The immune system must differentiate between harmless substances and potentially dangerous invaders. Antigens are molecules that can trigger an immune response, but not all antigens are foreign. The body produces its own antigens, known as “self-antigens,” which are normal components of cells and tissues. The immune system’s ability to recognize and tolerate these self-antigens is fundamental for maintaining health.
Defining Self Antigens
Self-antigens are molecules naturally found on or within the body’s own cells and tissues. These molecules, which can be proteins or carbohydrates, serve as unique identifiers for an individual’s cells. They are distinct from foreign antigens, which originate from external sources like bacteria, viruses, fungi, or toxins. All nucleated cells in the body express self-antigens, and these can vary between different cell types and individuals.
An important group of self-antigens are presented by Major Histocompatibility Complex (MHC) molecules, also known as Human Leukocyte Antigens (HLA). These glycoproteins are located on the surface of cells and distinguish self from non-self. MHC molecules bind to small protein fragments, called peptides, from within the cell and display them on the cell surface for immune surveillance. This presentation allows immune cells to inspect the cell’s internal contents.
MHC molecules are categorized into two main classes. MHC class I molecules are present on most nucleated cells, presenting peptides derived from proteins synthesized inside the cell. This allows the immune system to confirm the cell is healthy. MHC class II molecules are primarily found on specialized immune cells called antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells. These cells present peptides from external proteins they have engulfed, which activates certain immune responses.
How the Immune System Distinguishes Self
The immune system learns not to attack the body’s own tissues through a process known as immune tolerance. This tolerance is established through two main phases: central tolerance and peripheral tolerance. These processes ensure self-reactive immune cells are either eliminated or controlled before they can cause harm.
Central tolerance occurs during the development of immune cells in primary lymphoid organs. T cells undergo selection in the thymus, while B cells mature in the bone marrow. During this “education,” developing lymphocytes that react to self-antigens are eliminated through clonal deletion. This negative selection prevents potentially harmful self-reactive cells from reaching maturity and entering circulation.
Some self-reactive immune cells may still escape into the peripheral circulation. Peripheral tolerance mechanisms act as a secondary line of defense in various tissues and organs, including the spleen and lymph nodes. These mechanisms include anergy, where self-reactive immune cells become inactive upon encountering self-antigens without the necessary co-stimulation. Another mechanism involves regulatory T cells, which actively suppress the activation and function of self-reactive immune cells. These processes allow the immune system to protect against pathogens while avoiding attacks on healthy cells.
When Self-Recognition Fails
When immune tolerance is disrupted, the immune system can mistakenly identify self-antigens as foreign, leading to an attack on the body’s own tissues. This malfunction is termed autoimmunity, resulting in autoimmune diseases. The reasons for this breakdown are complex and involve a combination of factors.
Genetic predisposition plays a role, as certain genetic variations can increase susceptibility to autoimmune conditions. Environmental triggers are also implicated, with infections, exposure to toxins, or dietary factors potentially initiating or exacerbating an autoimmune response. One proposed mechanism is molecular mimicry, where a foreign antigen shares structural similarities with a self-antigen. This can lead the immune system to mistakenly target the self-antigen after mounting a response against the pathogen.
Another mechanism is bystander activation, where an infection or tissue damage causes inflammation. This leads to the release of self-antigens and activates immune cells in a non-specific manner. This inflammatory environment can then trigger a response against self-antigens that would normally be ignored. Viral persistence, where a virus remains in the body, can also contribute to autoimmunity by continuously exposing the immune system to viral antigens, potentially leading to chronic immune activation and subsequent self-targeting.
Common Autoimmune Conditions
Autoimmune diseases manifest in diverse ways, depending on which self-antigens or tissues the immune system mistakenly targets. These conditions can range from organ-specific to systemic, affecting multiple parts of the body. Understanding the specific targets aids in diagnosis and management.
Type 1 Diabetes
Type 1 Diabetes is an autoimmune condition where the immune system attacks and destroys the insulin-producing beta cells in the pancreas. Targeted self-antigens include insulin, glutamic acid decarboxylase (GAD65), insulinoma-associated antigen-2 (IA-2), and zinc transporter 8 (ZnT8). This destruction results in the body’s inability to produce sufficient insulin, leading to high blood sugar levels.
Rheumatoid Arthritis (RA)
Rheumatoid Arthritis (RA) involves the immune system attacking the lining of the joints, the synovium, causing inflammation, pain, and joint damage. Common targets include citrullinated proteins, such as vimentin, α-enolase, and fibrinogen, which are modified self-proteins the immune system recognizes as foreign. Antibodies against these modified proteins, known as anti-citrullinated protein antibodies (ACPAs), are a hallmark of the disease.
Multiple Sclerosis (MS)
Multiple Sclerosis (MS) is characterized by the immune system attacking the myelin sheath, the protective covering around nerve fibers in the brain and spinal cord. This damage disrupts nerve communication, leading to neurological symptoms. Self-antigens targeted in MS include myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP). Activated T cells, particularly CD4+ T cells, play a role in this process.
Systemic Lupus Erythematosus (SLE)
Systemic Lupus Erythematosus (SLE), commonly known as lupus, is a systemic autoimmune disease that can affect various organs, including the skin, joints, kidneys, and brain. In lupus, the immune system produces autoantibodies against self-antigens, predominantly nuclear components like double-stranded DNA (dsDNA) and proteins associated with RNA, such as Sm/RNP, Ro/SS-A, and La/SS-B antigens. These autoantibodies form immune complexes that can deposit in tissues, triggering inflammation and damage.