What Are Autoreactive B Cells and Why Do They Matter?

B cells are a component of the immune system that produce antibodies to neutralize foreign invaders like bacteria and viruses. A feature of a healthy immune system is its ability to differentiate between the body’s own tissues (“self”) and external threats (“non-self”). Autoreactive B cells are a subset of immune cells that erroneously recognize the body’s own components as targets.

What Are Autoreactive B Cells?

Autoreactivity in B cells is a malfunction where their B cell receptors (BCRs) on the cell surface bind to the body’s own molecules, or self-antigens. This binding is the first step in a potential immune response against one’s own tissues. The process that creates diverse BCRs is random, making the accidental creation of self-recognizing receptors a frequent occurrence during B cell development in the bone marrow.

A high percentage of newly produced B cells, possibly up to 70% in humans, initially show some autoreactivity. These immature B cells carry BCRs that could target a wide array of self-antigens. The presence of these cells is not a sign of disease, as healthy immune systems have quality-control mechanisms to manage or eliminate them before they cause damage.

Normal Control of Autoreactive B Cells

The immune system uses a process known as B cell tolerance to prevent autoreactive B cells from causing harm. This begins early in a B cell’s life within the bone marrow during a phase called central tolerance. Here, newly formed B cells are tested for self-reactivity. If an immature B cell strongly binds to a self-antigen, it is eliminated through programmed cell death, a process called clonal deletion.

Some autoreactive B cells can undergo receptor editing, which allows the cell to modify its B cell receptor to create one that is not self-reactive. If this editing is successful, the cell continues its development; if not, it is deleted. These central tolerance mechanisms are the first line of defense against autoimmunity.

Autoreactive B cells that escape the bone marrow are subject to peripheral tolerance mechanisms in tissues like the spleen and lymph nodes. One mechanism is anergy, where the B cell is rendered functionally inactive but not killed. An anergic B cell persists but cannot be activated to produce antibodies. Other mechanisms include suppression by regulatory immune cells that inhibit the function of autoreactive cells.

When Autoreactive B Cells Cause Disease

Autoimmune diseases can arise when tolerance mechanisms fail, allowing autoreactive B cells to activate and multiply. Once activated, these cells contribute to disease by maturing into plasma cells that produce large quantities of autoantibodies. These autoantibodies circulate and bind to self-antigens in various tissues, leading to inflammation and damage.

Autoreactive B cells also worsen disease by acting as antigen-presenting cells (APCs), presenting self-antigens to T cells. This interaction can activate autoreactive T cells, which contribute to the attack on the body’s tissues and create a cycle of inflammation. These B cells can also release signaling molecules called cytokines that promote an inflammatory environment and cause further tissue injury.

In systemic lupus erythematosus (SLE), autoreactive B cells produce autoantibodies against components of the cell nucleus, damaging the skin, joints, and kidneys. In rheumatoid arthritis, they produce autoantibodies that target joint linings, causing chronic inflammation and destruction. In multiple sclerosis, autoreactive B cells are thought to contribute to the attack on the myelin sheath that protects nerve fibers.

Targeting Autoreactive B Cells in Medicine

The role of autoreactive B cells in autoimmune diseases has led to the development of targeted therapies. These treatments interfere with the harmful actions of these cells to reduce disease activity and are more specific than general immune-suppressing drugs. This specificity helps reduce side effects associated with broad immunosuppression.

One therapeutic strategy is B cell depletion, which uses monoclonal antibodies like rituximab. These antibodies are engineered to bind to a protein on the surface of B cells, marking them for destruction by the immune system. This reduces the number of both normal and autoreactive B cells, which can halt autoantibody production and disrupt the inflammatory cycle.

Other approaches focus on blocking the signals B cells need to survive and activate. By interfering with these pathways, these therapies prevent autoreactive B cells from maturing and producing autoantibodies. Such targeted treatments have shown success in managing conditions like rheumatoid arthritis and lupus, offering a more focused way to control the autoimmune response.