Immune tolerance
Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.
Central tolerance is crucial for enabling the immune system to differentiate between self and non-self antigens, thereby preventing autoimmunity.
Peripheral tolerance plays a significant role in preventing excessive immune reactions to environmental agents, including allergens and gut microbiota.
Deficiencies in either central or peripheral tolerance mechanisms can lead to autoimmune diseases, with conditions such as systemic lupus erythematosus,[3] rheumatoid arthritis, type 1 diabetes,[4] autoimmune polyendocrine syndrome type 1 (APS-1),[5] and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX)[6] as examples.
[4] In the context of pregnancy, immune tolerance is vital for the gestation of genetically distinct offspring, as it moderates the alloimmune response sufficiently to prevent miscarriage.
[8] Additionally, the induction of peripheral tolerance within the local microenvironment is a strategy employed by many cancers to avoid detection and destruction by the host's immune system.
However, they were not thinking of the immunological consequences of their work at the time: as Medawar explains:[citation needed] 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 Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion.
[10] Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.
[1] 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.
It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system.
Immune tolerance also does not usually refer to artificially induced immunosuppression by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc.
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 pathogens.
[16] 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.
[18] Some DCs can make Indoleamine 2,3-dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness.
[17] Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells.
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).
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.
[citation needed] 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.
Maternal T cells specific for paternal antigens are also suppressed by tolerogenic DCs and activated iTregs or cross-reacting nTregs.
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.
The newly differentiated regulatory T cells travel to the lamina propria, where they suppress the immune reaction against the recognized antigens.
[citation needed] Dendritic cells play a crucial role in establishing oral tolerance for food antigens.
Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis.
There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7.
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.
In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.
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 detection and/or elimination by the host immune system.
Induction of regulatory T cells, for instance, has been noted in infections with Helicobacter pylori, Listeria monocytogenes, Brugia malayi, and other worms and parasites.
[47] The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.
