21. Immunological tolerance

Tolerance is the act when the immune system does not act against a specific antigen. It happens all the time, because your immune system meets with antigens from your own body every second. However, some types of tolerance work by having the immune system never meet the antigen in the first place, as we will see. Unless you have a problem with your immune system, it should always tolerate self-antigens and never ever attack them. However, for some of us, that’s not the case. We separate tolerance into passive and active tolerance.

Passive tolerance

The “passive” in passive tolerance means that either no cells will recognize the antigen that is tolerated, or the response against it is stopped just after the recognition. Passive tolerance is further divided into two parts: the central and the peripheral tolerance.

The central tolerance is established by the negative selection of both T and B-cells. By killing off almost every single developing lymphocyte that would recognize self-antigens, we make sure that none or very few of the fully developed lymphocyte can recognize these antigens. This is accomplished by negative selection of both T and B-cells. T-cells are negatively selected in the thymus, but what about B-cells? Recall that B-cells develop in the bone marrow. The bone marrow has a steady blood flow, so the developing B-cells will be in contact with blood and all the antigens that can be found in it. If any of these developing B-cells recognize and bind any antigen found in the blood, they will be killed by apoptosis. This is the negative selection of B-cells in the bone marrow.

However, nothing is perfect and that counts for negative selection as well. It cannot eliminate all self-reacting lymphocytes. That’s why we also have a peripheral tolerance, to complement the central tolerance.

The peripheral tolerance involves keeping some antigens out of reach for the immune system, so that the lymphocytes cannot even meet the antigens in the first place. This is seen in the case of the eyeball and inside the blood-testis barrier created by the Sertoli cells in the testis. These parts of the body are totally separated from the immune system in every healthy person. If there would be physical damage to either the eye or the blood-testis barrier, immune cells could start entering these tissues, where they would start an immune reaction against them. This can cause blindness or infertility.

This figure shows how the anti-inflammatory environment (like the pancreatic islets) don’t induce APCs into expressing B7.

Another part of peripheral tolerance is stopping or killing T-cells that have recognized self-antigens before they can start an immune response against it. Treg cells that express CTLA-4 are present in all tissues and suppress the T-cells that would recognize self-antigens. Also recall that T-cells require co-stimulation by B7 proteins to be activated. In all tissues in the body where there is no current inflammation, the anti-inflammatory cytokines IL-4, IL-10 and TGFβ are present. When these cytokines are present in the tissue, no APCs will express the B7 proteins necessary to activate T-cells. When the TCR binds to the antigen without receiving co-stimulation from B7, the T-cell undergoes anergy, which means that the it does not start a reaction.

The anti-inflammatory cytokines present in tissues are also important in how the immune system doesn’t react against antigens in food or against bacteria in the gut. Most people don’t have an immune reaction against milk when drinking it, but everyone would have a severe immune reaction if they had milk injected into their arm! This is because the mucosa of the intestinal tract contains these anti-inflammatory cytokines, which prevents the immune system from reacting. These cytokines are not present in the subcutaneous tissue, for example.

If the antigen is present in the body in a high dose, APCs will kill T and B-cells that recognize self-antigens by the FAS-FASL interaction, causing them to undergo apoptosis. This is called deletion.

Active tolerance

The active tolerance has two parts – the anti-idiotype network and the natural immune system.

The anti-idiotype network was explained in a previous chapter.

The natural immune system is comprised of B1 CD5+ B-cells, γδ T cells, iγδ T cells, innate lymphoid cells (ILC), mucosal associated invariant T-cells (MAIT), intraepithelial lymphocytes (IEL) and invariant NKT cells (iNKT).

The B1 B-cells produce IgM (mostly) and IgG autoantibodies which can recognize several serum proteins, cell surface structures and intracellular structures that are naturally found in everyone. They may improve the tolerance by binding to these self-antigens and covering them so that the “normal” immune system cannot recognize them and react against them.