The human immune system contains a protein called TNFSF13B, encoded by the TNFSF13B gene. This protein is more commonly known as B-cell activating factor, or BAFF. As a member of the tumor necrosis factor (TNF) ligand family, TNFSF13B is a type of cytokine that acts as a messenger between cells. It is expressed on the surface of various immune cells but can be cleaved and released to circulate in the blood.
The Role of TNFSF13B in the Immune System
In a healthy immune system, the primary function of TNFSF13B is to regulate the development and survival of white blood cells called B-cells. These cells are responsible for producing antibodies, the proteins that identify and neutralize foreign invaders like bacteria and viruses. TNFSF13B acts as a survival signal, binding to receptors on the surface of B-cells to guide their maturation and activation.
The production of TNFSF13B is handled by other immune cells, including monocytes, macrophages, and dendritic cells, which are among the first to encounter pathogens. When these cells detect a threat, they increase their production of TNFSF13B. This surge of the protein promotes the survival and proliferation of B-cells that can produce the specific antibodies needed to fight the infection.
Without sufficient TNFSF13B, most B-cells would not complete their development and undergo programmed cell death. By binding to three distinct receptors on B-cells—BAFF-R, TACI, and BCMA—TNFSF13B manages the B-cell population. This ensures the body has a ready supply of antibody producers to protect against potential infections.
Connection to Autoimmune Disorders
While TNFSF13B is necessary for a normal immune response, excessively high levels can disrupt the immune system’s balance. Too much TNFSF13B can lead to the survival of self-reactive B-cells. These cells mistakenly produce autoantibodies, which are antibodies that target the body’s own healthy tissues and organs instead of foreign pathogens.
Under normal conditions, the immune system has checkpoints to eliminate self-reactive B-cells. However, an overabundance of the TNFSF13B survival signal can allow these cells to bypass these checkpoints, mature, and proliferate. The resulting autoantibodies can cause widespread inflammation and damage, leading to autoimmune diseases.
This connection is well-documented in Systemic Lupus Erythematosus (SLE), a chronic autoimmune disease where the immune system attacks its own tissues. Many patients with lupus have elevated levels of TNFSF13B, which is believed to contribute to the disease’s progression. High levels of the protein are also implicated in other autoimmune conditions, such as Sjögren’s syndrome, which affects moisture-producing glands, and Rheumatoid Arthritis.
Link to Cancers
The survival-promoting function of TNFSF13B can also be exploited by cancerous cells. In certain cancers, especially those involving B-cells, malignant cells can use the protein to fuel their growth and survival. This mechanism allows cancer cells to multiply and resist therapies designed to eliminate them.
This link is most established in B-cell malignancies. In diseases like Multiple Myeloma, a cancer of plasma cells (a type of mature B-cell), high levels of TNFSF13B can enhance the survival of malignant cells in the bone marrow. Its presence is also associated with the progression of B-cell lymphomas, such as Diffuse Large B-cell Lymphoma, and Chronic Lymphocytic Leukemia (CLL).
In these contexts, cancer cells express high levels of the receptors that bind to TNFSF13B, making them sensitive to its survival signals. This interaction helps create a favorable microenvironment for the tumor, allowing it to thrive and evade defenses and medical treatments. Research has shown an association between certain genetic variations in the TNFSF13B gene and an increased risk for developing CLL.
Therapeutic Targeting of TNFSF13B
Given the role of excess TNFSF13B in driving certain diseases, it has become a target for therapeutic intervention. The strategy involves using drugs known as “BAFF inhibitors,” which are designed to block the protein’s activity. These medications work by binding to TNFSF13B, preventing it from interacting with its receptors on B-cells.
A prominent example of this approach is a drug called Belimumab. Belimumab is a monoclonal antibody engineered to identify and neutralize soluble TNFSF13B in the blood. By doing so, it reduces the survival signals reaching B-cells. This leads to a decrease in the overall number of B-cells, including the self-reactive ones.
This reduction in self-reactive B-cells helps to lower the levels of autoantibodies. Belimumab is approved for the treatment of Systemic Lupus Erythematosus and has shown success in managing the disease. The development of BAFF inhibitors represents a targeted approach to treating autoimmunity. Research continues to explore its potential for other autoimmune disorders and certain B-cell cancers.