Immunological tolerance

Immunotolerance (from latin. tolerantia = endurance) is an acquired property of the immune system, which exclusively affects the adaptive (specific) immune system and which leads to a tolerance of the body's own epitopes, thus preventing autoaggressive mechanisms. Under certain circumstances, however, immunotolerance can also be generated towards foreign epitopes. It is assumed that immunotolerance plays an important role in the development and spread of tumor cells.

Note: Allergy, autoimmunology (see also autoimmune disease) or other specific false reactions of the acquired immunity is the "loss of tolerance" of the immune system to harmless or damaging foreign antigens or to endogenous epitopes (autoantigens) of the organism.

Central tolerance

• Central tolerance occurs during ontogeny in the central lymphoid organs. It persists throughout life. Here, T and B cells form an infinite number of receptor molecules independent of antigen contact and this in a complex random process.

Peripheral tolerance

• Peripheral tolerance affects mature, differentiated lymphocytes that have left the central lymphoid organs. Here, a clonal anergy to the antigen develops.

T cells: During the developmental process of T cells in the thymus, a large number of cytotoxic T cells with a wide variety of specificities are generated. These early T cells undergo a complex selection process that ends in apoptosis for many lymphocytes. Pre-T cell receptors are initially generated in the immature T cells, each of which assembles into a complex with CD3 surface molecules. In addition, the T cells express both CD4 and CD8 antigen. These double-positive cells survive only 3-4 days. Approximately 95% of these immature T cells are driven into programmed cell death (apoptosis). 5% of the cells are available to the organism as naive cytotoxic T cells. All T cells that bind to exogenous but not to endogenous epitopes expressed by dendritic cells or thymic epithelial cells are driven into apoptosis (negative selection). In this way, self-reactive T cells are eliminated, eventually resulting in a mature T cell repertoire that is matched to both the individual's MHC pattern and self-tolerance.

In peripheral tolerance, which involves differentiated T lymphocytes, naive CD8+ cytotoxic T cells are transformed into activated and thus fully functional cytotoxic T cells. This requires an antigen-specific interaction of the naive cytotoxic T cells with professional antigen-presenting cells (mostly mature dendritic cells). Prior to this, the antigens must be prepared and presented on specific endogenous receptors, the class I and class II protein complexes encoded by the major histocompatibility complex (MHC), on the cell surface. Thus prepared, free antigens can be actively presented by antigen-presenting cells (APC) (so-called MHC restriction) and recognized by cytotoxic T lymphocytes.

The recognition of infected or malignant cells by means of the highly specific T cell receptor also occurs via the binding sites of the MHC-I binding complex. After their immunological imprinting, cytotoxic T cells circulate through blood, lymph nodes, skin and other organs. Healthy, uninfected (non-antigenic) somatic cells present a variable mixture of diverse, cell-specific epitopes (self-peptides). This "epitope pattern" identifies them as "healthy" to the cells of the immune system.

With the help of the transcription factor AIRE (autoimmune regulator), the antigen-presenting cells also express genes that are actually only found in completely different organs. This effect is also known as promiscuous gene expression and serves to make the T cells tolerant to organ-specific expressed antigens of the body (Anderson M et al. 2011).

B cells: When B cells in the bone marrow recognize an autoantigen (polyvalent) with high affinity, they receive a signal that induces apoptosis (clonal deletion). B cells can sometimes escape this signal by synthesizing a new light receptor chain with an altered binding specificity (receptor editing). Overall, it is assumed that about 85% of newly formed B cells are discarded in the bone marrow and only 15% migrate to the periphery. The next selection and maturation process then takes place in the spleen, so that the number of potentially autoreactive B cells is reduced again. Ultimately, about 5 to 10% of the originally generated B cells form a pool of mature naive B lymphocytes. They can be stimulated by a suitable antigen under costimulatory action of Th cells and then differentiate into antibody-producing plasma cells as well as memory B cells.

Autoreactive antibodies: The occurrence of autoreactive antibodies is not uncommon even in healthy individuals. B cells that randomly synthesize autoreactive proteins are basically recognized as foreign by the immune system and eliminated. They are only tolerated if the appropriate T helper cells are missing, which would activate the autoantibody-producing B cells to proliferate and differentiate during the process of autoimmunity (autoaggression). In this case, B-cell tolerance may also arise as a consequence of T-cell tolerance.

Treg cells as controllers: Just as with B cells, sporadic self-reactive T cells also enter the periphery. In this case, peripheral tolerance mechanisms are now acting, leading to clonal deletion, anergy or immunological ignorance. In addition, regulatory T cells (Treg cells) take control of these self-reactive cells. Treg arise whenever T cells receive strong signals but just fail to induce apoptosis in the sense of negative selection.

Loss of tolerance

Various mechanisms and processes are involved in the loss of tolerance of B and especially T cells to autoantigens. Genetic and immunological factors, but also environmental factors play a role. There is increasing evidence that many autoreactive T cells have unusual binding properties for their MHC peptide ligands. Indeed, autoreactive T cells with unusual TCR topologies may escape thymic deletion if binding to the MHC/peptide complex is too imprecise to trigger apoptosis. This theory is supported by structural analyses of T cell receptors isolated from patients with multiple sclerosis and type 1 diabetes.

However, loss of tolerance in T cells can also occur as a result of infection. Various mechanisms have been described such as molecular mimicry. Apparently, certain viruses or bacteria are responsible for the fact that humans can develop an autoimmune disease after an infection. Thus, astonishing homologies are found between different short protein sequences of bacteria or viruses or the body's own cells. This is the case with the basic myelin protein, which has similar epitopes to the polymerase of the hepatitis B virus. In the case of an infection, virus-specific T cells are activated which recognise this homologous epitope and subsequently target the myelin sheaths of the nerve cells.

Hyposensitization to induce tolerance

Allergies in particular, but also some autoimmune diseases, can be treated by specific tolerance induction (e.g. by desensitization: repeated exposure to smallest doses of the allergen induces freedom from symptoms - or improvement). Also, in children with a disposition for peanut allergy, early and continuous contact with the allergen can prevent the (peanut) allergy. (LEAP study; Learning Early About Peanut Allergy).

A quite successful approach is the immunotolerance induction (ITI) in haemophilia patients who develop antibodies against factor VIII used for substitution. Patients receive up to 300 I.U. of factor VIII per kg body weight/day i.v. in order to eliminate the neutralizing antibodies in the long term.

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