B-cell activating factor
Encyclopedia
B-cell activating factor (BAFF) also known as tumor necrosis factor ligand superfamily member 13B is a protein
that in humans is encoded by the TNFLSF13B gene
. BAFF is also known as B Lymphocyte Stimulator (BLyS) and TNF- and APOL-related leukocyte expressed ligand (TALL-1) and the Dendritic cell-derived TNF-like molecule (CD257 antigen; cluster of differentiation
257).
that belongs to the tumor necrosis factor
(TNF) ligand family. This cytokine is a ligand for receptors TNFRSF13B
/TACI, TNFRSF17
/BCMA, and TNFRSF13C
/BAFFR. This cytokine is expressed in B cell
lineage cells, and acts as a potent B cell activator. It has been also shown to play an important role in the proliferation and differentiation of B cells.
BAFF is a 285-amino acid long peptide glycoprotein
which undergoes glycosylation
at residue 124. It is expressed as transmembrane protein
on various cell types including monocyte
s, dendritic cell
s and bone marrow stromal cells. The transmembrane form can be cleaved from the membrane, generating a soluble protein fragment. BAFF is the natural ligand of three unusual tumor necrosis factor receptor
s named BAFF-R
, TACI
, and BCMA
, all of which have differing binding affinities for it. These receptors are expressed mainly on mature B lymphocytes (TACI is also found on a subset of T-cells and BCMA on plasma cell
s). TACI binds worst since its affinity is higher for a protein similar to BAFF, called a proliferation-inducing ligand (APRIL). BCMA displays an intermediate binding phenotype and will work with either BAFF or APRIL to varying degrees. Signaling through BAFF-R and BCMA stimulates B lymphocytes to undergo proliferation and to counter apoptosis
. All these ligands act as heterotrimers (i.e. three of the same molecule) interacting with heterotrimeric receptors, although BAFF has been known to be active as either a hetero- or homotrimer.
with TNFRSF13B
, TNFSF13
and TNFRSF17
.
(Benlysta) is a monoclonal antibody developed by Human Genome Sciences
and GlaxoSmithKline
, with significant discovery input by Cambridge Antibody Technology
, which specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS) and is in clinical trials for treatment of
Systemic lupus erythematosus
and other auto-immune diseases..
Blisibimod
, a fusion protein
inhibitor of BAFF, is in development by Anthera Pharmaceuticals
, also primarily for the treatment of systemic lupus erythematosus.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TNFLSF13B gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. BAFF is also known as B Lymphocyte Stimulator (BLyS) and TNF- and APOL-related leukocyte expressed ligand (TALL-1) and the Dendritic cell-derived TNF-like molecule (CD257 antigen; cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
257).
Structure and function
BAFF is a cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
that belongs to the tumor necrosis factor
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
(TNF) ligand family. This cytokine is a ligand for receptors TNFRSF13B
TNFRSF13B
Tumor necrosis factor receptor superfamily member 13B, also known as TNFRSF13B or more commonly as TACI, is a transmembrane receptor protein found predominantly on the surface of B cells, which are an important part of the immune system....
/TACI, TNFRSF17
TNFRSF17
-Interactions:TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B. A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.-Further reading:...
/BCMA, and TNFRSF13C
TNFRSF13C
Tumor necrosis factor receptor superfamily member 13C is a protein that in humans is encoded by the TNFRSF13C gene.-Further reading:...
/BAFFR. This cytokine is expressed in B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
lineage cells, and acts as a potent B cell activator. It has been also shown to play an important role in the proliferation and differentiation of B cells.
BAFF is a 285-amino acid long peptide glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
which undergoes glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
at residue 124. It is expressed as transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
on various cell types including monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s, dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s and bone marrow stromal cells. The transmembrane form can be cleaved from the membrane, generating a soluble protein fragment. BAFF is the natural ligand of three unusual tumor necrosis factor receptor
Tumor necrosis factor receptor
A tumor necrosis factor receptor , or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors . The receptor cooperates with an adaptor protein , which is important in determining the outcome of the response A tumor necrosis factor receptor (TNFR), or death receptor, is a...
s named BAFF-R
TNFRSF13C
Tumor necrosis factor receptor superfamily member 13C is a protein that in humans is encoded by the TNFRSF13C gene.-Further reading:...
, TACI
TNFRSF13B
Tumor necrosis factor receptor superfamily member 13B, also known as TNFRSF13B or more commonly as TACI, is a transmembrane receptor protein found predominantly on the surface of B cells, which are an important part of the immune system....
, and BCMA
TNFRSF17
-Interactions:TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B. A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.-Further reading:...
, all of which have differing binding affinities for it. These receptors are expressed mainly on mature B lymphocytes (TACI is also found on a subset of T-cells and BCMA on plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s). TACI binds worst since its affinity is higher for a protein similar to BAFF, called a proliferation-inducing ligand (APRIL). BCMA displays an intermediate binding phenotype and will work with either BAFF or APRIL to varying degrees. Signaling through BAFF-R and BCMA stimulates B lymphocytes to undergo proliferation and to counter apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. All these ligands act as heterotrimers (i.e. three of the same molecule) interacting with heterotrimeric receptors, although BAFF has been known to be active as either a hetero- or homotrimer.
Interactions
B-cell activating factor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TNFRSF13B
TNFRSF13B
Tumor necrosis factor receptor superfamily member 13B, also known as TNFRSF13B or more commonly as TACI, is a transmembrane receptor protein found predominantly on the surface of B cells, which are an important part of the immune system....
, TNFSF13
TNFSF13
Tumor necrosis factor ligand superfamily member 13 also known as a proliferation-inducing ligand is a protein that in humans is encoded by the TNFSF13 gene. TNFSF13 has also been designated CD256 .- Function :The protein encoded by this gene is a member of the tumor necrosis factor ligand ...
and TNFRSF17
TNFRSF17
-Interactions:TNFRSF17 has been shown to interact with the B-cell activating factor TNFSF13B. A conserved domain at the N-terminus, BCMA TALL-1 binding domain, is required for binding to the TNFSF13B.-Further reading:...
.
Clinical significance
BelimumabBelimumab
Belimumab is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator , also known as B cell activation factor of the TNF family...
(Benlysta) is a monoclonal antibody developed by Human Genome Sciences
Human Genome Sciences
Human Genome Sciences is a biopharmaceutical corporation founded in 1992. It uses the human DNA sequence to develop protein and antibody drugs. As of 2008, it has drugs under development to treat such diseases as hepatitis C, systemic lupus erythmatosis, anthrax disease, cancer, rheumatoid...
and GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
, with significant discovery input by Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
, which specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS) and is in clinical trials for treatment of
Systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
and other auto-immune diseases..
Blisibimod
Blisibimod
Blisibimod is a selective peptibody antagonist of B-cell activating factor , being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus...
, a fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
inhibitor of BAFF, is in development by Anthera Pharmaceuticals
Anthera Pharmaceuticals
Anthera Pharmaceuticals, Inc. is a pharmaceutical company that specializes in developing treatments for serious cardiovascular and autoimmune diseases...
, also primarily for the treatment of systemic lupus erythematosus.