Clonal anergy

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Anergy, within the realm of immunology, characterizes the absence of a response from the body's defense mechanisms when confronted with foreign substances. This phenomenon involves the direct induction of 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 lymphocytes that exhibit an inability to react to their designated antigen. Notably, anergy constitutes one of the essential processes fostering tolerance within the immune system, alongside clonal deletion and immunoregulation. [1] These processes collectively act to modify the immune response, preventing the inadvertent self-destruction that could result from an overactive immune system.

Contents

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 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 ). [2]

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 viruses, bacteria and parasites. 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. [2] 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 signaling pathways. [2]

Molecular mechanism of anergy induction in T lymphocytes

Stimulation of the T cell receptor (TCR) along with costimulatory receptors of a T lymphocyte triggers balanced activation of all the T-cell’s signalling pathways (full T-cell stimulation). In this case, beside other pathways, calcium dependent arm of a lymphocyte signalling is activated by 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 T-cell stimulation a costimulatory receptor CD28 activates PI3K or other pathways that eventually lead to increased nuclear levels of rel, NF-κB and AP-1 (transcription factors) much more than just by the TCR activation alone. [4] AP-1, fos/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]

NFAT homodimers are directly responsible for the expression of anergy associated genes such as ubiquitin ligase GRAIL or a protease caspase 3. [6] Moreover, the expression levels of IL-2, but also for example 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 T-cells either by IL-2 or by 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 cyclosporine. Anergy may also be used to induce activated lymphocytes to become unresponsive with autoimmune diseases 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 cellular immunity. It is an intradermal test of skin reactivity (similar to tuberculin tests) in which a control (glycerol) is used with seven antigens of bacterial or fungal origin (tetanus toxoid, tuberculin, diphtheria, streptococcus, 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, Ca+II chelators such as 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.

PMA, phorbol 12-myristate 13-acetate, along with ionomycin is used to induce full T cells activation by mimicking signals provided naturally by TCR/costimulatory receptors activation. [4]

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. Superantigens act by binding to the MHC proteins on antigen-presenting cells (APCs) and to the TCRs on their adjacent helper T-cells, bringing the signaling molecules together, and thus leading to the activation of the T-cells, regardless of the peptide displayed on the MHC molecule. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognizes antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

<span class="mw-page-title-main">CD28</span> Mammalian protein found in humans

CD28 is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor (TCR) can provide a potent signal for the production of various interleukins.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">CD83</span>

CD83 is a human protein encoded by the CD83 gene.

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

<span class="mw-page-title-main">Activation-induced cell death</span>

AICD is programmed cell death caused by the interaction of Fas receptors and Fas ligands. AICD is a negative regulator of activated T lymphocytes that results from repeated stimulation of their T-cell receptors (TCR) and helps to maintain peripheral immune tolerance. Alteration of the process may lead to autoimmune diseases.

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.

References

  1. 1 2 Schwartz RH (August 1993). "T cell anergy". Scientific American. 269 (2): 61–71. doi:10.1038/scientificamerican0893-62. PMID   8351512.
  2. 1 2 3 Janeway Jr CA, Travers P, Walport M, Shlomchik M (2001). Immunobiology (Fifth ed.). New York and London: Garland Science. ISBN   0-8153-4101-6.
  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. 1 2 3 4 Macián F, García-Cózar F, Im SH, Horton HF, Byrne MC, Rao A (June 2002). "Transcriptional mechanisms underlying lymphocyte tolerance". Cell. 109 (6): 719–731. doi: 10.1016/S0092-8674(02)00767-5 . PMID   12086671.
  5. 1 2 3 4 5 Rudensky AY, Gavin M, Zheng Y (July 2006). "FOXP3 and NFAT: partners in tolerance". Cell. 126 (2): 253–256. doi: 10.1016/j.cell.2006.07.005 . PMID   16873058.
  6. 1 2 3 4 Soto-Nieves N, Puga I, Abe BT, Bandyopadhyay S, Baine I, Rao A, Macian F (April 2009). "Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance". The Journal of Experimental Medicine. 206 (4): 867–876. doi:10.1084/jem.20082731. PMC   2715123 . PMID   19307325.
  7. ↑ Saibil SD, Deenick EK, Ohashi PS (December 2007). "The sound of silence: modulating anergy in T lymphocytes". Current Opinion in Immunology. 19 (6): 658–664. doi:10.1016/j.coi.2007.08.005. PMID   17949964.
  8. ↑ Rolland J, O'Hehir R (December 1998). "Immunotherapy of allergy: anergy, deletion, and immune deviation". Current Opinion in Immunology. 10 (6): 640–645. doi:10.1016/s0952-7915(98)80082-4. PMID   9914222.
  9. ↑ Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M (February 2008). "Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer". Nature Immunology. 9 (2): 194–202. doi:10.1038/ni1549. PMID   18157133. S2CID   7005085.
  10. ↑ Hermann-Kleiter N, Baier G (April 2010). "NFAT pulls the strings during CD4+ T helper cell effector functions". Blood. 115 (15): 2989–2997. doi: 10.1182/blood-2009-10-233585 . PMID   20103781.
  11. ↑ Müller N, Schneider T, Zeitz M, Marth T (2001). "Whipple's disease: new aspects in pathogenesis and diagnoses" (PDF). Acta Endoscopica. 31: 243–253. doi:10.1007/BF03020891. S2CID   30195122.
  12. ↑ Spornraft P, Fröschl M, Ring J, Meurer M, Goebel FD, Ziegler-Heitbrock HW, et al. (July 1988). "T4/T8 ratio and absolute T4 cell numbers in different clinical stages of Kaposi's sarcoma in AIDS" (PDF). The British Journal of Dermatology. 119 (1): 1–9. doi:10.1111/j.1365-2133.1988.tb07095.x. PMID   3261596. S2CID   29214452. Archived from the original (PDF) on 2011-06-11.
  13. ↑ De Flora S, Grassi C, Carati L (July 1997). "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment". The European Respiratory Journal. 10 (7): 1535–1541. doi: 10.1183/09031936.97.10071535 . PMID   9230243.

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