587:), resulting in graft reaction. However, there are two general cases in which an allograft may be accepted. One is when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance (like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in the brain). The second is when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection. Long-term exposure to a foreign antigen from fetal development or birth may result in establishment of central tolerance, as was observed in Medawar's mouse-allograft experiments. In usual transplant cases, however, such early prior exposure is not possible. Nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance. CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that dampen cytotoxic responses to grafted organs, are thought to play a role. In addition, genes involved in
667:. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers(epithelium barriers). Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both
436:, in immune tolerance was recognized in 1995 when animal models showed that CD4+ CD25+ T cells were necessary and sufficient for the prevention of autoimmunity in mice and rats. Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells. A more specific depletion and reconstitution experiment established the phenotype of these cells as CD4+ and CD25+. Later in 2003, experiments showed that Treg cells were characterized by the expression of the
977:
219:
instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system. Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution, tolerance does not refer to the change in the pathogen but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced
1119:
strains of mice fall neatly along a spectrum of being more tolerant but less resistant or more resistant but less tolerant. Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against
618:(MHC) proteins. However, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. Placental
968:
general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader. Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a
861:
hypersensitivity reactions have been mixed. The systemic effects of oral tolerance may be explained by the extensive recirculation of immune cells primed in one mucosal tissue in another mucosal tissue, allowing extension of mucosal immunity. The same probably occurs for cells mediating mucosal immune tolerance.
1114:
Evolution works to optimize host fitness, so whether elimination or tolerance occurs depends on which would benefit the organism most in a given scenario. If the antigen is from a rare, dangerous invader, the costs of tolerating its presence are high and it is more beneficial to the host to eliminate
984:
The advantages of immune tolerance, in particular, may be seen in experiments with mice infected with malaria, in which more tolerant mice have higher fitness at greater pathogen burdens. In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust
708:
is vulnerable to pathogenic penetration. The immune system must maintain its responsiveness to pathogenic antigens to prevent infections. The immune system has developed mechanisms in which orally ingested antigens can suppress following immune responses on a local and systemic level. Oral tolerance
745:
Dendritic cells play a crucial role in establishing oral tolerance for food antigens. The dendritic cells in the intestines cannot directly sample the antigens, as they are located behind the epithelial wall. There are different mechanisms in which the dendritic cells come in contact with the food
988:
Though it seems that the existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor, it comes with important evolutionary disadvantages. Some infectious microbes take advantage of existing mechanisms of tolerance to avoid
860:
reactions in certain cases. Records from 1829 indicate that
American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other
214:
In their Nobel
Lecture, Medawar and Burnet define immune tolerance as "a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response." Other more recent definitions have remained more or less the same. The 8th edition of Janeway's
443:
It was assumed that, since the presence of the Treg cells originally characterized was dependent on the neonatal thymus, these cells were thymically derived. By the mid-2000s, however, evidence was accruing of conversion of naïve CD4+ T cells to Treg cells outside of the thymus. These were later
289:
The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of
178:
twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Although Owen did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues.
967:
Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in
819:
and α4β7 expression. The mesenteric lymph node stromal cells also release retinoic acid and are required for gut localisation of the mesenteric lymph node T cell population. The differentiated regulatory T cells subsequently migrate to the lamina propria, where they multiply. CX3CR1+ macrophages
293:
This process of negative selection ensures that T and B cells that could initiate a potent immune response to the host's own tissues are eliminated while preserving the ability to recognize foreign antigens. It is the step in lymphocyte education that is key for preventing autoimmunity (entire
227:
Immune tolerance is formally differentiated into central or peripheral; however, alternative terms such as "natural" or "acquired" tolerance have at times been used to refer to establishment of tolerance by physiological means or by artificial, experimental, or pharmacological means. These two
1118:
Despite having mechanisms for both immune resistance and tolerance, any one organism may be overall more skewed toward a tolerant or resistant phenotype depending on individual variation in both traits due to genetic and environmental factors. In mice infected with malaria, different genetic
218:
Immune tolerance encompasses the range of physiological mechanisms by which the body reduces or eliminates an immune response to particular agents. It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection
309:
develops after T and B cells mature and enter the peripheral tissues and lymph nodes. It is established by a number of partly overlapping mechanisms that mostly involve control at the level of T cells, especially CD4+ helper T cells, which orchestrate immune responses and give B cells the
613:
The fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. Women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and
1015:. The injection of Treg cells specific for a tumor antigen also can reverse experimentally-mediated tumor rejection based on that same antigen. The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.
189:"We did not set out with the idea in mind of studying the immunological consequences of the phenomenon described by Owen; on the contrary, we had been goaded by Dr. H.P. Donald into trying to devise a foolproof method of distinguishing monozygotic from dizygotic twins... ."
310:
confirmatory signals they need in order to produce antibodies. Inappropriate reactivity toward normal self-antigen that was not eliminated in the thymus can occur, since the T cells that leave the thymus are relatively but not completely safe. Some will have receptors (
278:, a state of non-activity. Weakly autoreactive B cells may also remain in a state of immunological ignorance where they simply do not respond to stimulation of their B cell receptor. Some weakly self-recognizing T cells are alternatively differentiated into natural
798:
After antigen interaction the CD103+ dendritic cells travel to the mesenteric lymph nodes where they interact with their T cell population. Within the mesenteric lymph nodes the CD103+ dendritic cells will induce differentiation of the naïve T cell population into
183:
in 1953, who showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as
Medawar explains:
267:. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor
223:
by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non-reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed.
899:. Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic
827:
In the lamina propria the regulatory T cell population creates a tolerogenic environment to food antigens. It is known that tolerance to food antigens is systemic. The mechanism that establishes this systemic tolerance is not yet fully understood.
972:
of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data. Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described.
1023:
Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead.
1027:
Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite. Each strategy has its unique costs and benefits for host fitness:
341:
Appropriate reactivity toward certain antigens can also be quieted by induction of tolerance after repeated exposure, or exposure in a certain context. In these cases, there is a differentiation of naïve CD4+ helper T cells into induced
704:. The intestine harbours many non-self-antigens that are able to induce an immune reaction. The immune system in the gut needs to restrain from responding to these antigens to prevent constant inflammation. On the other hand, the thin
919:, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as
444:
defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells. Both types of Treg cells quieten autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms including:
650:
to reactive T cells These mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. A break in this peripheral tolerance results in miscarriage and fetal loss. (for more information, see
675:
efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining. Break in this tolerance is thought to underlie the pathogenesis of
2456:
Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. (May 2007). "T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells".
298:). Lymphocyte development and education is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.
1115:
it. Conversely, if experience (of the organism or its ancestors) has shown that the antigen is innocuous, then it would be more beneficial to tolerate the presence of the antigen rather than pay the costs of inflammation.
113:
333:
Those self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively muzzled in the peripheral tissue chiefly by nTreg cells (see
228:
methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind.
959:(MDSCs), which also induce peripheral tolerance. In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.
927:, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including
2103:
Maher S, Toomey D, Condron C, Bouchier-Hayes D (April 2002). "Activation-induced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack".
871:
in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually,
239:
refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the
194:
However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by
569:
nTreg cells are specific, modestly, for self-antigen while iTreg cells recognize allergens, commensal bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.
372:
are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells, including
786:
extend in between enterocytes and directly take up antigens form the intestinal lumen. These macrophages are not capable of traveling to the mesenteric lymph nodes. They form
290:
pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.
3492:
3336:
Kretschmer K, Apostolou I, Jaeckel E, Khazaie K, von
Boehmer H (August 2006). "Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer".
3293:
Ghiringhelli F, Ménard C, Martin F, Zitvogel L (December 2006). "The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression".
1011:, and other worms and parasites. Another important disadvantage of the existence of tolerance may be susceptibility to cancer progression. Treg cells inhibit anti-tumor
807:
instead. The local microenvironment determines if CD103+ dendritic cells act tolerogenic or immunogenic. The differentiation into regulatory T cells is dependent on
848:
from the liver and mesenteric lymph node can induce anergy or deletion of antigen specific T cells. Anergic T cells are hyporesponsive to their specific antigen.
274:
Those lymphocytes that have receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of
206:. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.
158:
that manage to evade immune elimination. Additionally, the induction of peripheral tolerance within the local microenvironment is a strategy employed by many
53:
and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either
634:, which represses maternal T cell responses by amino acid starvation. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic
980:
Schematic of the reaction norm of tolerance (after). Organisms of genotype 2 are considered more tolerant to the pathogen than organisms of genotype 1.
1423:"Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases"
737:. The newly differentiated regulatory T cells travel to the lamina propria, where they suppress the immune reaction against the recognized antigens.
583:
Immune recognition of non-self-antigens typically complicates transplantation and engrafting of foreign tissue from an organism of the same species (
951:. Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer. Tumor-derived vesicles known as
500:
109:
3485:
73:. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.
536:
nTreg cells and iTreg cells, however, have a few important distinguishing characteristics that suggest they have different physiological roles:
2885:
1936:
1652:
1251:
373:
3379:
Råberg L, Sim D, Read AF (November 2007). "Disentangling genetic variation for resistance and tolerance to infectious diseases in animals".
663:
The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the
2682:"All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation"
421:
840:
or deletion of antigen specific T cells. This process can take place in the liver. The liver is exposed to many food antigens through the
555:
nTreg cells develop from Foxp3- CD25+ CD4+ cells while iTreg cells develop from Foxp3+ CD25- CD4- cells (both become Foxp3+ CD25+CD4+).
3478:
923:, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing
80:. Central tolerance is crucial for enabling the immune system to differentiate between self and non-self antigens, thereby preventing
256:
388:
cells, as well as other less well-characterized cells that help establish a local tolerogenic environment. B cells also express
3824:
615:
2592:"Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1⁺ macrophages to CD103⁺ dendritic cells"
956:
808:
780:
726:
668:
518:
397:
381:
355:
1668:
Fenner F (June 1983). "The Florey lecture, 1983. Biological control, as exemplified by smallpox eradication and myxomatosis".
3819:
701:
549:
466:
84:. Peripheral tolerance plays a significant role in preventing excessive immune reactions to environmental agents, including
696:
Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut
3762:
652:
608:
1160:
97:
3128:"The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells"
2000:
Vadasz Z, Haj T, Kessel A, Toubi E (June 2013). "B-regulatory cells in autoimmunity and immune mediated inflammation".
1194:
392:, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes
3451:
928:
845:
631:
401:
282:(nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see
1957:
Sakaguchi S, Miyara M, Costantino CM, Hafler DA (July 2010). "FOXP3+ regulatory T cells in the human immune system".
1372:"Expression of the autoimmune regulator gene and its relevance to the mechanisms of central and peripheral tolerance"
412:
in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs. In addition,
3648:
1128:
677:
125:
891:, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in
408:
needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce
3464:
985:
commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.
492:
1871:
Hogquist KA, Baldwin TA, Jameson SC (October 2005). "Central tolerance: learning self-control in the thymus".
3083:
Ramsay AG (August 2013). "Immune checkpoint blockade immunotherapy to activate anti-tumour T-cell immunity".
2187:
Braza F, Soulillou JP, Brouard S (September 2012). "Gene expression signature in transplantation tolerance".
202:, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed
3828:
3586:
940:
623:
363:
260:
195:
154:
However, immune tolerance is not without its drawbacks. It can permit the successful infection of a host by
2780:"Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria"
3850:
3568:
3504:
2819:
Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, et al. (September 2008).
1001:
924:
540:
nTreg cells develop in the thymus; iTreg cells develop outside the thymus in chronically inflamed tissue,
1721:"Studies on the mechanism of the immunological paralysis induced in mice by pneumococcal polysaccharides"
3797:
3653:
3631:
1140:
705:
116:(IPEX) as examples. Furthermore, disruptions in immune tolerance are implicated in the development of
3814:
3747:
3658:
3582:
3388:
3193:
2009:
1677:
1150:
647:
326:
322:
306:
268:
101:
66:
3470:
2731:"Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo"
3921:
3874:
3809:
3792:
3626:
3544:
2877:
2778:
Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, et al. (February 2011).
1928:
1644:
1243:
1012:
995:
627:
588:
584:
155:
93:
773:. Goblet cell-associated antigen passages (GAP) transfer low molecular weight soluble antigens to
595:
function associated with tolerance have been implicated for liver transplant patients. The unique
3694:
3422:
3361:
3318:
3108:
3016:
2932:
2250:
2128:
2033:
1982:
1896:
1804:
1750:
1701:
1617:
685:
321:
the T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the
318:
are present in such high concentration outside the thymus that they can bind to "weak" receptors.
255:, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by
2271:
Clark DA, Chaouat G (December 2012). "Regulatory T cells and reproduction: how do they do it?".
681:
1775:"Mechanisms of natural tolerance in the intestine: implications for inflammatory bowel disease"
976:
803:
regulatory T cells (iTregs). Under inflammatory conditions, CD103+ dendritic cells will induce
3742:
3508:
3414:
3353:
3310:
3275:
3219:
3157:
3100:
3065:
3008:
2973:
2924:
2881:
2850:
2801:
2760:
2711:
2662:
2613:
2572:
2523:
2474:
2438:
2389:
2337:
2288:
2242:
2204:
2169:
2120:
2082:
2025:
1974:
1932:
1888:
1853:
1796:
1742:
1693:
1648:
1609:
1553:
1501:
1452:
1403:
1352:
1298:
1247:
990:
952:
896:
872:
734:
433:
369:
343:
295:
279:
264:
236:
220:
54:
638:
and activated iTregs or cross-reacting nTregs. Some maternal Treg cells also release soluble
350:(lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by
3862:
3802:
3774:
3769:
3724:
3714:
3460:
3404:
3396:
3345:
3302:
3265:
3257:
3209:
3201:
3147:
3139:
3092:
3055:
3047:
3000:
2963:
2914:
2869:
2840:
2832:
2791:
2750:
2742:
2701:
2693:
2652:
2644:
2633:"Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells"
2603:
2562:
2554:
2541:
McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA, et al. (March 2012).
2513:
2505:
2466:
2428:
2420:
2379:
2371:
2327:
2319:
2280:
2234:
2196:
2159:
2112:
2072:
2064:
2017:
1966:
1920:
1880:
1843:
1835:
1786:
1732:
1685:
1636:
1599:
1591:
1543:
1491:
1483:
1442:
1434:
1393:
1383:
1342:
1334:
1288:
1280:
1235:
868:
857:
766:
surface of the enterocytes. Here dendritic cells can interact with the presented antigens.
417:
347:
2729:
Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Förster R, Pabst O (October 2008).
815:. Retinoic acid is also programming the T cells to stay in the gut environment by inducing
592:
215:
Immunobiology defines tolerance as "immunologically unresponsive...to another's tissues.".
3757:
3455:
1532:"Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?"
876:
697:
385:
311:
203:
105:
46:
2870:
1921:
1637:
1236:
440:
transcription factor, which is responsible for the suppressive phenotype of these cells.
3392:
3250:
Philosophical
Transactions of the Royal Society of London. Series B, Biological Sciences
3197:
2013:
1828:
Philosophical
Transactions of the Royal Society of London. Series B, Biological Sciences
1681:
1604:
1579:
179:
This observation was experimentally validated by Leslie Brent, Rupert E. Billingham and
3784:
3729:
3670:
3590:
3563:
3270:
3245:
3214:
3181:
3152:
3127:
3060:
3035:
2901:
Soyer OU, Akdis M, Ring J, Behrendt H, Crameri R, Lauener R, Akdis CA (February 2013).
2845:
2820:
2755:
2730:
2706:
2681:
2657:
2632:
2567:
2543:"Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine"
2542:
2518:
2493:
2384:
2359:
2332:
2307:
2077:
2052:
1848:
1823:
1496:
1471:
1447:
1422:
1398:
1371:
1347:
1322:
1293:
1268:
821:
722:
718:
635:
599:
of these patients implies their physiology may be predisposed toward immune tolerance.
596:
525:
393:
359:
89:
2433:
2408:
45:'s state of unresponsiveness to substances or tissues that would otherwise trigger an
3915:
3752:
3641:
3349:
3306:
2509:
2254:
2116:
1791:
1774:
1145:
1007:
969:
880:
844:
and is therefore also a site of food tolerance induction. Upon high antigen exposure
837:
812:
804:
763:
672:
351:
180:
42:
3426:
3365:
3322:
3020:
2936:
2132:
2037:
1986:
1754:
1705:
1621:
3719:
3704:
3699:
3636:
3534:
3112:
1808:
1155:
1120:
948:
920:
787:
755:
521:, which sensitizes cells to suppression and promotes Treg-like cell differentiation
477:
199:
81:
2494:"Enterocytes: active cells in tolerance to food and microbial antigens in the gut"
2021:
1900:
2836:
2796:
2779:
2608:
2591:
2470:
2323:
2238:
1548:
1531:
1438:
777:
dendritic cells. CD103+ dendritic cells are associated with tolerance induction.
841:
770:
619:
244:
171:
148:
92:. Deficiencies in either central or peripheral tolerance mechanisms can lead to
77:
70:
62:
2409:"Oral tolerance, an active immunologic process mediated by multiple mechanisms"
1338:
907:
to cause allergic reactions, can also reduce antibiotic allergies in children.
3842:
3595:
3501:
2284:
2200:
1595:
1284:
936:
888:
783:
747:
664:
643:
541:
413:
405:
144:
17:
1737:
1720:
3900:
3605:
3400:
3205:
2164:
2147:
2146:
Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T (October 2009).
884:
856:
The hypo-responsiveness induced by oral exposure is systemic and can reduce
175:
140:
136:
132:
85:
3448:
3418:
3357:
3314:
3279:
3261:
3223:
3161:
3104:
3069:
3012:
2991:
Cernadas JR (February 2013). "Desensitization to antibiotics in children".
2977:
2928:
2854:
2805:
2764:
2715:
2666:
2617:
2576:
2527:
2478:
2442:
2393:
2341:
2292:
2246:
2208:
2173:
2124:
2086:
2029:
1978:
1919:
Murphy K (2012). "Chapter 8: The
Development and Survival of Lymphocytes".
1892:
1857:
1839:
1800:
1746:
1689:
1613:
1557:
1505:
1456:
1407:
1356:
1302:
824:, which is required for the expansion of the regulatory T cell population.
2648:
1697:
1388:
1323:"Coordination of tolerogenic immune responses by the commensal microbiota"
790:
with CD103+ dendritic cells and transfer antigens to the dendritic cells.
3890:
3675:
3663:
3621:
3575:
3539:
2746:
2697:
2225:
Gökmen R, Hernandez-Fuentes MP (August 2013). "Biomarkers of tolerance".
1670:
Proceedings of the Royal
Society of London. Series B, Biological Sciences
932:
916:
900:
759:
751:
709:
may have evolved to prevent hypersensitivity reactions to food proteins.
459:
455:
2968:
2951:
2558:
3895:
3709:
3558:
3529:
1124:
955:
have also been implicated promoting differentiation of iTreg cells and
864:
50:
3246:"Decomposing health: tolerance and resistance to parasites in animals"
3143:
3126:
Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ (February 2013).
3096:
3034:
Aktipis CA, Boddy AM, Gatenby RA, Brown JS, Maley CC (December 2013).
3004:
2919:
2902:
2375:
1487:
530:
Cytokine absorption leading to cytokine deprivation-mediated apoptosis
3867:
3855:
3600:
3551:
3409:
2424:
989:
detection and/or elimination by the host immune system. Induction of
944:
904:
892:
730:
563:
545:
496:
470:
409:
275:
252:
248:
240:
159:
117:
58:
3051:
2068:
1970:
1884:
114:
immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
3443:
1051:
Pain, swelling, and disruption of tissue function by inflammation.
975:
800:
774:
725:. After receiving an antigen these dendritic cells migrate to the
717:
The soluble antigens in the lumen of intestine are transported to
437:
377:
121:
2189:
Clinica
Chimica Acta; International Journal of Clinical Chemistry
1234:
2680:
Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (August 2007).
2590:
Mazzini E, Massimiliano L, Penna G, Rescigno M (February 2014).
1472:"Role of plasmacytoid dendritic cell subsets in allergic asthma"
816:
639:
559:
488:
484:
389:
162:
to avoid detection and destruction by the host's immune system.
3474:
1719:
Felton LD, Kauffmann G, Prescott B, Ottinger B (January 1955).
1578:
Becker JC, Andersen MH, Schrama D, Thor Straten P (July 2013).
1580:"Immune-suppressive properties of the tumor microenvironment"
2148:"Regulatory T cells: how do they suppress immune responses?"
1635:
Murphy K (2012). "Chapter 1: Basic Concepts in Immunology".
1269:"The pathogenesis of systemic lupus erythematosus-an update"
769:
Another pathway of soluble antigen transport occurs through
2868:
Murphy K (2012). "Chapter 12: The Mucosal Immune System".
170:
The phenomenon of immune tolerance was first described by
1054:
Tissue damage by inflammatory mediators (immunopathology)
935:, and high expression of tolerance-inducing ligands like
903:. Repeated administration of antibiotics, which can form
915:
Immune tolerance is an important means by which growing
76:
Immune tolerance is important for normal physiology and
358:
from any of a variety of sources, including tolerizing
3180:
Medzhitov R, Schneider DS, Soares MP (February 2012).
2051:
Ganguly D, Haak S, Sisirak V, Reizis B (August 2013).
2821:"Plasmacytoid dendritic cells mediate oral tolerance"
1070:
Neutralizes toxins and eliminates dangerous organisms
3883:
3841:
3783:
3684:
3614:
3522:
3515:
1100:
Less selection pressure on pathogens for resistance
1087:
Direct damage by pathogen (toxins, digestion, etc.)
754:. The partially degraded antigens are presented on
3175:
3173:
3171:
1525:
1523:
1521:
1519:
1517:
1515:
1470:Maazi H, Lam J, Lombardi V, Akbari O (June 2013).
993:, for instance, has been noted in infections with
762:. The MHCII carrying vesicles are released on the
750:. The antigens are then partially degraded in the
642:(sFGL2), which suppresses the function of DCs and
2903:"Mechanisms of peripheral tolerance to allergens"
1321:Round JL, O'Connell RM, Mazmanian SK (May 2010).
1019:Tradeoffs between immune tolerance and resistance
346:(iTreg cells) in the peripheral tissue or nearby
1530:Curotto de Lafaille MA, Lafaille JJ (May 2009).
432:The involvement of T cells, later classified as
3239:
3237:
3235:
3233:
1914:
1912:
1910:
1229:
1227:
1225:
1223:
1221:
1219:
1217:
1215:
1188:
1186:
1184:
1182:
1180:
1178:
1176:
1060:Risk of autoimmunity, hypersensitivity, allergy
836:Oral tolerance is also established by inducing
746:antigens Dissolved antigens can be taken up by
366:, or in certain conditions surrounding tissue.
2952:"Allergen immunotherapy for allergic rhinitis"
2631:Laffont S, Siddiqui KR, Powrie F (July 2010).
2098:
2096:
1952:
1950:
1948:
1573:
1571:
1569:
1567:
713:Mechanisms of oral tolerance for food antigens
49:. It arises from prior exposure to a specific
27:State of unresponsiveness of the immune system
3486:
3244:Råberg L, Graham AL, Read AF (January 2009).
3036:"Life history trade-offs in cancer evolution"
2053:"The role of dendritic cells in autoimmunity"
1768:
1766:
1764:
1316:
1314:
1312:
8:
3449:International Conference on Immune Tolerance
2876:(8th ed.). Garland Sciences. pp.
1927:(8th ed.). Garland Sciences. pp.
1643:(8th ed.). Garland Sciences. pp.
758:after lysosome merging with MHCII carrying
3519:
3493:
3479:
3471:
1242:(8th ed.). Garland Science. pp.
1097:Reduced tissue damage from immune response
473:(reduced proliferation and IL-2 signaling)
314:) that can respond to self-antigens that:
3463:at the U.S. National Library of Medicine
3408:
3269:
3213:
3182:"Disease tolerance as a defense strategy"
3151:
3059:
2967:
2918:
2844:
2795:
2754:
2705:
2656:
2607:
2566:
2517:
2432:
2383:
2331:
2220:
2218:
2163:
2076:
1847:
1790:
1736:
1603:
1547:
1495:
1446:
1397:
1387:
1346:
1292:
1267:Choi J, Kim ST, Craft J (December 2012).
626:(HLA-G) that inhibits attack by maternal
562:costimulation, while iTreg cells require
325:, brain, or spinal cord not expressed by
283:
2266:
2264:
2227:Current Opinion in Organ Transplantation
1421:Verbsky JW, Chatila TA (December 2013).
1195:"Nobel Lecture: Immunological Tolerance"
1030:
501:lymphocyte function-associated antigen 1
110:autoimmune polyendocrine syndrome type 1
1376:Clinical & Developmental Immunology
1172:
741:Antigen presentation to dendritic cells
335:
2413:The Journal of Clinical Investigation
2353:
2351:
1090:Energy and resources lost to pathogen
558:nTreg cells, when activated, require
354:produced upon T cell activation, and
7:
2735:The Journal of Experimental Medicine
2686:The Journal of Experimental Medicine
2498:Clinical and Experimental Immunology
820:present in this environment secrete
574:Tolerance in physiology and medicine
135:, immune tolerance is vital for the
69:, taking place in other tissues and
852:Hypersensitivity and oral tolerance
404:(IDO) that depletes the amino acid
376:that make IL-10 but do not express
2950:Petalas K, Durham SR (June 2013).
2273:Journal of Reproductive Immunology
1824:"The thymus and central tolerance"
1822:Sprent J, Kishimoto H (May 2001).
832:Other mechanisms of oral tolerance
25:
2492:Miron N, Cristea V (March 2012).
1141:Evolutionary medicine § tradeoffs
257:medullary thymic epithelial cells
147:response sufficiently to prevent
3350:10.1111/j.0105-2896.2006.00411.x
3307:10.1111/j.1600-065x.2006.00445.x
2993:Pediatric Allergy and Immunology
2510:10.1111/j.1365-2249.2011.04523.x
2360:"Oral tolerance to food protein"
2117:10.1046/j.1440-1711.2002.01068.x
1792:10.1097/00054725-200407000-00023
1773:Jump RL, Levine AD (July 2004).
1584:Cancer Immunology, Immunotherapy
957:myeloid derived suppressor cells
733:and induce differentiation into
729:. Here they interact with naïve
616:major histocompatibility complex
2306:Christiansen OB (August 2013).
1193:Medawar P (December 12, 1960).
702:its associated lymphoid tissues
400:also exists. Some DCs can make
3820:Immunoglobulin class switching
3085:British Journal of Haematology
2637:European Journal of Immunology
2358:Pabst O, Mowat AM (May 2012).
550:gut-associated lymphoid tissue
1:
2022:10.1016/j.febslet.2013.05.023
1427:Current Opinion in Pediatrics
1273:Current Opinion in Immunology
879:at mucosal surfaces suppress
653:Immune tolerance in pregnancy
646:involved in inflammation and
609:Immune tolerance in pregnancy
422:activation-induced cell death
2837:10.1016/j.immuni.2008.06.017
2797:10.1016/j.immuni.2011.01.016
2609:10.1016/j.immuni.2013.12.012
2471:10.1053/j.gastro.2007.02.043
2324:10.1016/j.molimm.2012.08.025
2239:10.1097/MOT.0b013e3283636fd5
1549:10.1016/j.immuni.2009.05.002
1439:10.1097/mop.0000000000000029
1161:Plant tolerance to herbivory
846:plasmacytoid dendritic cells
98:systemic lupus erythematosus
2105:Immunology and Cell Biology
1779:Inflammatory Bowel Diseases
1131:, and other such diseases.
678:inflammatory bowel diseases
630:. These cells also express
402:Indoleamine 2,3-dioxygenase
3938:
3649:Polyclonal B cell response
2407:Weiner HL (October 2000).
2057:Nature Reviews. Immunology
1959:Nature Reviews. Immunology
1873:Nature Reviews. Immunology
1339:10.1016/j.jaut.2009.11.007
1129:inflammatory bowel disease
911:The tumor microenvironment
869:hypersensitivity reactions
640:fibrinogen-like proteins 2
606:
491:costimultory molecules on
196:Sir Frank McFarlane Burnet
126:inflammatory bowel disease
96:, with conditions such as
2308:"Reproductive immunology"
2285:10.1016/j.jri.2012.07.007
2201:10.1016/j.cca.2012.04.024
1596:10.1007/s00262-013-1434-6
1285:10.1016/j.coi.2012.10.004
3465:Medical Subject Headings
3444:Immune Tolerance Network
2152:International Immunology
1738:10.4049/jimmunol.74.1.17
1045:Elimination (resistance)
493:antigen presenting cells
469:after contact, inducing
364:antigen presenting cells
174:in 1945, who noted that
139:of genetically distinct
3401:10.1126/science.1148526
3206:10.1126/science.1214935
2872:Janeway's Immunobiology
1923:Janeway's Immunobiology
1639:Janeway's Immunobiology
1327:Journal of Autoimmunity
1238:Janeway's Immunobiology
1067:Reduces pathogen burden
881:type 2 CD4 helper cells
624:Human Leukocyte Antigen
622:cells express a unique
35:immunological tolerance
3763:Tolerance in pregnancy
3505:adaptive immune system
3262:10.1098/rstb.2008.0184
3040:Nature Reviews. Cancer
1840:10.1098/rstb.2001.0846
1690:10.1098/rspb.1983.0039
1002:Listeria monocytogenes
981:
925:tumor microenvironment
727:mesenteric lymph nodes
495:upon interaction with
462:secretion upon contact
420:tissues can result in
261:thymic dendritic cells
143:, as it moderates the
3798:Somatic hypermutation
3632:Polyclonal antibodies
3627:Monoclonal antibodies
3338:Immunological Reviews
3295:Immunological Reviews
2649:10.1002/eji.200939957
2165:10.1093/intimm/dxp095
1725:Journal of Immunology
1103:Promotes commensalism
979:
428:nTreg vs. iTreg cells
210:Definitions and usage
166:Historical background
3815:Junctional diversity
3583:Antigen presentation
2747:10.1084/jem.20080039
2698:10.1084/jem.20070719
2312:Molecular Immunology
2195:(17–18): 1414–1418.
1151:Infectious tolerance
648:antigen presentation
323:islets of Langerhans
307:Peripheral tolerance
302:Peripheral tolerance
284:peripheral tolerance
102:rheumatoid arthritis
67:peripheral tolerance
3810:V(D)J recombination
3793:Affinity maturation
3545:Antigenic variation
3393:2007Sci...318..812R
3198:2012Sci...335..936M
2969:10.4193/Rhino12.086
2559:10.1038/nature10863
2014:2013FEBSL.587.2074V
1682:1983RSPSB.218..259F
1389:10.1155/2012/207403
1370:Perniola R (2012).
1073:Prevents parasitism
996:Helicobacter pylori
579:Allograft tolerance
510:Contact-independent
329:in thymic tissues).
156:pathogenic microbes
94:autoimmune diseases
57:, occurring in the
3454:2011-02-19 at the
2364:Mucosal Immunology
991:regulatory T cells
982:
794:Regulatory T cells
735:regulatory T cells
686:ulcerative colitis
483:Downregulation of
448:Contact-dependent:
280:regulatory T cells
131:In the context of
3909:
3908:
3837:
3836:
3587:professional APCs
3387:(5851): 812–814.
3192:(6071): 936–941.
3144:10.1111/imm.12036
3097:10.1111/bjh.12380
3005:10.1111/pai.12001
2920:10.1111/all.12085
2887:978-0-8153-4243-4
2741:(11): 2483–2490.
2553:(7389): 345–349.
2376:10.1038/mi.2012.4
2158:(10): 1105–1111.
2008:(13): 2074–2078.
1938:978-0-8153-4243-4
1834:(1409): 609–616.
1676:(1212): 259–285.
1654:978-0-8153-4243-4
1488:10.1111/all.12166
1253:978-0-8153-4243-4
1112:
1111:
1106:Lower energy cost
897:atopic dermatitis
603:Fetal development
476:Interaction with
418:immune privileged
336:central tolerance
294:process detailed
265:bone marrow cells
237:Central tolerance
232:Central tolerance
221:immunosuppression
55:central tolerance
16:(Redirected from
3929:
3803:Clonal selection
3775:Immune privilege
3770:Immunodeficiency
3725:Cross-reactivity
3715:Hypersensitivity
3520:
3495:
3488:
3481:
3472:
3461:Immune+tolerance
3431:
3430:
3412:
3376:
3370:
3369:
3333:
3327:
3326:
3290:
3284:
3283:
3273:
3241:
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3177:
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3165:
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3123:
3117:
3116:
3080:
3074:
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2922:
2898:
2892:
2891:
2875:
2865:
2859:
2858:
2848:
2816:
2810:
2809:
2799:
2775:
2769:
2768:
2758:
2726:
2720:
2719:
2709:
2692:(8): 1765–1774.
2677:
2671:
2670:
2660:
2643:(7): 1877–1883.
2628:
2622:
2621:
2611:
2587:
2581:
2580:
2570:
2538:
2532:
2531:
2521:
2489:
2483:
2482:
2465:(5): 1866–1876.
2459:Gastroenterology
2453:
2447:
2446:
2436:
2425:10.1172/jci11348
2404:
2398:
2397:
2387:
2355:
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2177:
2167:
2143:
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2100:
2091:
2090:
2080:
2048:
2042:
2041:
1997:
1991:
1990:
1954:
1943:
1942:
1926:
1916:
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1716:
1710:
1709:
1665:
1659:
1658:
1642:
1632:
1626:
1625:
1607:
1590:(7): 1137–1148.
1575:
1562:
1561:
1551:
1527:
1510:
1509:
1499:
1467:
1461:
1460:
1450:
1418:
1412:
1411:
1401:
1391:
1367:
1361:
1360:
1350:
1333:(3): J220–J225.
1318:
1307:
1306:
1296:
1264:
1258:
1257:
1241:
1231:
1210:
1209:
1207:
1205:
1190:
1057:High energy cost
1031:
858:hypersensitivity
465:Upregulation of
41:, refers to the
33:, also known as
31:Immune tolerance
21:
3937:
3936:
3932:
3931:
3930:
3928:
3927:
3926:
3912:
3911:
3910:
3905:
3879:
3833:
3779:
3758:Clonal deletion
3686:
3680:
3610:
3511:
3499:
3456:Wayback Machine
3440:
3435:
3434:
3378:
3377:
3373:
3335:
3334:
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3292:
3291:
3287:
3256:(1513): 37–49.
3243:
3242:
3231:
3179:
3178:
3169:
3125:
3124:
3120:
3082:
3081:
3077:
3052:10.1038/nrc3606
3046:(12): 883–892.
3033:
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2181:
2145:
2144:
2140:
2102:
2101:
2094:
2069:10.1038/nri3477
2050:
2049:
2045:
1999:
1998:
1994:
1971:10.1038/nri2785
1956:
1955:
1946:
1939:
1918:
1917:
1908:
1885:10.1038/nri1707
1879:(10): 772–782.
1870:
1869:
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1310:
1266:
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1233:
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1213:
1203:
1201:
1199:The Nobel Prize
1192:
1191:
1174:
1169:
1137:
1021:
965:
913:
854:
834:
796:
743:
719:dendritic cells
715:
706:intestinal wall
694:
682:Crohn's disease
661:
611:
605:
597:gene signatures
581:
576:
430:
360:dendritic cells
348:lymphoid tissue
304:
234:
212:
204:clonal deletion
168:
106:type 1 diabetes
47:immune response
39:immunotolerance
28:
23:
22:
15:
12:
11:
5:
3935:
3933:
3925:
3924:
3914:
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3907:
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3898:
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3832:
3831:
3822:
3817:
3812:
3807:
3806:
3805:
3800:
3789:
3787:
3785:Immunogenetics
3781:
3780:
3778:
3777:
3772:
3767:
3766:
3765:
3760:
3755:
3750:
3745:
3733:
3732:
3730:Co-stimulation
3727:
3722:
3717:
3712:
3707:
3702:
3697:
3690:
3688:
3682:
3681:
3679:
3678:
3673:
3671:Immune complex
3667:
3666:
3661:
3656:
3651:
3646:
3645:
3644:
3639:
3634:
3629:
3618:
3616:
3612:
3611:
3609:
3608:
3603:
3598:
3593:
3591:Dendritic cell
3579:
3578:
3573:
3572:
3571:
3569:Conformational
3566:
3555:
3554:
3549:
3548:
3547:
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3526:
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3513:
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3500:
3498:
3497:
3490:
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3439:
3438:External links
3436:
3433:
3432:
3371:
3328:
3285:
3229:
3167:
3138:(2): 105–115.
3118:
3091:(3): 313–325.
3075:
3026:
2983:
2942:
2913:(2): 161–170.
2893:
2886:
2860:
2831:(3): 464–475.
2811:
2790:(2): 237–246.
2770:
2721:
2672:
2623:
2602:(2): 248–261.
2582:
2533:
2504:(3): 405–412.
2484:
2448:
2419:(8): 935–937.
2399:
2370:(3): 232–239.
2347:
2298:
2260:
2233:(4): 416–420.
2214:
2179:
2138:
2111:(2): 131–137.
2092:
2063:(8): 566–577.
2043:
1992:
1965:(7): 490–500.
1944:
1937:
1906:
1863:
1814:
1785:(4): 462–478.
1760:
1711:
1660:
1653:
1627:
1563:
1542:(5): 626–635.
1511:
1482:(6): 695–701.
1462:
1433:(6): 708–714.
1413:
1362:
1308:
1279:(6): 651–657.
1259:
1252:
1211:
1171:
1170:
1168:
1165:
1164:
1163:
1158:
1153:
1148:
1143:
1136:
1133:
1110:
1109:
1108:
1107:
1104:
1101:
1098:
1093:
1092:
1091:
1088:
1083:
1077:
1076:
1075:
1074:
1071:
1068:
1063:
1062:
1061:
1058:
1055:
1052:
1047:
1041:
1040:
1037:
1034:
1020:
1017:
964:
961:
912:
909:
853:
850:
833:
830:
795:
792:
742:
739:
723:lamina propria
714:
711:
693:
692:Oral tolerance
690:
660:
659:The microbiome
657:
607:Main article:
604:
601:
580:
577:
575:
572:
571:
570:
567:
566:costimulation.
556:
553:
534:
533:
532:
531:
528:
522:
512:
511:
507:
506:
505:
504:
481:
474:
463:
450:
449:
429:
426:
416:expression by
331:
330:
319:
303:
300:
233:
230:
211:
208:
192:
191:
167:
164:
90:gut microbiota
26:
24:
18:Oral tolerance
14:
13:
10:
9:
6:
4:
3:
2:
3934:
3923:
3920:
3919:
3917:
3902:
3899:
3897:
3894:
3892:
3889:
3888:
3886:
3882:
3876:
3873:
3869:
3866:
3865:
3864:
3861:
3857:
3854:
3853:
3852:
3849:
3848:
3846:
3844:
3840:
3830:
3826:
3823:
3821:
3818:
3816:
3813:
3811:
3808:
3804:
3801:
3799:
3796:
3795:
3794:
3791:
3790:
3788:
3786:
3782:
3776:
3773:
3771:
3768:
3764:
3761:
3759:
3756:
3754:
3753:Clonal anergy
3751:
3749:
3746:
3744:
3741:
3740:
3739:
3735:
3734:
3731:
3728:
3726:
3723:
3721:
3718:
3716:
3713:
3711:
3708:
3706:
3703:
3701:
3698:
3696:
3692:
3691:
3689:
3683:
3677:
3674:
3672:
3669:
3668:
3665:
3662:
3660:
3657:
3655:
3652:
3650:
3647:
3643:
3642:Microantibody
3640:
3638:
3635:
3633:
3630:
3628:
3625:
3624:
3623:
3620:
3619:
3617:
3613:
3607:
3604:
3602:
3599:
3597:
3594:
3592:
3588:
3584:
3581:
3580:
3577:
3574:
3570:
3567:
3565:
3562:
3561:
3560:
3557:
3556:
3553:
3550:
3546:
3543:
3541:
3538:
3536:
3533:
3532:
3531:
3528:
3527:
3525:
3521:
3518:
3514:
3510:
3506:
3503:
3496:
3491:
3489:
3484:
3482:
3477:
3476:
3473:
3466:
3462:
3459:
3457:
3453:
3450:
3447:
3445:
3442:
3441:
3437:
3428:
3424:
3420:
3416:
3411:
3406:
3402:
3398:
3394:
3390:
3386:
3382:
3375:
3372:
3367:
3363:
3359:
3355:
3351:
3347:
3343:
3339:
3332:
3329:
3324:
3320:
3316:
3312:
3308:
3304:
3300:
3296:
3289:
3286:
3281:
3277:
3272:
3267:
3263:
3259:
3255:
3251:
3247:
3240:
3238:
3236:
3234:
3230:
3225:
3221:
3216:
3211:
3207:
3203:
3199:
3195:
3191:
3187:
3183:
3176:
3174:
3172:
3168:
3163:
3159:
3154:
3149:
3145:
3141:
3137:
3133:
3129:
3122:
3119:
3114:
3110:
3106:
3102:
3098:
3094:
3090:
3086:
3079:
3076:
3071:
3067:
3062:
3057:
3053:
3049:
3045:
3041:
3037:
3030:
3027:
3022:
3018:
3014:
3010:
3006:
3002:
2998:
2994:
2987:
2984:
2979:
2975:
2970:
2965:
2962:(2): 99–110.
2961:
2957:
2953:
2946:
2943:
2938:
2934:
2930:
2926:
2921:
2916:
2912:
2908:
2904:
2897:
2894:
2889:
2883:
2879:
2874:
2873:
2864:
2861:
2856:
2852:
2847:
2842:
2838:
2834:
2830:
2826:
2822:
2815:
2812:
2807:
2803:
2798:
2793:
2789:
2785:
2781:
2774:
2771:
2766:
2762:
2757:
2752:
2748:
2744:
2740:
2736:
2732:
2725:
2722:
2717:
2713:
2708:
2703:
2699:
2695:
2691:
2687:
2683:
2676:
2673:
2668:
2664:
2659:
2654:
2650:
2646:
2642:
2638:
2634:
2627:
2624:
2619:
2615:
2610:
2605:
2601:
2597:
2593:
2586:
2583:
2578:
2574:
2569:
2564:
2560:
2556:
2552:
2548:
2544:
2537:
2534:
2529:
2525:
2520:
2515:
2511:
2507:
2503:
2499:
2495:
2488:
2485:
2480:
2476:
2472:
2468:
2464:
2460:
2452:
2449:
2444:
2440:
2435:
2430:
2426:
2422:
2418:
2414:
2410:
2403:
2400:
2395:
2391:
2386:
2381:
2377:
2373:
2369:
2365:
2361:
2354:
2352:
2348:
2343:
2339:
2334:
2329:
2325:
2321:
2317:
2313:
2309:
2302:
2299:
2294:
2290:
2286:
2282:
2278:
2274:
2267:
2265:
2261:
2256:
2252:
2248:
2244:
2240:
2236:
2232:
2228:
2221:
2219:
2215:
2210:
2206:
2202:
2198:
2194:
2190:
2183:
2180:
2175:
2171:
2166:
2161:
2157:
2153:
2149:
2142:
2139:
2134:
2130:
2126:
2122:
2118:
2114:
2110:
2106:
2099:
2097:
2093:
2088:
2084:
2079:
2074:
2070:
2066:
2062:
2058:
2054:
2047:
2044:
2039:
2035:
2031:
2027:
2023:
2019:
2015:
2011:
2007:
2003:
1996:
1993:
1988:
1984:
1980:
1976:
1972:
1968:
1964:
1960:
1953:
1951:
1949:
1945:
1940:
1934:
1930:
1925:
1924:
1915:
1913:
1911:
1907:
1902:
1898:
1894:
1890:
1886:
1882:
1878:
1874:
1867:
1864:
1859:
1855:
1850:
1845:
1841:
1837:
1833:
1829:
1825:
1818:
1815:
1810:
1806:
1802:
1798:
1793:
1788:
1784:
1780:
1776:
1769:
1767:
1765:
1761:
1756:
1752:
1748:
1744:
1739:
1734:
1730:
1726:
1722:
1715:
1712:
1707:
1703:
1699:
1695:
1691:
1687:
1683:
1679:
1675:
1671:
1664:
1661:
1656:
1650:
1646:
1641:
1640:
1631:
1628:
1623:
1619:
1615:
1611:
1606:
1601:
1597:
1593:
1589:
1585:
1581:
1574:
1572:
1570:
1568:
1564:
1559:
1555:
1550:
1545:
1541:
1537:
1533:
1526:
1524:
1522:
1520:
1518:
1516:
1512:
1507:
1503:
1498:
1493:
1489:
1485:
1481:
1477:
1473:
1466:
1463:
1458:
1454:
1449:
1444:
1440:
1436:
1432:
1428:
1424:
1417:
1414:
1409:
1405:
1400:
1395:
1390:
1385:
1381:
1377:
1373:
1366:
1363:
1358:
1354:
1349:
1344:
1340:
1336:
1332:
1328:
1324:
1317:
1315:
1313:
1309:
1304:
1300:
1295:
1290:
1286:
1282:
1278:
1274:
1270:
1263:
1260:
1255:
1249:
1245:
1240:
1239:
1230:
1228:
1226:
1224:
1222:
1220:
1218:
1216:
1212:
1200:
1196:
1189:
1187:
1185:
1183:
1181:
1179:
1177:
1173:
1166:
1162:
1159:
1157:
1154:
1152:
1149:
1147:
1146:Immunotherapy
1144:
1142:
1139:
1138:
1134:
1132:
1130:
1126:
1122:
1116:
1105:
1102:
1099:
1096:
1095:
1094:
1089:
1086:
1085:
1084:
1082:
1079:
1078:
1072:
1069:
1066:
1065:
1064:
1059:
1056:
1053:
1050:
1049:
1048:
1046:
1043:
1042:
1038:
1035:
1033:
1032:
1029:
1025:
1018:
1016:
1014:
1010:
1009:
1008:Brugia malayi
1004:
1003:
998:
997:
992:
986:
978:
974:
971:
970:reaction norm
962:
960:
958:
954:
950:
946:
942:
938:
934:
930:
926:
922:
921:stromal cells
918:
910:
908:
906:
902:
898:
894:
890:
886:
882:
878:
874:
870:
866:
862:
859:
851:
849:
847:
843:
839:
831:
829:
825:
823:
818:
814:
813:retinoic acid
810:
806:
802:
793:
791:
789:
788:gap junctions
785:
782:
778:
776:
772:
767:
765:
761:
757:
753:
749:
740:
738:
736:
732:
728:
724:
720:
712:
710:
707:
703:
699:
691:
689:
687:
683:
679:
674:
673:retinoic acid
670:
666:
658:
656:
654:
649:
645:
641:
637:
633:
629:
625:
621:
617:
610:
602:
600:
598:
594:
590:
586:
578:
573:
568:
565:
561:
557:
554:
551:
547:
543:
539:
538:
537:
529:
527:
524:Secretion of
523:
520:
517:Secretion of
516:
515:
514:
513:
509:
508:
502:
498:
494:
490:
486:
482:
479:
475:
472:
468:
464:
461:
457:
454:
453:
452:
451:
447:
446:
445:
441:
439:
435:
427:
425:
423:
419:
415:
411:
407:
403:
399:
395:
391:
387:
383:
379:
375:
371:
367:
365:
362:(DCs), other
361:
357:
353:
349:
345:
339:
337:
328:
324:
320:
317:
316:
315:
313:
308:
301:
299:
297:
291:
287:
285:
281:
277:
272:
270:
266:
262:
258:
254:
253:B lymphocytes
250:
246:
242:
238:
231:
229:
225:
222:
216:
209:
207:
205:
201:
197:
190:
187:
186:
185:
182:
181:Peter Medawar
177:
173:
165:
163:
161:
157:
152:
150:
146:
142:
138:
134:
129:
127:
123:
119:
115:
112:(APS-1), and
111:
107:
103:
99:
95:
91:
87:
83:
79:
74:
72:
68:
64:
60:
56:
52:
48:
44:
43:immune system
40:
36:
32:
19:
3737:
3720:Inflammation
3705:Alloimmunity
3700:Autoimmunity
3685:Immunity vs.
3637:Autoantibody
3535:Superantigen
3384:
3380:
3374:
3341:
3337:
3331:
3298:
3294:
3288:
3253:
3249:
3189:
3185:
3135:
3131:
3121:
3088:
3084:
3078:
3043:
3039:
3029:
2996:
2992:
2986:
2959:
2955:
2945:
2910:
2906:
2896:
2871:
2863:
2828:
2824:
2814:
2787:
2783:
2773:
2738:
2734:
2724:
2689:
2685:
2675:
2640:
2636:
2626:
2599:
2595:
2585:
2550:
2546:
2536:
2501:
2497:
2487:
2462:
2458:
2451:
2416:
2412:
2402:
2367:
2363:
2315:
2311:
2301:
2279:(1–2): 1–7.
2276:
2272:
2230:
2226:
2192:
2188:
2182:
2155:
2151:
2141:
2108:
2104:
2060:
2056:
2046:
2005:
2002:FEBS Letters
2001:
1995:
1962:
1958:
1922:
1876:
1872:
1866:
1831:
1827:
1817:
1782:
1778:
1731:(1): 17–26.
1728:
1724:
1714:
1673:
1669:
1663:
1638:
1630:
1587:
1583:
1539:
1535:
1479:
1475:
1465:
1430:
1426:
1416:
1379:
1375:
1365:
1330:
1326:
1276:
1272:
1262:
1237:
1202:. Retrieved
1198:
1156:Mithridatism
1121:autoimmunity
1117:
1113:
1080:
1044:
1026:
1022:
1006:
1000:
994:
987:
983:
966:
914:
863:
855:
835:
826:
797:
779:
771:goblet cells
768:
744:
716:
695:
662:
612:
582:
535:
442:
431:
424:of T cells.
368:
340:
332:
305:
292:
288:
273:
235:
226:
217:
213:
200:Frank Fenner
193:
188:
169:
153:
130:
82:autoimmunity
75:
38:
34:
30:
29:
3843:Lymphocytes
3502:Lymphocytic
3344:: 163–169.
3301:: 229–238.
2318:(1): 8–15.
889:eosinophils
875:, TR1, and
842:portal vein
784:macrophages
764:basolateral
748:enterocytes
644:macrophages
620:trophoblast
542:lymph nodes
384:-secreting
245:bone marrow
172:Ray D. Owen
149:miscarriage
78:homeostasis
71:lymph nodes
63:bone marrow
3922:Immunology
3884:Substances
3748:Peripheral
3736:Inaction:
3615:Antibodies
3596:Macrophage
3509:complement
3132:Immunology
2999:(1): 3–9.
1382:: 207403.
1167:References
885:mast cells
873:Treg cells
665:microbiome
585:allografts
480:on T cells
434:Treg cells
406:tryptophan
370:Treg cells
344:Treg cells
145:alloimmune
3901:Cytolysin
3891:Cytokines
3738:Tolerance
3687:tolerance
3606:Immunogen
3410:1842/2140
2956:Rhinology
2255:205838923
1081:Tolerance
1039:Benefits
963:Evolution
877:Th3 cells
805:Th1 cells
760:endosomes
752:lysosomes
374:TR1 cells
176:dizygotic
141:offspring
137:gestation
133:pregnancy
86:allergens
3916:Category
3851:Cellular
3695:Immunity
3693:Action:
3676:Paratope
3664:Idiotype
3654:Allotype
3622:Antibody
3576:Mimotope
3540:Allergen
3523:Antigens
3516:Lymphoid
3452:Archived
3427:16697260
3419:17975068
3366:19863894
3358:16903913
3323:37377768
3315:17100888
3280:18926971
3224:22363001
3162:23216602
3105:23691926
3070:24213474
3021:27655449
3013:22963144
2978:23671890
2937:24008758
2929:23253293
2855:18789731
2825:Immunity
2806:21333554
2784:Immunity
2765:18852290
2716:17620363
2667:20432234
2618:24462723
2596:Immunity
2577:22422267
2528:22288583
2479:17484880
2443:11032852
2394:22318493
2342:23062611
2293:23021867
2247:23838646
2209:22580152
2174:19737784
2133:13419948
2125:11940113
2087:23827956
2038:23330772
2030:23707422
1987:10861133
1979:20559327
1893:16200080
1858:11375064
1801:15475760
1755:33224134
1747:13233513
1706:20599562
1622:20996186
1614:23666510
1605:11029603
1558:19464985
1536:Immunity
1506:23662841
1457:24240290
1408:23125865
1357:19963349
1303:23131610
1135:See also
1013:NK cells
953:exosomes
933:arginase
901:rhinitis
628:NK cells
593:γδT cell
460:perforin
456:Granzyme
338:above).
286:below).
3896:Opsonin
3875:NK cell
3863:Humoral
3743:Central
3710:Allergy
3659:Isotype
3559:Epitope
3530:Antigen
3389:Bibcode
3381:Science
3271:2666700
3215:3564547
3194:Bibcode
3186:Science
3153:3575763
3113:9062219
3061:4010142
2907:Allergy
2846:3545652
2756:2571923
2707:2118687
2658:6108414
2568:3313460
2519:3374272
2385:3328017
2333:1383872
2078:4160805
2010:Bibcode
1849:1088448
1809:5751200
1698:6136042
1678:Bibcode
1497:3693732
1476:Allergy
1448:4047515
1399:3485510
1348:3155383
1294:3508331
1204:24 July
1125:allergy
905:haptens
865:Allergy
781:CX3CR1+
731:T cells
721:in the
589:NK cell
552:(GALT).
503:(LFA-1)
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945:CTLA-4
917:tumors
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887:, and
838:anergy
801:Foxp3+
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698:mucosa
564:CTLA-4
548:, and
546:spleen
497:CTLA-4
471:anergy
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241:thymus
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3423:S2CID
3362:S2CID
3319:S2CID
3109:S2CID
3017:S2CID
2933:S2CID
2251:S2CID
2129:S2CID
2034:S2CID
1983:S2CID
1897:S2CID
1805:S2CID
1751:S2CID
1702:S2CID
1647:–15.
1618:S2CID
1036:Costs
822:IL-10
756:MHCII
680:like
669:TGF-β
526:IL-10
519:TGF-β
438:Foxp3
398:TGF-β
394:IL-10
382:TGF-β
378:Foxp3
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