Clonal anergy

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Anergy, within the realm of

immunoregulation.[1]
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

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).[2]

At the cellular level, "anergy" is the inability of an

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

signaling pathways.[2]

Molecular mechanism of anergy induction in T lymphocytes

Stimulation of the

TCR. This leads to an elevation of intracellular Ca+II concentration.[3] Under this condition, calcium dependent phosphatase calcineurin removes phosphates from a transcriptional factor NFAT
, which in turn translocates to the nucleus.

Additionally, during full

jun heterodimer, further heterodimerizes with NFAT forming a transcriptional complex which promotes transcription of T-cell productive response associated genes.[5] Those are for example IL-2 and its receptor.[5]

On the contrary,

TCR signalling without costimulatory receptors sufficiently activates only the calcium arm of the signalling leading only to the activation of NFAT. However without the necessary induction of AP-1 by other pathways, activated NFAT is unable to form the transcriptional complex with AP-1, as it does during complete T-cell activation (productive response). In this case NFAT homodimerizes (complexes with itself), working as a transcriptional factor that induces anergy in the lymphocyte instead.[6]

TNFα and IFNγ, typical for productive response, are actively decreased in the anergized cell.[4] Anergized cells tend to produce antiinflammatory IL-10 instead.[5] There are 3 NFAT proteins in the T-cell, NFAT1, NFAT2 and NFAT4 and apparently are redundant to some extent.[6]

Thus when an antigen is properly presented to the T lymphocytes by an antigen presenting cell (APC), which displays the antigen on its MHC II complex and which activates T cell´s costimulatory receptors, T lymphocytes undergo productive response. However, when T cells interacts with an antigen not presented by the APCs, that is very probably not the antigen that an immune response should be held against, the T cell undergoes anergy. It has also been shown that certain antigens properly presented by the APCs induce the T cell activation only weakly. This weak stimuli still activates NFAT sufficiently, however AP-1 is not, thereby the anergistic response takes place even with the costimulation.[6] Strong stimulation of

TCR/costimulatory receptors can break the anergy.[4][5]

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

diabetes mellitus, multiple sclerosis and rheumatoid arthritis.[1] Likewise, preventing anergy in response to a tumoral growth may help in anti-tumor responses.[7] It might also be used for immunotherapeutic treatment of allergies.[8]

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 T-reg cells which actively ablate the immune response are developed from the naive T lymphocyte. Similarly to recessive tolerance, unopposed NFAT signalling is also important for T-reg induction. In this case, the NFAT pathway activates another transcription factor – FOXP3[9] that is a marker of T-regs and participates in their genetic program.[5][10]

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

candida, trichophyton, and 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 mm, hypoergy as a reaction of 2–9 mm in response to fewer than three antigens, normergic as a reaction of 10–39 mm or to three or more antigens, and hyperergy for a reaction of 40 mm or more.[11][12][13]

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 cells can be induced by Ionomycin, the ionophore capable of raising intracellular concentration of calcium ions artificially.[citation needed]

Conversely,

EGTA can sequester Calcium ions making them unable to cause the anergy. Blocking of the pathway leading to the anergy can be also done by cyclosporin A, which is capable of inhibiting calcineurin – the phosphatase responsible for dephosphorylating of NFAT
priming its activation.

TCR/costimulatory receptors activation.[4]

References

  1. ^ .
  2. ^ .
  3. ^ Burnett, D. L., Reed, J. H., Christ, D., & Goodnow, C. C. (2019). Clonal redemption and clonal anergy as mechanisms to balance b cell tolerance and immunity. Immunological Reviews, 292(1), 61–75. https://doi.org/10.1111/imr.12808
  4. ^
    PMID 12086671
    .
  5. ^ .
  6. ^ .
  7. .
  8. .
  9. .
  10. .
  11. .
  12. S2CID 29214452. Archived from the original
    (PDF) on 2011-06-11.
  13. .

Further reading

External links