TNFSF13 - TNF superfamily member 13 |Elisa - Clia - Antibody - Protein

Background

TNFSF13, also known as APRIL (A Proliferation-Inducing Ligand), is a protein within the tumor necrosis factor (TNF) superfamily involved in immune system regulation, especially in B-cell survival, proliferation, and antibody production. This ligand, encoded by the TNFSF13 gene, binds to specific receptors on immune cells, including TACI (Transmembrane Activator and Calcium-Modulating Cyclophilin Ligand Interactor) and BCMA (B-Cell Maturation Antigen), to initiate signaling pathways that promote immune responses and sustain humoral immunity. APRIL, along with BAFF (B-cell Activating Factor), another TNF family ligand, is essential for adaptive immunity, supporting B cell maturation and differentiation.

APRIL is mainly expressed by myeloid cells, such as dendritic cells and macrophages, and some types of lymphoid cells. Beyond its role in immune cell survival, APRIL has clinical significance, as its overexpression has been associated with autoimmune diseases, certain cancers, and inflammatory disorders. The APRIL/BAFF signaling pathways represent crucial targets for immunotherapy, especially in treating autoimmune diseases and B-cell malignancies.

Protein Structure

APRIL, a type II transmembrane protein, undergoes proteolytic processing to release its soluble form, which exerts biological functions through receptor binding. Key structural aspects of TNFSF13/APRIL include:

Intracellular Domain:

• The intracellular segment of APRIL is relatively short and plays a minimal role in its signaling. This segment helps anchor APRIL to the cell membrane before it is cleaved to release the active extracellular portion.

Transmembrane Domain:

• APRIL’s transmembrane domain is essential for its membrane-bound form and assists in localizing the protein within the cell membrane until cleavage by furin proteases releases the soluble form.

Extracellular Domain:

• The extracellular region of APRIL contains a TNF homology domain (THD), which is characteristic of TNF family ligands and is crucial for APRIL’s biological function. This domain is responsible for APRIL’s trimerization and binding to receptors, including BCMA and TACI.
• Structurally, APRIL exists as a homotrimer, a common feature in TNF family ligands that facilitates stable binding to its receptors and effective signal transduction. Trimerization strengthens the ligand’s affinity for receptors, enhancing downstream signaling.
• APRIL’s extracellular domain also contains sites for N-linked glycosylation, a modification that improves its stability, prolongs its half-life in circulation, and supports effective receptor binding.

Classification and Subtypes

APRIL belongs to the TNF superfamily, specifically designated as TNFSF13. Within this family, APRIL is closely related to BAFF (TNFSF13B) due to shared structural features and overlapping functions in immune regulation. The TNFSF13 gene does not produce distinct subtypes; instead, APRIL exists in two functional forms:

Membrane-Bound APRIL:

• Initially produced as a type II transmembrane protein, APRIL is bound to the cell membrane on cells such as macrophages and dendritic cells. The membrane-bound form can serve as a precursor that, upon cleavage, releases the active, soluble form.

Soluble APRIL:

• Cleavage by proteases, including furin, releases the active form of APRIL into the extracellular space, where it can interact with receptors on B cells and other immune cells. This soluble form is crucial for APRIL’s role in supporting B cell survival and proliferation in the periphery.

Function and Biological Significance

APRIL is a pivotal factor in regulating B cell function and immune responses. Key roles of APRIL include:

B Cell Survival and Maturation:

• APRIL’s primary function is to promote B cell survival, especially within the germinal centers and peripheral immune tissues, where B cells undergo differentiation and antibody production. By binding to receptors such as TACI and BCMA, APRIL activates signaling pathways that inhibit apoptosis in B cells, promoting survival and aiding humoral immunity.
• APRIL plays an essential role in maintaining immune tolerance and in preventing premature apoptosis of B cells, which is particularly important in long-term immunity.

T Cell Interaction and Immune Regulation:

• In addition to B cells, APRIL influences T cell function, particularly in dendritic cell–mediated T cell activation. APRIL can modulate T cell responses indirectly by enhancing the antigen-presenting ability of dendritic cells, which can influence the strength and duration of T cell activation.

Immune Tolerance and Homeostasis:

• APRIL is involved in promoting immune tolerance by regulating the survival of autoreactive B cells. This function is important in preventing autoimmunity, as APRIL-mediated signals can help eliminate self-reactive B cells. Dysregulation of APRIL levels or receptor expression can disrupt immune tolerance, leading to autoimmune diseases.

Cancer Biology:

• Elevated APRIL expression has been noted in certain cancers, particularly B-cell malignancies. APRIL supports cancer cell survival by providing pro-survival signals that prevent apoptosis. Additionally, APRIL’s role in immune evasion by tumors, where it helps create an immunosuppressive environment, is an area of ongoing research.

Clinical Issues

Disruptions in APRIL signaling are associated with several clinical conditions:

Autoimmune Diseases:

• Elevated levels of APRIL are linked with autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis. In these conditions, excessive APRIL signaling contributes to the survival of autoreactive B cells, leading to autoantibody production and chronic inflammation.
• Therapeutic targeting of APRIL, often in combination with BAFF inhibition, is an approach used to reduce autoreactive B cell populations, aiming to alleviate symptoms in autoimmune patients. Monoclonal antibodies like atacicept, which targets both APRIL and BAFF, have been developed for treating autoimmune diseases.

B-Cell Malignancies:

• APRIL is overexpressed in various B-cell malignancies, including multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. By promoting B cell survival and proliferation, APRIL aids in the persistence and growth of these malignant cells. Targeting APRIL signaling in such cancers has emerged as a potential therapeutic strategy to limit tumor growth and improve patient outcomes.

Immune Deficiencies:

• Reduced APRIL levels or mutations affecting its receptors (TACI, BCMA) can lead to immune deficiencies, as B cell maturation and immunoglobulin production are compromised. Such immune deficiencies increase susceptibility to infections and impair vaccine responses, underscoring the importance of balanced APRIL signaling in healthy immune function.

Chronic Inflammatory Diseases:

• Chronic inflammatory diseases, such as inflammatory bowel disease (IBD), may also involve elevated APRIL levels, contributing to sustained inflammation. By supporting B cell survival in inflamed tissues, APRIL signaling can exacerbate inflammatory responses. Therapies targeting APRIL are being explored to control inflammation and prevent tissue damage in chronic inflammatory diseases.

Summary

TNFSF13 (APRIL) is a TNF superfamily ligand that plays a crucial role in B cell survival, immune regulation, and inflammation. Structurally, APRIL is a type II transmembrane protein with an extracellular TNF homology domain that facilitates trimerization and binding to receptors such as TACI and BCMA. This structure allows APRIL to support B cell maturation, regulate immune responses, and maintain immune tolerance, both as a membrane-bound and soluble protein. APRIL’s involvement in immune homeostasis and tolerance highlights its significance in humoral immunity.

Clinically, APRIL is implicated in autoimmune diseases, B-cell malignancies, immune deficiencies, and chronic inflammatory diseases. Its role in autoimmune pathogenesis, where it supports autoreactive B cells, makes it a target for therapeutic intervention. Monoclonal antibodies and APRIL-BAFF inhibitors are being studied and used in autoimmune disease and cancer treatments to control pathological B cell survival and proliferation.

The importance of APRIL in immune regulation and disease underscores its relevance in immunotherapy. Understanding APRIL’s role in both physiological and pathological processes can aid in the development of therapies for autoimmune diseases, B cell malignancies, and chronic inflammatory conditions. Targeting APRIL signaling has potential not only for managing immune disorders but also for enhancing immune responses where B cell support is beneficial.