Systemic lupus erythematosus is an autoimmune disease where the immune system, designed to protect the body, mistakenly attacks its own healthy tissues. This can lead to widespread inflammation and damage in various parts of the body, including the joints, skin, kidneys, and brain. To understand how this process is driven, researchers are focusing on specific immune cells. A particular subset, age-associated B cells (ABCs), is gaining attention for its role in how lupus develops and progresses.
Defining Age-Associated B Cells (ABCs)
To understand age-associated B cells (ABCs), one must first recognize the function of B cells. These cells are a part of the immune system, primarily responsible for producing antibodies that identify and neutralize foreign invaders like bacteria and viruses. They also form the body’s immunological memory, allowing for a swift response to previously encountered pathogens.
This unique B cell subset was first identified as accumulating in older individuals, hence the name “age-associated.” However, their presence is not limited to aging; they are also found in greater numbers in individuals with chronic inflammatory conditions and autoimmune diseases like lupus. In patients with lupus, an increase in the number of these cells in the blood correlates with the severity of disease symptoms.
Unlike conventional B cells, ABCs are characterized by a unique set of proteins on their surface. An identifying marker is the expression of a transcription factor called T-bet, which is not found in most resting B cells. The expression of T-bet, along with surface markers like CD11c, distinguishes ABCs from other B cell populations.
The Role of ABCs in Lupus Pathogenesis
The accumulation of ABCs is a factor in the progression of lupus. These cells contribute to the disease through several mechanisms, acting as drivers of the autoimmune response. Their most direct impact is their capacity to become highly efficient producers of autoantibodies. These are harmful antibodies that attack the body’s own DNA and proteins, leading to tissue damage.
Beyond producing autoantibodies, ABCs perpetuate the cycle of inflammation that characterizes lupus. They are effective at presenting self-antigens—pieces of the body’s own proteins—to other immune cells called T cells. This interaction activates the T cells, which in turn release inflammatory signals that encourage more B cells to become ABCs. This creates a self-sustaining loop of immune activation that contributes to organ damage, especially in the kidneys, a condition known as lupus nephritis.
This dual function of producing autoantibodies and activating T cells makes ABCs problematic in lupus. Studies using mouse models of lupus have shown that these cells are direct contributors to the disease. When ABCs are genetically depleted in these models, the severity of the disease is reduced, underscoring their direct involvement in driving inflammatory processes.
Triggers and Formation of ABCs
The development of ABCs is driven by specific molecular triggers within the immune system. This process involves a family of immune sensors known as Toll-like receptors (TLRs). These receptors are designed to recognize molecular patterns associated with pathogens, but in lupus, certain TLRs, particularly TLR7 and TLR9, become improperly activated.
This activation occurs when TLRs are stimulated by the body’s own genetic material, such as self-DNA and RNA, which is more accessible during the cell damage seen in lupus. This stimulation drives conventional B cells to differentiate and acquire the characteristics of ABCs. This pathway is distinct from the standard activation route for B cells, which relies on signals from their B-cell receptor (BCR).
The differentiation into ABCs is further supported by signals from other immune cells. Cytokines, which are signaling proteins released by T cells—such as interferon-gamma (IFN-γ) and interleukin-21 (IL-21)—also promote the formation of these cells. This combination of TLR stimulation and cytokine signals programs naive B cells to become T-bet-expressing ABCs.
Therapeutic Targeting of ABCs
Given their direct role in driving lupus, ABCs have become a focus for the development of new, more precise therapies. Many existing treatments for lupus involve broad immunosuppressants, which can be effective but also compromise the patient’s ability to fight off infections. Targeting ABCs offers a more focused approach, aiming to disrupt the specific cellular machinery that causes the disease without disabling other parts of the immune system.
Researchers are exploring several strategies to eliminate or inhibit the function of ABCs. One approach involves developing drugs that block the T-bet transcription factor. Another strategy is to target surface markers uniquely expressed on ABCs, such as CD11c, to selectively deplete them. By focusing on these unique features, it is possible to remove the harmful cells while leaving beneficial, infection-fighting B cells intact.
This area of research is active and holds promise for a new generation of lupus treatments. While these targeted therapies are in developmental and testing phases, they represent a shift towards precision medicine for autoimmune diseases. The goal is to offer patients more effective treatments with fewer side effects by halting the specific cellular processes that lead to organ damage.