Selftolerance

Self-tolerance is the ability of an organism’s immune system to distinguish self from non-self and to prevent immune responses against the body’s own tissues. It aims to preserve defense against pathogens while avoiding injury to host cells and organs.

Central tolerance occurs during the development of immune cells. In the thymus, developing T cells that strongly recognize self-antigens are deleted or diverted into regulatory lineages, reducing the chance of autoimmunity. In the bone marrow, developing B cells that react to self-antigens are edited, deleted, or rendered anergic. These processes limit autoreactive clones before they mature.

Peripheral tolerance acts on self-reactive cells that escape central mechanisms. It includes anergy, where T or B cells become functionally unresponsive if activation signals are insufficient; deletion through apoptosis; and suppression by regulatory T cells. Inhibitory signaling through immune checkpoints such as CTLA-4 and PD-1 also helps prevent inappropriate activation. Tolerance can be reinforced by ignorance or sequestration of hidden self-antigens and by clonal exhaustion in chronic stimulation contexts.

Breakdown of self-tolerance can lead to autoimmune diseases, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. Genetic susceptibility, environmental triggers, infections, tissue injury, and regulatory defects can compromise tolerance and reveal or enhance autoreactive responses. The gut microbiota and tissue-specific factors influence the establishment and maintenance of tolerance.

Understanding self-tolerance informs therapies in transplantation and autoimmunity, such as strategies to induce antigen-specific tolerance or expand regulatory T cells. Conversely, cancer immunotherapy often seeks to overcome tolerance by blocking inhibitory pathways, which can risk triggering autoimmunity if not carefully managed.