B-cell activating factor

B-cell activating factor (BAFF) also known as tumor necrosis factor ligand superfamily member 13B is a is_associated_with::protein that in humans is encoded by the TNFSF13B is_associated_with::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; is_associated_with::cluster of differentiation 257).

Structure and function
BAFF is a is_associated_with::cytokine that belongs to the is_associated_with::tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptors is_associated_with::TNFRSF13B/TACI, is_associated_with::TNFRSF17/BCMA, and is_associated_with::TNFRSF13C/BAFF-R. This cytokine is expressed in is_associated_with::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 is_associated_with::glycoprotein which undergoes is_associated_with::glycosylation at residue 124. It is expressed as a membrane-bound type II is_associated_with::transmembrane protein on various cell types including is_associated_with::monocytes, is_associated_with::dendritic cells and bone marrow stromal cells. The transmembrane form can be cleaved from the membrane, generating a soluble protein fragment. BAFF steady-state concentrations depend on B cells and also on the expression of BAFF-binding receptors. BAFF is the natural ligand of three unusual is_associated_with::tumor necrosis factor receptors named BAFF-R (BR3), TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), and BCMA (B-cell maturation antigen), all of which have differing binding affinities for it. These receptors are expressed mainly on mature is_associated_with::B lymphocytes and their expression varies in dependence of B cell maturation (TACI is also found on a subset of is_associated_with::T-cells and BCMA on is_associated_with::plasma cells). BAFF-R is involved in the positive regulation during B cell development. TACI binds worst since its affinity is higher for a protein similar to BAFF, called is_associated_with::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 is_associated_with::apoptosis. All these ligands act as homotrimers (i.e. three of the same molecule) interacting with homotrimeric receptors, although BAFF has been known to be active as either a hetero- or homotrimer (can aggregate into 60-mer depending on the primary structure of the protein).

Interactions
B-cell activating factor has been shown to interact with is_associated_with::TNFRSF13B, is_associated_with::TNFSF13 and is_associated_with::TNFRSF17.

Interaction between BAFF and BAFF-R activates classical and noncanonical is_associated_with::NF-κB signaling pathways. This interaction triggers signals essential for the formation and maintenance of B cell, thus it is important for a B-cell survival.

Recombinant production
Human BLyS has been expressed and purified in E. Coli. The BLyS protein in the engineered bacteria can be as much as 50% to the bacteria’s total protein content and still retains activity after an purification procedure.

Clinical significance
As an immunostimulant, BAFF (BLyS, TALL-1) is necessary for maintaining normal immunity. Inadequate level of BAFF will fail to activate B cells to produce enough immunoglobulin and will lead to immunodeficiency.

Excessive level of BAFF causes abnormally high antibody production, results in systemic lupus erythmatosis, rheumatoid arthritis, and many other autoimmune diseases.

is_associated_with::Belimumab (Benlysta) is a is_associated_with::monoclonal antibody developed by is_associated_with::Human Genome Sciences and is_associated_with::GlaxoSmithKline, with significant discovery input by is_associated_with::Cambridge Antibody Technology, which specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS) and is in clinical trials for treatment of is_associated_with::Systemic lupus erythematosus and other auto-immune diseases.

BAFF has been found in renal transplant biopsies with acute rejection and correlate with appearance C4d. Increased levels of BAFF may initiate aloreactive B cell and is_associated_with::T cell immunity, therefore may promote allograft rejection. Lower level of BAFF transcripts (or a higher level of soluble BAFF) show a higher risk of producing donor-specific antibodies in the investigated patients. Donor-specific antibodies bind with high affinity to the vascular is_associated_with::endothelium of graft and activate complement. This process result in neutrophils infiltration, hemorrhage, fibrin deposition and is_associated_with::platelet aggregation. Targeting BAFF-R interactions may provide new therapeutic possibilities in transplantation.

is_associated_with::Blisibimod, a is_associated_with::fusion protein inhibitor of BAFF, is in development by is_associated_with::Anthera Pharmaceuticals, also primarily for the treatment of systemic lupus erythematosus.

BAFF may also be a new mediator of food-related inflammation. Higher levels of BAFF are present in non-atopic compared with atopic patients, and there is not any correlation between BAFF and IgE, suggesting that BAFF might be particularly involved in non-IgE-mediated reactions. BAFF is one of the most important cytokines involves in the modulation of the immune system and is deeply connected with food and nutrition; it is also produced by cells of bowel mucosa when some foods react with the innate immunity and determine inflammation. This fact is easy to understand, because BAFF had been first studied in patients with inflammatory bowel disease. Moreover, in patients with celiac disease, serum BAFF levels are reduced after a gluten-free diet. The same reduction can be present in the recently defined “Non Celiac Gluten sensitivity” (a reaction to gluten which provokes almost the same symptoms of celiac disease and could involve up to 20% of apparently healthy individuals. The symptoms connected with this kind of food induced inflammatory phenomena, are often indistinguishable from symptoms of celiac disease. BAFF is also a specific inducer of insulin resistance and can be a strong link between inflammation and diabetes or obesity.  BAFF gives the organism a sort of danger signal and usually, according to the evolutionary theories, every human being responds to danger activating thrifty genes in order to store fat and to avoid starvation. BAFF shares many activities with PAF (Platelet Activating Factor) an they are both markers of non-IgE-mediated reactions in food-reactivity.