TNFSF13B - TNF superfamily member 13B |Elisa - Clia - Antibody - Protein

Background

TNFSF13B, commonly known as BAFF (B-cell activating factor), is a cytokine that belongs to the tumor necrosis factor (TNF) superfamily and is critical for B cell survival, maturation, and immune function. This ligand is primarily produced by myeloid cells, such as monocytes, macrophages, and dendritic cells, but can also be secreted by activated T cells. BAFF plays a pivotal role in maintaining peripheral B cell populations, supporting antibody production, and promoting immune tolerance. It interacts with specific receptors on B cells and related immune cells, including BAFF-R, TACI (Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor), and BCMA (B Cell Maturation Antigen), to initiate intracellular signaling pathways crucial for B cell homeostasis and function. Dysregulation of BAFF expression or receptor binding is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis, and rheumatoid arthritis.

Protein Structure

BAFF is a type II transmembrane protein initially synthesized as a precursor that is membrane-bound. Key structural aspects of TNFSF13B/BAFF include:

Intracellular Domain:

• The intracellular portion of BAFF is relatively short and anchors the protein to the cell membrane. This segment is not directly involved in signal transduction, as BAFF’s activity is largely attributed to its extracellular portion.

Transmembrane Domain:

• BAFF’s transmembrane domain is essential for the membrane-bound form of the protein and assists in localizing BAFF to the cell surface before proteolytic cleavage. This domain is pivotal for the protein’s initial cellular anchoring before it is released as an active soluble molecule.

Extracellular Domain:

• The extracellular domain of BAFF contains a TNF homology domain (THD), which allows it to form a homotrimer, a common structure among TNF ligands. This trimeric arrangement is critical for BAFF’s biological function and its high-affinity binding to receptors, which is necessary for effective downstream signaling.
• The THD also includes receptor-binding sites for BAFF-R, TACI, and BCMA, each of which mediates distinct functions related to B cell proliferation, differentiation, and survival.
• BAFF is processed and released into the extracellular space in a soluble form through cleavage by furin proteases, which results in an active, circulating cytokine that can bind to receptors on distant B cells. Both membrane-bound and soluble forms of BAFF are biologically active, although they may have varying impacts on immune cell responses.

Classification and Subtypes

BAFF, also referred to as TNFSF13B, is categorized as a member of the TNF superfamily and is closely related to APRIL (A Proliferation-Inducing Ligand), another TNF family ligand that shares structural and functional similarities with BAFF. Unlike APRIL, which predominantly binds to TACI and BCMA, BAFF also binds specifically to BAFF-R (BAFF receptor), which is unique to BAFF. This receptor specificity makes BAFF’s signaling pathway distinct, especially in supporting B cell maturation and immune responses.

Function and Biological Significance

BAFF has a range of essential functions within the immune system, particularly in the regulation of B cell physiology. Major functions include:

B Cell Survival and Maturation:

• BAFF is essential for the survival of immature and mature B cells. Through its interaction with BAFF-R, BAFF promotes anti-apoptotic signals that are crucial for B cell persistence in peripheral lymphoid organs, enabling the immune system to maintain a ready pool of B cells for pathogen defense.
• BAFF also supports the transition of B cells from immature to mature stages and plays a role in T cell-dependent and T cell-independent antibody responses.

Antibody Production and Immunoglobulin Class Switching:

• BAFF signaling aids in immunoglobulin (Ig) class switching, which is the process that enables B cells to produce antibodies of different classes, such as IgA and IgG. This mechanism is vital for effective immune responses to pathogens, as different classes of antibodies have specialized roles in immunity.

Immune Tolerance:

• By regulating the survival and selection of B cells, BAFF plays a role in establishing central and peripheral immune tolerance. BAFF signaling prevents the survival of autoreactive B cells in healthy individuals, thus maintaining immune tolerance and preventing autoimmunity. However, dysregulated BAFF levels can lead to an increased survival of autoreactive B cells, contributing to autoimmune disease.

Cooperation with APRIL:

• BAFF and APRIL have overlapping functions and can form heterotrimers that bind to shared receptors (TACI and BCMA). This interaction allows for a coordinated regulation of B cell homeostasis and enhances the ability of these cytokines to promote immune responses under inflammatory conditions.

Clinical Issues

The clinical significance of BAFF is evident in its association with various immune-related disorders, particularly autoimmune diseases and B-cell malignancies.

Autoimmune Diseases:

• Increased BAFF levels are observed in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjögren’s syndrome. Excessive BAFF enables the survival and persistence of autoreactive B cells, leading to the production of autoantibodies and chronic inflammation.
• Therapeutic agents that target BAFF, such as belimumab (a monoclonal antibody that binds to soluble BAFF), have been developed and are used to reduce disease severity in SLE and other autoimmune disorders. These therapies aim to decrease autoreactive B cell populations by inhibiting BAFF signaling.

B-Cell Malignancies:

• Elevated BAFF expression is also linked to certain B-cell malignancies, including multiple myeloma and chronic lymphocytic leukemia. BAFF promotes the survival and proliferation of malignant B cells, contributing to the progression of these cancers.
• Targeting BAFF in these malignancies could reduce tumor burden by limiting the growth and survival of cancerous B cells. Clinical trials continue to explore the efficacy of BAFF inhibitors in treating B-cell malignancies.

Immunodeficiencies:

• Insufficient BAFF signaling, often due to genetic mutations affecting BAFF or its receptors, can result in immunodeficiency. In these cases, reduced BAFF levels impair B cell survival, leading to diminished antibody production and increased susceptibility to infections. Such immunodeficiencies highlight the importance of balanced BAFF signaling in maintaining a functional immune system.

Transplantation and Allogeneic Reactions:

• BAFF has been implicated in graft-versus-host disease (GVHD) and other transplantation-related immune responses. By promoting B cell activity, elevated BAFF levels can exacerbate GVHD symptoms, underscoring the potential of BAFF inhibition as a therapeutic strategy to manage post-transplant immune complications.

Summary

TNFSF13B (BAFF) is a crucial member of the TNF superfamily that regulates B cell survival, maturation, and immune tolerance. Structurally, BAFF is a type II transmembrane protein with an extracellular TNF homology domain that facilitates trimerization and receptor binding. Through its interactions with BAFF-R, TACI, and BCMA, BAFF promotes B cell homeostasis, antibody production, and immune regulation. Dysregulation of BAFF expression or receptor function is implicated in several clinical conditions, including autoimmune diseases, B-cell malignancies, and immunodeficiencies. BAFF inhibitors, such as belimumab, offer therapeutic potential for autoimmune disorders by reducing autoreactive B cell populations and suppressing pathological immune responses.

Understanding BAFF’s role in immune homeostasis and disease progression is essential for developing targeted therapies in autoimmune diseases, cancers, and immune-related disorders. By modulating BAFF signaling, therapeutic strategies aim to restore immune balance, control inflammation, and mitigate symptoms in patients with BAFF-related diseases.