444..323J | doi-access = free }} When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.{{cite journal | vauthors = Baulcombe D | title = RNA silencing in plants | journal = Nature | volume = 431 | issue = 7006 | pages = 356–63 | date = Sep 2004 | pmid = 15372043 | doi = 10.1038/nature02874 | bibcode = 2004Natur.431..356B | s2cid = 4421274 }}

Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (for example, immunoglobulins and T-cell receptors) exist only in jawed vertebrates. A distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.{{cite journal | vauthors = Alder MN, Rogozin IB, Iyer LM, Glazko GV, Cooper MD, Pancer Z | title = Diversity and function of adaptive immune receptors in a jawless vertebrate | journal = Science | volume = 310 | issue = 5756 | pages = 1970–73 | date = Dec 2005 | pmid = 16373579 | doi = 10.1126/science.1119420 | bibcode = 2005Sci...310.1970A | doi-access = free }}

The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.{{cite journal | vauthors = Finlay BB, McFadden G | s2cid = 15418509 | title = Anti-immunology: evasion of the host immune system by bacterial and viral pathogens | journal = Cell | volume = 124 | issue = 4 | pages = 767–82 | date = Feb 2006 | pmid = 16497587 | doi = 10.1016/j.cell.2006.01.034 | doi-access = free }} Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system.{{cite journal | vauthors = Cianciotto NP | title = Type II secretion: a protein secretion system for all seasons | journal = Trends in Microbiology | volume = 13 | issue = 12 | pages = 581–88 | date = Dec 2005 | pmid = 16216510 | doi = 10.1016/j.tim.2005.09.005 }} Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.{{cite journal | vauthors = Winstanley C, Hart CA | title = Type III secretion systems and pathogenicity islands | journal = Journal of Medical Microbiology | volume = 50 | issue = 2 | pages = 116–26 | date = Feb 2001 | pmid = 11211218 | doi = 10.1099/0022-1317-50-2-116 }}

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium spp.) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement.{{cite journal | vauthors = Finlay BB, Falkow S | title = Common themes in microbial pathogenicity revisited | journal = Microbiology and Molecular Biology Reviews | volume = 61 | issue = 2 | pages = 136–69 | date = Jun 1997 | doi = 10.1128/mmbr.61.2.136-169.1997 | pmid = 9184008 | pmc = 232605 }} Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, such as the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.{{cite journal | vauthors = Kobayashi H | s2cid = 31788349 | title = Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections | journal = Treatments in Respiratory Medicine | volume = 4 | issue = 4 | pages = 241–53 | year = 2005 | pmid = 16086598 | doi = 10.2165/00151829-200504040-00003 }} Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).{{cite journal | vauthors = Housden NG, Harrison S, Roberts SE, Beckingham JA, Graille M, Stura E, Gore MG | title = Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 3 | pages = 716–18 | date = Jun 2003 | pmid = 12773190 | doi = 10.1042/BST0310716 | s2cid = 10322322| url = http://pdfs.semanticscholar.org/a2a4/223fb0694e0137c5c82d002e7e9e07b7143b.pdf | archive-url = https://web.archive.org/web/20190302214414/http://pdfs.semanticscholar.org/a2a4/223fb0694e0137c5c82d002e7e9e07b7143b.pdf | url-status = dead | archive-date = 2019-03-02 }}

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus.{{cite journal | vauthors = Burton DR, Stanfield RL, Wilson IA | title = Antibody vs. HIV in a clash of evolutionary titans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 42 | pages = 14943–48 | date = Oct 2005 | pmid = 16219699 | pmc = 1257708 | doi = 10.1073/pnas.0505126102 | bibcode = 2005PNAS..10214943B | doi-access = free }} The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.{{cite journal | vauthors = Taylor JE, Rudenko G | title = Switching trypanosome coats: what's in the wardrobe? | journal = Trends in Genetics | volume = 22 | issue = 11 | pages = 614–20 | date = Nov 2006 | pmid = 16908087 | doi = 10.1016/j.tig.2006.08.003 }} Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.{{cite journal | vauthors = Cantin R, Méthot S, Tremblay MJ | title = Plunder and stowaways: incorporation of cellular proteins by enveloped viruses | journal = Journal of Virology | volume = 79 | issue = 11 | pages = 6577–87 | date = Jun 2005 | pmid = 15890896 | pmc = 1112128 | doi = 10.1128/JVI.79.11.6577-6587.2005 }}

{{further|History of immunology}}

File:Paul Ehrlich 1915.jpg (1854–1915) was awarded a Nobel Prize in 1908 for his contributions to immunology.]]

Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time.{{cite journal | vauthors = Retief FP, Cilliers L | title = The epidemic of Athens, 430–426 BC | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 88 | issue = 1 | pages = 50–53 | date = Jan 1998 | pmid = 9539938 }} In the 18th century, Pierre-Louis Moreau de Maupertuis experimented with scorpion venom and observed that certain dogs and mice were immune to this venom.{{cite journal | vauthors = Ostoya P |title=Maupertuis et la biologie |journal=Revue d'histoire des sciences et de leurs applications |year=1954 |volume=7 |issue=1 |pages=60–78 |doi=10.3406/rhs.1954.3379}} In the 10th century, Persian physician al-Razi (also known as Rhazes) wrote the first recorded theory of acquired immunity,{{cite journal | vauthors = Doherty M, Robertson MJ | title = Some early Trends in Immunology | journal = Trends in Immunology | volume = 25 | issue = 12 | pages = 623–31 | date = December 2004 | pmid = 15530829| doi = 10.1016/j.it.2004.10.008 }}{{sfn |Silverstein |1989 |p=6}} noting that a smallpox bout protected its survivors from future infections. Although he explained the immunity in terms of "excess moisture" being expelled from the blood—therefore preventing a second occurrence of the disease—this theory explained many observations about smallpox known during this time.{{sfn |Silverstein |1989 |p=7}}

These and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease.{{cite journal | vauthors = Plotkin SA | title = Vaccines: past, present and future | journal = Nature Medicine | volume = 11 | issue = 4 Suppl | pages = S5–11 | date = Apr 2005 | pmid = 15812490 | doi = 10.1038/nm1209 | pmc = 7095920 }} Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease.[http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ The Nobel Prize in Physiology or Medicine 1905] {{Webarchive|url=https://web.archive.org/web/20061210184150/http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ |date=10 December 2006 }} Nobelprize.org Retrieved on 8 January 2009. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.[https://web.archive.org/web/20071023070838/http://www.wramc.amedd.army.mil/welcome/history/ Major Walter Reed, Medical Corps, U.S. Army] Walter Reed Army Medical Center. Retrieved on 8 January 2007.

Immunology made a great advance towards the end of the 19th century, through rapid developments in the study of humoral immunity and cellular immunity.{{cite book| vauthors = Metchnikoff E | author-link = Elie Metchnikoff | translator-last = Binnie FG | title =Immunity in Infective Diseases| publisher =Cambridge University Press| year =1905 |url=https://archive.org/details/immunityininfec01metcgoog | quote =history of humoral immunity. | format =Full Text Version: Internet Archive| lccn = 68025143}} Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a joint Nobel Prize in 1908, along with the founder of cellular immunology, Elie Metchnikoff.{{cite web|url= http://nobelprize.org/nobel_prizes/medicine/laureates/1908/ |title= The Nobel Prize in Physiology or Medicine 1908 |publisher= The Nobel Prize |access-date=8 January 2007}} In 1974, Niels Kaj Jerne developed the immune network theory; he shared a Nobel Prize in 1984 with Georges J. F. Köhler and César Milstein for theories related to the immune system.{{cite web |url= https://www.nobelprize.org/prizes/medicine/1984/jerne/facts/ | title= Niels K. Jerne |access-date= 27 November 2020 |publisher= The Nobel Prize}}{{cite journal|title=He put the Id in Idiotype|journal=EMBO Reports|date=4 October 2003|vauthors= Yewdell J |volume=4|issue=10|page=931|pmc=1326409|doi=10.1038/sj.embor.embor951|type= Book review}}

• Fc receptor
• List of human cell types
• Neuroimmune system
• Original antigenic sin – when the immune system uses immunological memory upon encountering a slightly different pathogen
• Plant disease resistance
• Polyclonal response

{{Reflist|33em}}

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• {{cite book | vauthors= Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walters P |title=Molecular Biology of the Cell | edition = Fourth | publisher = Garland Science| year = 2002 | location = New York and London |url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 | isbn = 978-0-8153-3218-3 }}
• {{cite book |veditors= Bertok L, Chow D |title= Natural Immunity |volume= 5 |edition= 1st |year= 2005 |isbn= 978-0-44451-755-5| vauthors = Bertok L, Chow D |publisher= Elsevier Science }}
• {{cite book | vauthors = Iriti M | title=Plant Innate Immunity 2.0 | publisher=MDPI |location=Basel| year=2019 | isbn=978-3-03897-580-9 | oclc=1105775088 |doi=10.3390/books978-3-03897-581-6 |doi-access=free}}
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• {{cite book | vauthors = Janeway CA |title=Immunobiology | edition = 6th | publisher = Garland Science |year=2005 | isbn = 0-443-07310-4 |author-link=Charles Janeway }}
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• {{cite book | vauthors=Sompayrac L | title=How the immune system works | publisher=Wiley-Blackwell | location=Hoboken, NJ | year=2019 | isbn=978-1-119-54212-4 | oclc=1083261548}}
• {{cite book|vauthors= Stvrtinová V, Jakubovský J, Hulín I |title= Pathophysiology: Principles of Disease |publisher=Academic Electronic Press |year=1995 |location=Computing Centre, Slovak Academy of Sciences }}
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{{refend}}

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• {{Cite book | vauthors = Dettmer P |year=2021 |title=Immune: A Journey into the Mysterious System that Keeps You Alive |url=https://books.google.com/books?id=ry9GEAAAQBAJ |others=Philip Laibacher (illustrations) |location=New York |publisher=Random House |isbn=9780593241318 |oclc=1263845194 |access-date=4 January 2022 |archive-date=24 November 2021 |archive-url=https://web.archive.org/web/20211124111657/https://kurzgesagt.org/immune-book-sources/ |url-status=live }} (The book's [https://kurzgesagt.org/immune-book-sources/ sources] are only online.) A popular science explanation of the immune system.

{{Commons category|Immune system}}

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