Editing Autoimmunity (section)

== Immunological tolerance ==
Pioneering work by [[Noel Rose]] and [[Ernst Witebsky]] in New York, and [[Ivan Roitt|Roitt]] and [[Deborah Doniach|Doniach]] at [[University College London]] provided clear evidence that, at least in terms of antibody-producing B cells (B lymphocytes), diseases such as rheumatoid arthritis and thyrotoxicosis are associated with loss of [[immunological tolerance]], which is the ability of an individual to ignore "self", while reacting to "non-self".  This breakage leads to the immune system mounting an effective and specific immune response against self antigens. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin.<ref>{{Cite journal |last=Brent |first=Leslie |date=February 1997 |title=The discovery of immunologic tolerance |url=https://linkinghub.elsevier.com/retrieve/pii/S0198885996002893 |journal=Human Immunology |language=en |volume=52 |issue=2 |pages=75–81 |doi=10.1016/S0198-8859(96)00289-3|pmid=9077556 |url-access=subscription }}</ref>

Three hypotheses have gained widespread attention among immunologists:
* '''[[Clonal deletion]]''' '''theory''', proposed by [[Macfarlane Burnet|Burnet]], according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine  "for discovery of acquired immunological tolerance".
* '''Clonal anergy theory''', proposed by [[Gustav Nossal|Nossal]], in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.<ref>{{cite journal | vauthors = Pike BL, Boyd AW, Nossal GJ | title = Clonal anergy: the universally anergic B lymphocyte | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 6 | pages = 2013–2017 | date = March 1982 | pmid = 6804951 | pmc = 346112 | doi = 10.1073/pnas.79.6.2013 | doi-access = free | bibcode = 1982PNAS...79.2013P }}</ref>
* '''Idiotype network theory''', proposed by [[Niels Kaj Jerne|Jerne]], wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.<ref>{{cite journal | vauthors = Jerne NK | title = Towards a network theory of the immune system | journal = Annales d'Immunologie | volume = 125C | issue = 1–2 | pages = 373–389 | date = January 1974 | pmid = 4142565 }}</ref>

In addition, two other theories are under intense investigation:
* '''Clonal ignorance theory''', according to which autoreactive T cells that are not represented in the thymus will mature and migrate to the periphery, where they will not encounter the appropriate antigen because it is inaccessible tissues. Consequently, auto-reactive B cells, that escape deletion, cannot find the antigen or the specific helper T cell.<ref name="scedu">{{Cite web |url=http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm |title=Tolerance and Autoimmunity<!-- Bot generated title --> |access-date=2007-03-19 |archive-date=2011-01-01 |archive-url=https://web.archive.org/web/20110101184311/http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm |url-status=dead }}</ref>
* '''Suppressor population''' or '''[[Regulatory T cell]] theory''', wherein regulatory T-lymphocytes (commonly CD4<sup>+</sup>FoxP3<sup>+</sup> cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses in the immune system.

Tolerance can also be differentiated into "central" and "peripheral" tolerance, on whether or not the above-stated checking mechanisms operate in the central lymphoid organs (thymus and bone marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where self-reactive B-cells may be destroyed). It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance.

A puzzling feature of the documented loss of tolerance seen in spontaneous human autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and where there is evidence for an abnormal T cell response it is usually not to the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to DNA, which cannot evoke a T cell response, and limited evidence for T cell responses implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has led to the idea that human autoimmune disease is in most cases (with probable exceptions including type I diabetes) based on a loss of B cell tolerance which makes use of normal T cell responses to foreign antigens in a variety of aberrant ways.<ref>{{cite journal | vauthors = Edwards JC, Cambridge G, Abrahams VM | title = Do self-perpetuating B lymphocytes drive human autoimmune disease? | journal = Immunology | volume = 97 | issue = 2 | pages = 188–196 | date = June 1999 | pmid = 10447731 | pmc = 2326840 | doi = 10.1046/j.1365-2567.1999.00772.x }}</ref>