Immunological tolerance is the immune system’s ability to avoid attacking the body’s own healthy cells and tissues. It represents a state of unresponsiveness to substances that would normally trigger an immune response. This process ensures the immune system can distinguish between “self” components and foreign invaders like bacteria or viruses.
The Body’s Self-Recognition System
The immune system must defend against foreign pathogens while leaving the body’s own cells unharmed. Immune cells, such as B and T cells, develop a vast array of receptors capable of recognizing diverse molecules. This random generation of receptors means some immune cells could, by chance, react against the body’s own “self” molecules.
This diversity requires a system to prevent self-reactivity. Without mechanisms to identify and neutralize potentially harmful self-reactive cells, the immune system could mistakenly target and destroy healthy tissues. The immune system learns this distinction through a screening process.
How Tolerance is Established
The body establishes immunological tolerance through two main processes: central tolerance and peripheral tolerance. These mechanisms work in concert to eliminate or inactivate self-reactive immune cells. Central tolerance acts as the initial checkpoint, while peripheral tolerance provides a backup system for any self-reactive cells that escape the first line of defense.
Central Tolerance
Central tolerance occurs in the primary lymphoid organs where immune cells mature: the thymus for T cells and the bone marrow for B cells. During this stage, immature lymphocytes are “educated” to remove or inactivate cells that react strongly to self-antigens. This process is known as negative selection.
For T cells, negative selection in the thymus eliminates those whose T-cell receptors (TCRs) bind too strongly to self-peptides presented on major histocompatibility complex (MHC) molecules. Thymic epithelial cells display self-antigens to developing T cells, ensuring highly self-reactive cells undergo programmed cell death (apoptosis). Similarly, immature B cells in the bone marrow undergo negative selection if their B-cell receptors (BCRs) strongly recognize self-peptides. Such B cells are deleted through apoptosis or undergo “receptor editing” to develop a new, non-self-reactive BCR.
Peripheral Tolerance
Despite the rigor of central tolerance, some self-reactive T and B cells may escape into the peripheral tissues and lymph nodes. Peripheral tolerance mechanisms then act as a failsafe to prevent these mature lymphocytes from causing harm. These mechanisms ensure that any remaining self-reactive cells become functionally unresponsive or are eliminated.
One mechanism is anergy, a state of functional unresponsiveness induced when T cells encounter antigens without the necessary co-stimulatory signals normally present during an active immune response. Another mechanism is peripheral deletion, which involves the programmed cell death of self-reactive T cells that have escaped the thymus. Regulatory T cells (Tregs), a specialized subset of T cells, also play a significant role in peripheral tolerance by actively suppressing the activity of other immune cells that might target self-antigens.
When Tolerance Fails
When immunological tolerance breaks down, the immune system mistakenly identifies the body’s own tissues as foreign, leading to autoimmune diseases. The immune system then attacks healthy cells, tissues, or organs. Both genetic and environmental factors can contribute to this failure.
Examples include Type 1 Diabetes, where the immune system destroys insulin-producing cells in the pancreas, and Rheumatoid Arthritis, an inflammatory disorder primarily affecting the joints. Systemic Lupus Erythematosus (SLE) is another example, a multisystem disease affecting organs like the skin, kidneys, and joints. Infections can also trigger autoimmunity by activating self-reactive immune cells or through molecular mimicry, where microbial antigens resemble self-antigens.
Medical Applications of Tolerance
Understanding immunological tolerance has led to various medical applications aimed at manipulating the immune system. In organ transplantation, the immune system naturally recognizes the transplanted organ as foreign and attempts to reject it. Inducing tolerance, or suppressing the immune response, is important for transplant success. Researchers are exploring ways to reprogram the immune system to accept the new organ without lifelong, broad immunosuppression, which carries risks like increased susceptibility to infections and cancer.
Allergies represent an inappropriate immune response to otherwise harmless substances, such as pollen or peanuts. Allergen-specific immunotherapy, often called desensitization, aims to re-educate the immune system by gradually exposing the individual to increasing amounts of the allergen. This process helps induce tolerance, reducing allergic symptoms and potentially preventing new allergies or conditions like asthma.
In cancer immunotherapy, the challenge lies in breaking the tolerance the immune system sometimes develops towards cancer cells. Cancer cells can evade immune detection because they originate from the body’s own cells, making them appear as “self.” Therapies are being developed to overcome this tolerance, allowing the immune system to recognize and attack tumor cells. These strategies include therapeutic vaccines that supply tumor antigens or checkpoint blockade therapies that remove “brakes” on immune cell activation, enhancing the anti-tumor response.