Self-tolerance is a process acquired during the development of T and B lymphocytes in the primary lymphoid organs (central tolerance) and in the periphery (peripheral tolerance), by elimination or inactivation of potentially self-reactive cell clones.1
Due to the dependence of B and Tc (cytotoxic) lymphocytes on Th (collaborators), it is considered that most autoimmune responses begin with the activation of autoreactive Th lymphocytes. The cause or specific cases that activate self-reactive T lymphocytes and trigger autoimmunity are not yet known, but all known data suggest that they are triggered by the action of an environmental factor acting on a genetically predisposed individual. It has been suggested that infections may be the most important environmental trigger. Infections do not result in a breakdown of central tolerance, but several mechanisms have been suggested by which they can break peripheral tolerance:1
- The structural similarity between microbial antigens and autoantigens (molecular mimicry) can lead to cross-reactions that damage one’s own antigens. In this case, the antibodies or T lymphocytes recognize, in addition to the antigens of the infectious agent, other antigens of the organism of similar structure.
- B lymphocytes capable of recognising their own antigen interact with it when it is associated with the bacteria that acts as a “carrier“, and can then receive help from Th lymphocytes.
- It has also been suggested that polyclonal activation by microbial superantigens of large numbers of T or B lymphocytes (some of them self-reactive) may be a mechanism of loss of tolerance.
- They can also release autoantigens sequestered in immunologically privileged sites through trauma or infection. For example, damage to the blood-brain barrier can bring central nervous system autoantigens into contact with lymphocytes, triggering autoimmunity.
- They can induce nonspecific activation of self-reactive T cells by cytokines (spectator effect) or expression of class II MHC molecules and/or co-stimulatory signals in the antigen-presenting cell, which will now specifically activate self-reactive T cells that it was previously unable to activate.
In the development of many, if not all, autoimmune pathologies there is, in addition to an environmental component (such as infections), an important genetic component.
However, these diseases are not transmitted as classical monogenic diseases. Most autoimmune diseases are polygenic, i.e. there are numerous susceptibility genes (actually a certain polymorphism of these genes) that act together to produce a given disease. These genes often present complex interactions, with low and incomplete penetration and non-Mendelian inheritance patterns. In addition, some polymorphisms may have a protective role in the disease. These allelic variants are normal in the population and by themselves do not determine whether or not an individual will develop the disease (they only increase or decrease the risk of suffering from them); only when they act together and there is also an environmental factor (probably infectious) will the disease develop. There is, therefore, a great genetic heterogeneity among patients who develop an autoimmune disease, which manifests itself as a great phenotypic variability among the different patients suffering from the same disease.1
The genes most strongly associated with most autoimmune diseases are those of certain HLA molecules, mainly class II, although there are also class I associations. This idea is not far-fetched at all, since not all HLA molecules will have the same ability to present autoantigen-derived peptides to T lymphocytes, nor will they be equally effective in developing an autoimmune response. In addition to HLA molecules, other genetic factors, some not directly related to the immune system, such as sex (usually more frequent in females than in males), are important in the development of autoimmune diseases.1
- Regueiro González J.R., López Larrea C., González Rodriguez S. y Martínez Naves E. Inmunología: Biología y patología del sistema inmunitario. 4ª edición. Editorial Médica Panamerica, 2010.