B-cell activating factor also known as tumor necrosis factor ligand superfamily member 13B is a protein that in humans is encoded by the TNFSF13B gene. BAFF is also known as B Lymphocyte Stimulator and TNF- and APOL-related leukocyte expressed ligand and the Dendritic cell-derived TNF-like molecule.
Structure and function
BAFF is a cytokine that belongs to the tumor necrosis factor ligand family. This cytokine is a ligand for receptors TNFRSF13B/TACI, TNFRSF17/BCMA, and TNFRSF13C/BAFF-R. 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 a membrane-bound type IItransmembrane protein on various cell types including monocytes, 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 tumor necrosis factor receptors named BAFF-R, TACI, and BCMA, all of which have differing binding affinities for it. These receptors are expressed mainly on mature B lymphocytes and their expression varies in dependence of B cell maturation. 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 a proliferation-inducing ligand. 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 homotrimers interacting with homotrimeric receptors, although BAFF has been known to be active as either a hetero- or homotrimer.
Interactions
B-cell activating factor has been shown to interact with TNFRSF13B, TNFSF13, TNFRSF13C, and TNFRSF17. Interaction between BAFF and BAFF-R activates classical and noncanonical NF-κBsignaling 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 a purification procedure.
Clinical significance
As an immunostimulant, BAFF 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 erythematosus, rheumatoid arthritis, and many other autoimmune diseases. Overexpression of BAFF also correlates with enhanced humoral immunity against malaria infection. Belimumab 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 and is in clinical trials for treatment of Systemic lupus erythematosus and other autoimmune diseases. BAFF has been found in renal transplant biopsies with acute rejection and correlate with appearance C4d. Increased levels of BAFF may initiate alloreactive B cell and T cell immunity, therefore may promote allograft rejection. Lower level of BAFF transcripts show a higher risk of producing donor-specific antibodies in the investigated patients. Donor-specific antibodies bind with high affinity to the vascular endothelium of graft and activate complement. This process result in neutrophils infiltration, hemorrhage, fibrin deposition and platelet aggregation. Targeting BAFF-R interactions may provide new therapeutic possibilities in transplantation. Blisibimod, a fusion protein inhibitor of BAFF, is in development by 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. In patients with celiac disease, serum BAFF levels are reduced after a gluten-free diet. The same reduction could be present in the recently defined “Non Celiac Gluten sensitivity” and they are both markers of non-IgE-mediated reactions in food-reactivity.
