Editing Clonal anergy

{{short description|Lack of response by the immune system to foreign substances}}
{{redirect|Anergy|the use of the term in thermodynamics|Exergy}}

In [[immunology]], '''anergy''' characterizes the absence of a response from the body's [[Immune system|defense mechanisms]] when confronted with [[Pathogen|foreign substances]]. This phenomenon involves the direct induction of [[Peripheral tolerance|peripheral lymphocyte tolerance]]. When an individual is in a state of anergy, it signifies that their immune system is incapable of mounting a typical response against a specific [[antigen]], typically a self-antigen. The term anergy specifically refers to [[lymphocyte]]s that exhibit an inability to react to their designated antigen. Notably, anergy constitutes one of the essential processes fostering [[Immune tolerance|tolerance]] within the immune system, alongside [[clonal deletion]] and [[immunoregulation]].<ref name="Schwartz">{{cite journal |vauthors=Schwartz RH |date=August 1993 |title=T cell anergy |journal=Scientific American |volume=269 |issue=2 |pages=61–71 |doi=10.1038/scientificamerican0893-62 |pmid=8351512}}</ref> These processes collectively act to modify the immune response, preventing the inadvertent self-destruction that could result from an overactive immune system.

==Mechanism==
This phenomenon was first described in B lymphocytes by [[Gustav Nossal]] and termed "'''clonal anergy'''." The clones of B lymphocytes in this case can still be found alive in the circulation, but are ineffective at mounting immune responses. Later [[Ronald Schwartz]] and [[Marc Jenkins (immunologist)|Marc Jenkins]] described a similar process operating in the T lymphocyte. Many [[viruses]] ([[HIV]] being the most extreme example) seem to exploit the immune system's use of tolerance induction to evade the immune system, though the suppression of specific antigens is done by fewer pathogens (notably ''[[Mycobacterium leprae]]'').<ref name=Janeway>{{cite book | vauthors = Janeway Jr CA, Travers P, Walport M, Shlomchik M |author-link=Charles Janeway |title=Immunobiology | edition = Fifth |publisher=Garland Science |year = 2001 |location = New York and London |url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10 |isbn=0-8153-4101-6}}</ref>

At the cellular level, "anergy" is the inability of an [[immune cell]] to mount a complete response against its target. In the immune system, circulating cells called lymphocytes form a primary army that defends the body against pathogenic [[virus]]es, [[bacteria]] and [[parasite]]s. There are two major kinds of lymphocytes – the [[T lymphocyte]] and the [[B lymphocyte]]. Among the millions of lymphocytes in the human body, only a few actually are specific for any particular infectious agent. At the time of infection, these few cells must be recruited and allowed to multiply rapidly. This process – called "clonal expansion" – allows the body to quickly mobilise an army of clones, as and when required. Such immune response is anticipatory and its specificity is assured by pre-existing clones of lymphocytes, which expand in response to specific [[antigen]] (process called "[[clonal selection]]"). This specific clonal army then combats the [[pathogen]] until the body is free of the infection. Following clearance of the infection, the clones that are no longer needed die away naturally.

However, a small number of the body's army of lymphocytes are able to react with proteins that are normally present in a healthy body. The clonal expansion of those cells can lead to [[autoimmune diseases]], wherein the body attacks itself. In order to prevent this process, lymphocytes possess an intrinsic quality-control mechanism. This machinery shuts down the lymphocytes' ability to expand, if the trigger for the expansion turns out to be the body's own protein. T-cell anergy can arise when the T-cell does not receive appropriate co-stimulation in the presence of specific antigen recognition.<ref name=Janeway/> B-cell anergy can be induced by exposure to soluble circulating antigen, and is often marked by a downregulation of surface [[IgM]] expression and partial blockade of [[intracellular]] [[cellular signaling|signaling]] pathways.<ref name=Janeway/>

==Molecular mechanism of anergy induction in T lymphocytes==
Understanding the molecular mechanism of anergy induction in [[T cell|T lymphocytes]] unveils the intricate interplay of signaling pathways governing immune responses. Upon stimulation, the [[T cell receptor]] (TCR) in conjunction with co-stimulatory receptors orchestrates a comprehensive activation of all the [[T cell|T-cell]]’s signaling pathways, collectively termed full T-cell stimulation. Among these pathways, the calcium-dependent arm of lymphocyte signaling is particularly pivotal, triggered by [[T cell receptor|TCR]] engagement. This initiates a cascade culminating in an elevation of intracellular [[Calcium|Ca<sup>+II</sup>]] concentration,<ref name="Macián et al">{{cite journal |vauthors=Macián F, García-Cózar F, Im SH, Horton HF, Byrne MC, Rao A |date=June 2002 |title=Transcriptional mechanisms underlying lymphocyte tolerance |journal=Cell |volume=109 |issue=6 |pages=719–731 |doi=10.1016/S0092-8674(02)00767-5 |pmid=12086671 |doi-access=free}}</ref> a critical event in T cell activation. Under such conditions, the calcium-dependent phosphatase [[calcineurin]] acts on the [[transcription factor]] [[NFAT]], facilitating its translocation to the nucleus, where it regulates gene expression.

Expanding upon this complexity, during full [[T cell|T-cell]] stimulation the [[Co-stimulation|co-stimulatory]] receptor [[CD28]] activates [[Phosphoinositide 3-kinase|PI3K]] and other pathways, augmenting the nuclear levels of key transcription factors such as [[REL|rel]], [[NF-kappaB|NF-κB]] and [[AP-1 transcription factor|AP-1]] beyond those induced by TCR activation alone.<ref name="Macián et al" /> The formation of [[AP-1 transcription factor|AP-1]], [[C-Fos|fos]]/[[C-jun|jun]] heterodimer, further complexes with [[NFAT]], creating a transcriptional complex crucial for the expression of genes<ref name="Rudensky et al">{{cite journal |vauthors=Rudensky AY, Gavin M, Zheng Y |date=July 2006 |title=FOXP3 and NFAT: partners in tolerance |journal=Cell |volume=126 |issue=2 |pages=253–256 |doi=10.1016/j.cell.2006.07.005 |pmid=16873058 |doi-access=free}}</ref> associated with [[T cell|T-cell]] productive responses, including [[Interleukin 2|IL-2]] and its [[IL-2 receptor|receptor]].<ref name="Rudensky et al" />

In contrast, [[T cell receptor|TCR]] signaling in the absence of co-stimulatory receptors predominantly activates the calcium arm of the signaling pathway, leading to [[NFAT]] activation alone. However, without the concurrent induction of [[AP-1 transcription factor|AP-1]] by other pathways, [[NFAT]] fails to form the transcriptional complex necessary for a productive [[T cell|T-cell]] response. Instead, [[NFAT]] homodimerizes, functioning as a transcriptional factor that induces anergy in the lymphocyte.<ref name="Soto-Nieves et al">{{cite journal |vauthors=Soto-Nieves N, Puga I, Abe BT, Bandyopadhyay S, Baine I, Rao A, Macian F |date=April 2009 |title=Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance |journal=The Journal of Experimental Medicine |volume=206 |issue=4 |pages=867–876 |doi=10.1084/jem.20082731 |pmc=2715123 |pmid=19307325}}</ref>

[[NFAT]] homodimers play a direct role in the expression of anergy-associated genes, such as the ubiquitin ligase [[RNF128|GRAIL]] and the protease [[caspase 3]].<ref name="Soto-Nieves et al" /> Furthermore, anergized cells exhibit decreased expression levels of [[Interleukin 2|IL-2]], [[Tumor necrosis factor alpha|TNFα]], and [[Interferon gamma|IFNγ]], characteristic of a productive response, while favoring the production of the anti-inflammatory cytokine [[Interleukin 10|IL-10]].<ref name="Macián et al" /> Although three [[NFAT]] proteins - NFAT1, NFAT2 and NFAT4 - are preset in T-cells, they demonstrate redundancy to some extent.<ref name="Soto-Nieves et al" />

In the context of antigen presentation by [[Antigen-presenting cell|antigen-presenting cells]] (APC), [[T cell|T lymphocytes]] undergo a productive response when the antigen is appropriately presented, activating T cell co-stimulatory receptors. However, encountering antigens not presented by the [[Antigen-presenting cell|APCs]] or weakly presented antigens induces anergic responses in T cells.<ref name="Soto-Nieves et al" /> Notably, strong stimulation through [[Interleukin 2|IL-2]] or [[T cell receptor|TCR]]/co-stimulatory receptors can overcome anergy, highlighting the dynamic nature of immune regulation.<ref name="Macián et al" /><ref name="Rudensky et al" />

Moreover, recent research has illuminated the role of regulatory T cells (Tregs) in modulating T cell responses and maintaining immune tolerance. Tregs, characterized by the expression of the transcription factor Foxp3, exert immunosuppressive effects by inhibiting the activation and function of effector T cells.<ref name="Soto-Nieves et al" /> Importantly, Tregs can directly interact with anergic T cells, further reinforcing their state of unresponsiveness and promoting peripheral tolerance. This interaction involves various mechanisms, including the secretion of inhibitory cytokines such as IL-10 and TGF-β, as well as cell-contact-dependent suppression mediated by molecules like CTLA-4.<ref name="Macián et al" /> Understanding the intricate crosstalk between Tregs and anergic T cells provides valuable insights into the maintenance of immune homeostasis and has implications for therapeutic strategies aimed at modulating immune responses in autoimmune diseases and transplantation.<ref name="Rudensky et al" /><ref name="Soto-Nieves et al" />

==Clinical significance==
Anergy may be taken advantage of for therapeutic uses. The immune response to grafting of transplanted organs and tissues could be minimized without weakening the entire immune system— a side effect of immunosuppressive drugs like [[cyclosporine]]. Anergy may also be used to induce activated lymphocytes to become unresponsive with autoimmune diseases like [[diabetes mellitus]], [[multiple sclerosis]] and [[rheumatoid arthritis]].<ref name=Schwartz/> Likewise, preventing anergy in response to a tumoral growth may help in anti-tumor responses.<ref name="Saibil et al">{{cite journal | vauthors = Saibil SD, Deenick EK, Ohashi PS | title = The sound of silence: modulating anergy in T lymphocytes | journal = Current Opinion in Immunology | volume = 19 | issue = 6 | pages = 658–664 | date = December 2007 | pmid = 17949964 | doi = 10.1016/j.coi.2007.08.005 }}</ref> It might also be used for immunotherapeutic treatment of allergies.<ref>{{cite journal | vauthors = Rolland J, O'Hehir R | title = Immunotherapy of allergy: anergy, deletion, and immune deviation | journal = Current Opinion in Immunology | volume = 10 | issue = 6 | pages = 640–645 | date = December 1998 | pmid = 9914222 | doi = 10.1016/s0952-7915(98)80082-4 }}</ref>

==Dominant tolerance==
Dominant and recessive tolerance are forms of a [[peripheral tolerance]] (the other tolerance beside peripheral is a [[central tolerance]]). Where so called recessive tolerance is associated with anergized lymphocytes as described above, in the dominant form of tolerance, specialized [[Regulatory T cell|T-reg cells]] which actively ablate the immune response are developed from the naive [[T cell|T lymphocyte]]. Similarly to recessive tolerance, unopposed [[NFAT]] signalling is also important for
[[Regulatory T cell|T-reg]] induction. In this case, the [[NFAT]] pathway activates another transcription factor – [[FOXP3]]<ref name="Tone et al">{{cite journal | vauthors = Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M | title = Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer | journal = Nature Immunology | volume = 9 | issue = 2 | pages = 194–202 | date = February 2008 | pmid = 18157133 | doi = 10.1038/ni1549 | s2cid = 7005085 }}</ref> that is a marker of [[Regulatory T cell|T-regs]] and participates in their genetic program.<ref name="Rudensky et al"/><ref name="Hermann-Kleiter N. and Baier G.">{{cite journal | vauthors = Hermann-Kleiter N, Baier G | title = NFAT pulls the strings during CD4+ T helper cell effector functions | journal = Blood | volume = 115 | issue = 15 | pages = 2989–2997 | date = April 2010 | pmid = 20103781 | doi = 10.1182/blood-2009-10-233585 | doi-access = free }}</ref>

==Testing==
The "Multitest Mérieux" or "CMI Multitest" system (Multitest IMC, Istituto Merieux Italia, Rome, Italy) has been used as a general test of the level of [[cellular immunity]]. It is an [[intradermal]] test of [[skin reactivity]] (similar to [[tuberculin test]]s) in which a control ([[glycerol]]) is used with seven antigens of bacterial or fungal origin ([[tetanus toxoid]], [[tuberculin]], [[diphtheria]], [[streptococcus]], [[Candida (genus)|candida]], [[trichophyton]], and [[Proteus (bacterium)|proteus]]). In this test reactions are categorized according to the number of antigens provoking a response and the summed extent of the skin response to all seven antigens. Here '''anergy''' is defined as a region of skin reactivity of 0–1&nbsp;mm, '''hypoergy''' as a reaction of 2–9&nbsp;mm in response to fewer than three antigens, '''normergic''' as a reaction of 10–39&nbsp;mm or to three or more antigens, and '''hyperergy''' for a reaction of 40&nbsp;mm or more.<ref name="Muller et al">{{cite journal | vauthors = Müller N, Schneider T, Zeitz M, Marth T |year=2001 |title=Whipple's disease: new aspects in pathogenesis and diagnoses |url=http://documents.irevues.inist.fr/bitstream/2042/7452/1/actaend_2001_3_243-253.pdf |journal=Acta Endoscopica |volume=31 |pages=243–253 |doi=10.1007/BF03020891 |s2cid=30195122 }}</ref><ref name="Spornraft et al">{{cite journal | vauthors = Spornraft P, Fröschl M, Ring J, Meurer M, Goebel FD, Ziegler-Heitbrock HW, Riethmüller G, Braun-Falco O | display-authors = 6 | title = T4/T8 ratio and absolute T4 cell numbers in different clinical stages of Kaposi's sarcoma in AIDS | journal = The British Journal of Dermatology | volume = 119 | issue = 1 | pages = 1–9 | date = July 1988 | pmid = 3261596 | doi = 10.1111/j.1365-2133.1988.tb07095.x | url = http://www.rethinkingaids.com/portals/0/TheCD/S/spo.pdf | url-status = dead | s2cid = 29214452 | archive-url = https://web.archive.org/web/20110611232418/http://www.rethinkingaids.com/portals/0/TheCD/S/spo.pdf | archive-date = 2011-06-11 }}</ref><ref name="De Flora et al">{{cite journal | vauthors = De Flora S, Grassi C, Carati L | title = Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment | journal = The European Respiratory Journal | volume = 10 | issue = 7 | pages = 1535–1541 | date = July 1997 | pmid = 9230243 | doi = 10.1183/09031936.97.10071535 | doi-access = free }}</ref>

==Experimental approaches to study anergy==
Various chemicals inducing/inhibiting described T cell signalling pathways can be used to study the anergy. The anergy in [[T cell]]s can be induced by [[Ionomycin]], the ionophore capable of raising intracellular concentration of [[calcium]] ions artificially.{{cn|date=March 2022}}

Conversely, [[Calcium|Ca<sup>+II</sup>]] chelators such as [[EGTA (chemical)|EGTA]] can sequester [[Calcium|calcium ions]] making them unable to cause the anergy. Blocking of the pathway leading to the anergy can be also done by [[Ciclosporin|cyclosporin A]], which is capable of inhibiting [[calcineurin]] – the phosphatase responsible for dephosphorylating of [[NFAT]] priming its activation.

[[12-O-Tetradecanoylphorbol-13-acetate|PMA]], phorbol 12-myristate 13-acetate, along with [[ionomycin]] is used to induce full [[T cell]]s activation by mimicking signals provided naturally by [[T cell receptor|TCR]]/costimulatory receptors activation.<ref name="Macián et al"/>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Jenkins MK | title = The role of cell division in the induction of clonal anergy | journal = Immunology Today | volume = 13 | issue = 2 | pages = 69–73 | date = February 1992 | pmid = 1349483 | doi = 10.1016/0167-5699(92)90137-V }}
{{refend}}

== External links ==
* {{MeshName|Clonal+anergy}}

{{Immune system}}

[[Category:Immunology]]
[[Category:Immune system]]