TNFRSF13B - TNF receptor superfamily member 13B | Elisa - Clia - Antibody - Protein

Background

TNFRSF13B, also known as TACI (Transmembrane Activator and CAML Interactor), is a critical receptor in the immune system, specifically involved in B cell biology. TNFRSF13B belongs to the tumor necrosis factor receptor superfamily (TNFRSF) and plays an essential role in immune regulation by binding ligands such as APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor). These interactions are vital for B cell survival, proliferation, and differentiation, particularly in the context of generating long-lasting immune responses and maintaining immune homeostasis.

Mutations in TNFRSF13B have been linked to various immunodeficiency disorders, such as Common Variable Immunodeficiency (CVID) and IgA deficiency. These conditions are associated with impaired antibody production, resulting in increased susceptibility to infections and autoimmune complications. Due to its importance in regulating immune responses, TNFRSF13B is studied intensively as a therapeutic target for both immunodeficiency disorders and autoimmune diseases where B cell activity is dysregulated.

Protein Structure

The structure of TNFRSF13B includes distinct domains that enable it to interact with its ligands and initiate intracellular signaling pathways essential for B cell function:

Extracellular Domain (ECD):

• The extracellular domain of TNFRSF13B contains two cysteine-rich domains (CRDs). These CRDs are essential for binding to its ligands, BAFF and APRIL. The first CRD (CRD1) and the second CRD (CRD2) contribute to the binding specificity and affinity of TNFRSF13B for BAFF and APRIL, ensuring effective signaling in response to these ligands.
• The ECD structure allows TNFRSF13B to be involved in ligand-dependent and ligand-independent signaling, where interactions with BAFF and APRIL trigger downstream signaling, but there is also evidence of constitutive activity even without ligand binding.

Transmembrane Domain (TMD):

• TNFRSF13B has a single transmembrane domain that anchors it in the cell membrane. This domain stabilizes TNFRSF13B, allowing its extracellular domain to interact with circulating ligands and its intracellular domain to interact with adaptor proteins for signal transduction.

Intracellular Domain (ICD):

• The intracellular domain of TNFRSF13B interacts with various adaptor proteins to initiate downstream signaling. One notable interaction is with CAML (calcium-modulator and cyclophilin ligand), a protein that plays a role in calcium signaling and the immune response.
• Unlike some other TNF receptors, TNFRSF13B does not have a death domain, meaning it typically does not induce apoptosis. Instead, it promotes cell survival and activation, particularly in B cells.
• Signaling pathways downstream of TNFRSF13B activation include NF-κB, MAPK, and PI3K/AKT pathways, which are integral to B cell survival, differentiation, and immune function.

The specific structure of TNFRSF13B, especially its unique CRDs, allows it to serve as a dual receptor for both APRIL and BAFF, mediating distinct but overlapping functions in B cell development and immune response.

Classification and Subtypes

TNFRSF13B is classified within the tumor necrosis factor receptor superfamily (TNFRSF), which consists of receptors that generally regulate immune responses, inflammation, and cell survival. Within this family, TNFRSF13B is closely related to TNFRSF13C (BAFF-R) and TNFRSF17 (BCMA), both of which also bind to BAFF and APRIL to mediate B cell survival and differentiation.

There are no known structural subtypes of TNFRSF13B; however, genetic variants in TNFRSF13B result in functional diversity that affects B cell responses and antibody production. These variants are particularly relevant in clinical settings, as they can lead to altered immune function and predispose individuals to immunodeficiency or autoimmunity.

Function and Biological Significance

B Cell Survival and Differentiation:

• TNFRSF13B signaling is crucial for the maturation and survival of B cells. By binding to BAFF and APRIL, TNFRSF13B helps B cells survive through activation of the NF-κB pathway, leading to the expression of genes that prevent apoptosis.
• TNFRSF13B also influences class-switch recombination (CSR) in B cells, a process essential for the generation of diverse antibody classes. This function is critical for the adaptive immune system to produce antibodies of various isotypes in response to infections.

Regulation of Immune Tolerance:

• TNFRSF13B signaling contributes to immune tolerance, helping to prevent autoimmune responses. By supporting the development of regulatory B cells, TNFRSF13B aids in maintaining immune balance, reducing the risk of B cells attacking self-antigens and causing autoimmune diseases.

Interaction with APRIL and BAFF:

• TNFRSF13B’s interaction with BAFF and APRIL modulates B cell proliferation and antibody production. High levels of these ligands, often seen in autoimmune conditions, can overstimulate B cells, leading to excessive antibody production and potential autoimmunity.
• In normal immune responses, TNFRSF13B-mediated signaling enhances B cell responses to infection and allows for effective memory B cell formation, essential for long-term immunity.

Role in Inflammatory Conditions:

• Beyond its function in B cell survival, TNFRSF13B signaling has been implicated in inflammation. Overexpression or excessive activation of TNFRSF13B can amplify inflammatory responses, which is observed in certain autoimmune conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Clinical Issues

Immunodeficiency Disorders:

• Mutations in TNFRSF13B are associated with Common Variable Immunodeficiency (CVID) and IgA deficiency, two conditions characterized by impaired antibody production and increased susceptibility to infections.
• CVID, one of the most common primary immunodeficiencies, often involves mutations in the TNFRSF13B gene that lead to altered receptor function, resulting in insufficient B cell activation and reduced immunoglobulin levels.
• In patients with IgA deficiency, mutations in TNFRSF13B may contribute to a failure in the differentiation of B cells into IgA-producing plasma cells, affecting mucosal immunity and leading to recurrent respiratory and gastrointestinal infections.

Autoimmune Diseases:

• Dysregulation of TNFRSF13B signaling is implicated in autoimmune diseases, where excessive B cell activation contributes to the production of autoantibodies. Elevated levels of BAFF and APRIL, along with overactive TNFRSF13B signaling, are observed in conditions like SLE, RA, and multiple sclerosis (MS).
• Targeting TNFRSF13B or its ligands is a therapeutic strategy in autoimmune diseases, aiming to reduce pathological B cell activation and autoantibody production.

Cancer:

• Some studies suggest a role for TNFRSF13B in B cell lymphomas, particularly in cancers involving dysregulated B cell activity. Overexpression of TNFRSF13B and its ligands can contribute to the survival and proliferation of malignant B cells.
• Therapeutic inhibition of TNFRSF13B signaling is being investigated as a potential approach to reduce B cell activity in cancers where B cell proliferation is a hallmark.

Therapeutic Targeting:

• In both immunodeficiency and autoimmune contexts, targeting the TACI pathway through biologics, small molecules, or monoclonal antibodies offers a means to either enhance or suppress B cell activity. Drugs like belimumab, which inhibits BAFF, have shown efficacy in reducing symptoms in autoimmune diseases like SLE by decreasing B cell survival and activity.

Summary

TNFRSF13B (TACI) is a TNF receptor superfamily member with a unique role in B cell biology. It is essential for B cell survival, differentiation, and the regulation of immune tolerance. Structurally, TNFRSF13B consists of two cysteine-rich extracellular domains, a transmembrane domain, and an intracellular domain that facilitates signaling through pathways like NF-κB and MAPK upon ligand binding.

Functionally, TNFRSF13B interacts with BAFF and APRIL to modulate B cell responses, making it crucial for antibody production and immune balance. Dysregulation of TNFRSF13B is associated with both immunodeficiency, such as CVID and IgA deficiency, and autoimmunity, seen in diseases like SLE and RA, due to altered B cell activity. TNFRSF13B is also being explored as a target in B cell cancers, where excessive survival signaling can drive malignancy.

In summary, TNFRSF13B’s role in immune regulation and its implications in a range of clinical conditions underscore its importance in B cell biology and its potential as a therapeutic target. Effective modulation of TNFRSF13B signaling could help manage immune-related disorders by either enhancing B cell function in immunodeficiencies or suppressing it in autoimmune diseases and certain cancers.