The immune system protects the body from outside threats like viruses and bacteria. Its ability to recognize and avoid attacking healthy tissues is a key aspect of this defense. This ability, known as immunological tolerance, prevents harmful self-directed responses. Central tolerance is the initial and most significant phase of this process, training developing immune cells within specialized organs. This ensures that only cells capable of distinguishing between the body’s own components and foreign invaders are allowed to mature and circulate.
T Cell Maturation in the Thymus
Immature T cells, originating from stem cells in the bone marrow, journey to the thymus, a specialized organ located in the chest, for maturation. This environment acts like a structured training ground where these developing cells, called thymocytes, undergo a series of tests. The objective is to produce T cells that can effectively recognize foreign threats presented by other cells, yet remain harmless to the body’s own tissues.
The first assessment is known as positive selection, which takes place in the thymic cortex. Thymocytes must demonstrate a moderate ability to bind to Major Histocompatibility Complex (MHC) molecules, displayed by cortical thymic epithelial cells. If a T cell’s receptor cannot bind to MHC molecules, it is considered non-functional and undergoes programmed cell death.
T cells that successfully engage with MHC molecules receive survival signals, indicating their potential usefulness in immune responses. This interaction ensures maturing T cells can recognize antigens presented by other cells. Without this capability, T cells cannot participate in immune defense.
After positive selection, surviving thymocytes migrate to the thymic medulla for the second, equally important test: negative selection. Here, T cells are exposed to a wide array of self-antigens, presented on MHC molecules by medullary thymic epithelial cells and dendritic cells. The purpose is to identify and eliminate T cells that react too strongly to these self-antigens.
If a T cell’s receptor binds with high affinity to a self-antigen, it signifies self-reactive potential. These self-reactive cells receive signals that trigger programmed cell death (apoptosis), removing them from the immune repertoire. This elimination process prevents the release of harmful T cells that could attack the body’s tissues.
Only T cells that successfully navigate both positive and negative selection, demonstrating appropriate MHC recognition without strong self-reactivity, exit the thymus. These T cells are released into the bloodstream, ready to patrol the body and respond to foreign pathogens without initiating an autoimmune attack.
B Cell Maturation in the Bone Marrow
Developing B cells, like T cells, undergo a careful selection process to prevent autoimmunity, but their maturation occurs primarily within the bone marrow. Immature B cells generate unique B cell receptors (BCRs) on their surface to recognize specific antigens. Before becoming fully functional, B cells must pass checkpoints to ensure they are not self-reactive.
One significant mechanism for eliminating self-reactive B cells is clonal deletion. If an immature B cell’s receptor strongly binds to a self-antigen present in the bone marrow, particularly a multivalent antigen, the cell receives signals to undergo programmed cell death. This ensures B cells with high affinity for the body’s components are removed before causing harm.
Receptor editing is a distinct mechanism for B cells, not seen in T cell maturation. This process provides a “second chance” for self-reactive B cells. If a B cell’s initial receptor is self-reactive, the cell can reactivate the machinery for rearranging its immunoglobulin genes. This allows the B cell to modify its light chain gene, attempting to create a new receptor with a different antigen specificity.
The B cell essentially tries to “edit” its receptor to become non-self-reactive. If the new receptor no longer binds strongly to self-antigens, the B cell is rescued from deletion and continues maturation. However, if successive attempts at receptor editing fail to produce a non-self-reactive receptor, or if no additional gene segments are available, the B cell is directed towards clonal deletion.
This combination of clonal deletion and receptor editing in the bone marrow ensures most B cells released into circulation are tolerant to self-antigens. While some self-reactive B cells might escape, these central tolerance mechanisms significantly reduce the risk of autoimmune responses mediated by antibodies.
The Function of the AIRE Gene
A specific challenge in T cell education is how the thymus screens developing T cells against the vast array of proteins found throughout the entire body, including those unique to organs like the pancreas or thyroid. The Autoimmune Regulator (AIRE) gene provides a solution to this logistical problem. AIRE is primarily expressed in medullary thymic epithelial cells (mTECs) within the thymus.
AIRE acts as a unique transcriptional regulator, compelling mTECs to express thousands of tissue-specific antigens (TSAs) or tissue-restricted antigens (TRAs) normally found only in peripheral organs. These include proteins from the liver, kidney, brain, and endocrine glands. This creates a diverse “library” of self-proteins within the thymus, allowing developing T cells to be exposed to a broad spectrum of the body’s molecular components.
By presenting these sequestered self-antigens, AIRE ensures self-reactive T cells are identified and eliminated during negative selection. This mechanism is fundamental for establishing robust central tolerance across a wide range of tissues. Mutations in the AIRE gene can compromise this process.
Individuals with AIRE gene mutations develop a rare but severe autoimmune syndrome called Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), also known as Autoimmune Polyglandular Syndrome Type 1 (APS-1). This condition is characterized by immune attacks on multiple endocrine glands, such as the parathyroid and adrenal glands, and often chronic candidiasis. This illustrates AIRE’s impact on preventing widespread autoimmunity.
Autoimmunity from Central Tolerance Failure
When the intricate processes of central tolerance fail, self-reactive immune cells can escape developmental checkpoints in the thymus or bone marrow. These T cells or B cells enter the circulation, potentially attacking the body’s healthy tissues. This breakdown in self-recognition is a primary cause of autoimmune diseases.
Once in the periphery, these self-reactive lymphocytes can encounter specific self-antigens in various organs. Upon recognition, they become activated and launch an immune response against these self-targets. The nature of the resulting autoimmune disease depends on which self-antigens are targeted and in which tissues the attack occurs.
For instance, if self-reactive T cells recognizing pancreatic beta cell proteins escape the thymus, they can travel to the pancreas. Their attack on these insulin-producing cells leads to Type 1 Diabetes, where the body no longer produces sufficient insulin. Similarly, if B cells producing antibodies against nerve-muscle junction components escape the bone marrow, they can cause Myasthenia Gravis.
In Myasthenia Gravis, these antibodies interfere with nerve-muscle communication, leading to muscle weakness and fatigue. The failure of central tolerance underscores the balance required for a functioning immune system, where the benefits of defense against pathogens must be weighed against the risk of self-destruction.