Anergy: Definition, Causes and Theory of Clonal Anergy from Induction of Immunology

It refers to the inability to mount a complete immune response against a target.

Self-targeting anergy functions as a self-tolerance mechanism to control self-reactive cells found in autoimmunity.

The clonal deletion in which lymphocytes are killed if they recognize an autoantigen during their maturation in the thymus gland or bone marrow is an important mechanism for the prevention of autoimmunity .

However, not all human autoantigens are expressed in the central lymphoid organs where lymphocytes develop. Therefore, an individual’s self-tolerance to antigens must also depend on mechanisms such as clonal anergy.

Theoretically, recognition of an autoantigen eliminates the proliferative capacity of autoreactive lymphocytes in the peripheral immune system. Another process, immunoregulation, uses regulatory T cells that weaken harmful or inappropriate lymphocyte responses.

Clonal T cell anergy is a proposed mechanism of immune self-tolerance in which T cells are functionally inactivated after prior stimulation.

The presentation of MHC class II restricted antigens by different cell types has been speculated to play a role in determining activation against anergy in responding T cells.

Human T cells express MHC class II upon activation and have been shown to exhibit high concentrations of degraded peptide antigen to autologous T cells resulting in clonal anergy.

Unlike clonal low-dose antigen T-cell anergy, which occurs in the absence of costimulation, T-cell anergy induced by human T-cell antigen presentation results in both primary proliferation and secondary unresponsiveness to antigen. antigenic stimulation in high doses.

In B-cell anergy, autoreactive B cells persist in the periphery yet remain insensitive to immunogen. Research results indicate that continued antigen binding and subsequent receptor signaling are essential for maintenance of anergy.

T cell anergy is induced when TCR stimulation “freezes” T cell responses until they receive a suitable subsequent antigenic signal from an antigen-presenting cell.

Such APC signals can rescue T cells from anergy, stimulating them to produce the lymphokines necessary for the growth of additional T cells.

During a productive immune response, CD4 + T cells respond to effective signals by producing interleukin 2 (IL-2) and proliferating.

Effective stimulating signals require both the ligation of TCRs with cognate antigens presented by MHC class II molecules on the surface of APC and activation of costimulatory receptors, such as CD28, that recognize ligands such as B7 proteins expressed on the surface of APC.

When T cells receive stimulus only TCR signals in the absence of compromised costimulatory receptors they enter a state of unresponsive anergy characterized by an ability to produce IL-2 or to proliferate upon re-stimulation.

Such anergic T cells show a deep block in the Ras / MAPK pathway that prevents the activation of the AP-1 (Fos / Jun) family of transcription factors.

GRAIL (gene related to anergy in lymphocytes) is an E3 ubiquitin ligase that is necessary for the induction of CD4 + T-cell anergy in vivo. It is positively regulated in naturally occurring (timically derived) CD4 + and CD25 + cells and anergized T cells.

It is believed that GRAIL could induce anergy through the ubiquitylation of membrane-associated targets required for T cell activation.

Two isoforms of otubain-1, together with the desubiquitylating enzyme USP8, have been shown to produce opposite effects on the expression and role of GRAIL in inducing anergy.

GRAIL is differentially expressed in naturally occurring and peripherally occurring CD25 + Treg cells, where it has been suggested that GRAIL expression is related to its functional “regulatory” activity.

Causes of anergy

There are many causes of anergy, however only a few will be named:

  • Food allergy.
  • Cutaneous candidiasis.
  • Coledocolitiasis.
  • Lack of iron.
  • You know.
  • Leukemia.
  • Massive trauma
  • Contact dermatitis.
  • Chronic lymphocytic leukemia.
  • Hodgkin’s disease.

The clonal anergy theory of immunology induction

It is established that immature cells of the B lymphocyte lineage can become immunologically tolerant of certain multivalent antigens both in vitro and in vivo.

We recently provided evidence that the stage in which the cell shows its greatest sensitivity to negative signaling was that of the first emergence of surface membrane immunoglobulin (mIg) receptors, that is, during pre-B cell transition. to B.

It is possible to introduce tolerogens into the developing tissues of the fetus by transplacental transfer (6) and thus guarantee interaction between lymphoid cells and tolerogen at the first appearance of specific antigen-binding receptors.

When fluorescein, human gamma globulin (FLU-HGG) was injected into mice at 14.5 days gestation, effective B cell tolerance was induced with doses much lower than those required to reduce the number of specific antigen-binding B cells. of influenza in the offspring.

In other words, B lymphocytes expressing a normal range of influenza-binding avidity appeared to emerge from the pre-B group of cells in normal numbers.

However, they were unable to give rise to anti-FLU antibody-forming cell (AFC) clones when challenged with an antigen-independent B-cell mitogen or T-lymphocyte.

This suggests that the interaction between the newly emerged anti-FLU receptors and the antigen had not prevented the subsequent development of a standard complement of mIg or directly led to the death of the anti-FLU B cell.

Rather, the cell, although still alive and capable of binding to the antigen, appeared to have received some signal that renders it unable to respond to activate the appropriate stimuli. We call this phenomenon clonal anergy.

This conclusion depended on a technology that enumerated and characterized B cells that bind to FLU.

By counting cells by specifically adhering to thin layers of hapten gelatin, and then analyzing the cells’ ability to bind fluorescein proteins using the fluorescence activated cell sorter (FACS).

We wish to strengthen the conclusion using an experimental design that avoids the complexities inherent in working with rare antigen-binding cells.

Consequently, we explored the properties of antibodies against the murine Ig / h chain as a “universal” B-cell tolerogen. It has long been known that injection of anti-A antibodies in early life can inhibit the emergence of B lymphocytes and produce an animal agammaglobulinemia.

On the contrary, it is sought to determine whether anti-M antibody concentrations are too low to prevent the development of a population of B cells with normal mlg receptors; however, it could functionally damage cells, creating a universally anergic B cell population.

We developed an in vitro strategy because the transplacental transfer of anti-p chain IgG would be inhibited by the large amount of IgM in the maternal circulation, leading to the formation of immune complexes; and intrafetal injections are accompanied by uncertainties related to leakage into the amniotic fluid.

In this paper, we document the effects on maturing B cells of very low concentrations of an anti-chain monoclonal antibody, E4, the product of a murine rat hybridoma, and the preparation and properties of which we have described.

Newborn bone marrow or spleen cells were fractionated on FACS to obtain mIg cells, which were cultured in the presence or absence of E4 for a period of 1 or 2 days, allowing many cells to mature into functional B lymphocytes in control cultures.

The cells were then analyzed on the FACS to determine their mIG density spectrum. The ability of these cells to divide or differentiate in AFC was also assessed using a cell-free filler.

This system in the presence of the two lipopolysaccharide mitogens from Escherichia coli (LPS) and dextran sulfate (DXS) allows a substantial proportion of individual B cells to proliferate and form a cluster of B cell explosions.

Studies showed that concentrations less than 1/1000 of those required to inhibit the appearance of mIg could prevent cells from dividing or forming antibodies, according to the theory of cell clonal anergy.

IL-2 signaling prevents T-cell anergy by inhibiting the expression of anergy-inducing genes.
T-cell responses are determined by the environment in which the antigen is found.

In the absence of adequate costimulation, anergization stimuli induce the activation of a specific gene expression program.

The proteins encoded by these genes impose a state of functional unresponsiveness on anergic T cells through the activation of different mechanisms including the damping of T cell receptor signaling and the direct inhibition of cytokine expression.

Anergy can be reversed by stimulating T cells in the presence of interleukin (IL-). Signaling through the IL-2 receptor has been shown to activate mTOR, which plays an important role in the integration of signals that determine the fate of T cells.

The mechanisms underlying the IL-2 dependent regulation of T cell tolerance are not yet fully elucidated.

In this study we demonstrate that IL-2 receptor signaling mediated through JAK3 and mTOR inhibits the expression of anergy-inducing genes independently of any effect on cell cycle progression.

Interestingly, we also demonstrated that this effect is likely due to changes in AP-1 activation levels induced by IL-2 receptor signaling in T cells.

Our data identify a mechanism that may explain how IL-2 can prevent or reverse the establishment of anergy in T cells and therefore help to understand how the cytokine environment may be determinant in shaping the outcome of cell responses. T.

It has also been shown that this effect is probably due to changes in the levels of AP-1 activation induced by IL-2 receptor signaling in T cells.

The data identify a mechanism that may explain how IL-2 can prevent or reverse the establishment of anergy in T cells and therefore help to understand how the cytokine environment may be determining in shaping the outcome of cell responses. T: intolerance or antigen activation is found.

It has also been shown that this effect is probably due to changes in the levels of AP-1 activation induced by IL-2 receptor signaling in T cells.

The data also identify a mechanism that may explain how IL-2 can prevent or reverse the establishment of anergy in T cells.

Therefore, help to understand how the cytokine environment can be determinant in shaping the outcome of T cell responses: antigen intolerance or activation is found.

Summary of Anergia Theory

Tolerance indicates that B lymphocytes that differentiate multivalent antigen in the transition from pre-B cells to B stage can receive and store a negative signal, rendering them anergic to subsequent triggering stimuli.

The theory was tested using an anti-IL chain monoclonal antibody, E4, as a tolerogenic model.

The fluorescence activated cell sorter is used to select cellular B cells in vitro. The presence of E4 at 21 µg / ml was required to prevent the development of normal numbers of B cells with full receptor status.

The subsequent ability of these B cells to respond in vitro to mitogens was a microculture system that allows insult B cells to proliferate and differentiate.

E4 concentrations far below those necessary to affect B cell generation In fact, 10-3 jig / ml of E4 markedly impaired both proliferation and antibody formation, and 10 ‘jig / ml, which had an effect on the Ig receptor development, abrogated functional ability.

Therefore, B cells are formed in the presence of E4 at 10 ‘jig / ml, although they possess the typical receptor status of B cells, they were functionally completely anergic. Exposure to E4 in evaluating the spontaneous death rate of newly formed B cells in vitro.

Whether the anergic cell also has a shortened live life is not known.