B-cell activating factor
|Tumor necrosis factor (ligand) superfamily, member 13b|
PDB rendering based on 1jh5.
|Symbols||; BAFF; BLYS; CD257; DTL; TALL-1; TALL1; THANK; TNFSF20; ZTNF4|
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 TNFSF13B 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).
Structure and function
BAFF is a cytokine that belongs to the tumor necrosis factor (TNF) 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 II transmembrane 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 (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 B lymphocytes and their expression varies in dependence of B cell maturation (TACI is also found on a subset of T-cells and BCMA on 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 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 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).
B-cell activating factor has been shown to interact with TNFRSF13B, TNFSF13 and TNFRSF17. Interaction between BAFF and BAFF-R activates classical and noncanonical 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.
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.
Human BLyS was expressed and purified in E. Coli. The BLyS protein in the engineered bacteria can be as rich as 50% to the bacteria’s total protein content and still retains activity after an easy purification procedure. Due to the ease of bacterial platform, the bacteria expressed BLyS will dramatically reduce the cost of BLyS as a potential pharmaceutical agent for immunodeficiency.
Excessive level of BAFF causes abnormally high antibody production, results in systemic lupus erythmatosis, rheumatoid arthritis, and many other autoimmune diseases.
Belimumab (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.
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 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 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.
- Shu HB, Hu WH, Johnson H (May 1999). "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". J. Leukoc. Biol. 65 (5): 680–3. PMID 10331498.
- Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J (June 1999). "BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth". J. Exp. Med. 189 (11): 1747–56. doi:10.1084/jem.189.11.1747. PMC 2193079. PMID 10359578.
- "Entrez Gene: tumor necrosis factor (ligand) superfamily".
- Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B et al. (2012). "Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors.". J Immunol 188 (1): 497–503. doi:10.4049/jimmunol.1102321. PMID 22124120.
- Thibault-Espitia A, Foucher Y, Danger R, Migone T, Pallier A, Castagnet S et al. (2012). "BAFF and BAFF-R levels are associated with risk of long-term kidney graft dysfunction and development of donor-specific antibodies.". Am J Transplant 12 (10): 2754–62. doi:10.1111/j.1600-6143.2012.04194.x. PMID 22883025.
- Oren DA, Li Y, Volovik Y, Morris TS, Dharia C, Das K, Galperina O, Gentz R, Arnold E (April 2002). "Structural basis of BLyS receptor recognition". Nat. Struct. Biol. 9 (4): 288–92. doi:10.1038/nsb769. PMID 11862220.
- Daridon C, Youinou P, Pers JO (February 2008). "BAFF, APRIL, TWE-PRIL: who's who?". Autoimmun Rev 7 (4): 267–71. doi:10.1016/j.autrev.2007.05.002. PMID 18295728.
- Wu Y, Bressette D, Carrell JA, Kaufman T, Feng P, Taylor K, Gan Y, Cho YH, Garcia AD, Gollatz E, Dimke D, LaFleur D, Migone TS, Nardelli B, Wei P, Ruben SM, Ullrich SJ, Olsen HS, Kanakaraj P, Moore PA, Baker KP (November 2000). "Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS". J. Biol. Chem. 275 (45): 35478–85. doi:10.1074/jbc.M005224200. PMID 10956646.
- Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M, Theill LE, Colombero A, Solovyev I, Lee F, McCabe S, Elliott R, Miner K, Hawkins N, Guo J, Stolina M, Yu G, Wang J, Delaney J, Meng SY, Boyle WJ, Hsu H (July 2000). "TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation". J. Exp. Med. 192 (1): 137–43. doi:10.1084/jem.192.1.137. PMC 1887716. PMID 10880535.
- Roschke V, Sosnovtseva S, Ward CD, Hong JS, Smith R, Albert V, Stohl W, Baker KP, Ullrich S, Nardelli B, Hilbert DM, Migone TS (October 2002). "BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases". J. Immunol. 169 (8): 4314–21. doi:10.4049/jimmunol.169.8.4314. PMID 12370363.
- Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, Pan CH, Martin WE, Murphy RC, Shu HB, Dai S, Zhang G (May 2003). "Ligand-receptor binding revealed by the TNF family member TALL-1". Nature 423 (6935): 49–56. doi:10.1038/nature01543. PMID 12721620.
- Shu HB, Johnson H (August 2000). "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9156–61. doi:10.1073/pnas.160213497. PMC 16838. PMID 10908663.
- Tian RY, Han W, Yu Y, Chen Y, Yu GS, Yang SL et al. (2003). "[The immunopotentiation of human B lymphocyte stimulator C-terminal peptide].". Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 35 (12): 1128–32. PMID 14673506.
- Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; for the BLISS-52 Study Group. (February 2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.". Lancet. 377 (9767): 721–431. doi:10.1016/S0140-6736(10)61354-2. PMID 21296403.
- Banham G, Prezzi D, Harford S, Taylor CJ, Hamer R, Higgins R et al. (2013). "Elevated Pretransplantation Soluble BAFF Is Associated With an Increased Risk of Acute Antibody-Mediated Rejection.". Transplantation 96 (4): 413–420. doi:10.1097/TP.0b013e318298dd65. PMID 23842189.
- Wasowska BA (2010). "Mechanisms involved in antibody- and complement-mediated allograft rejection.". Immunol Res 47 (1-3): 25–44. doi:10.1007/s12026-009-8136-3. PMC 2892186. PMID 20135240.
- ClinicalTrials.gov. "PEARL-SC Trial: A Study of the Efficacy, Safety, and Tolerability of A 623 Administration in Subjects With Systemic Lupus Erythematosus.". United States National Institute of Health. Retrieved 2011-07-15.
- Nardelli B, Moore PA, Li Y, Hilbert DM (2003). "B lymphocyte stimulator (BLyS): a therapeutic trichotomy for the treatment of B lymphocyte diseases.". Leuk. Lymphoma 43 (7): 1367–73. doi:10.1080/10428190290033297. PMID 12389615.
- Zhou T, Zhang J, Carter R, Kimberly R (2003). "BLyS and B cell autoimmunity.". Curr. Dir. Autoimmun. 6: 21–37. doi:10.1159/000066854. PMID 12408045.
- Stohl W (2005). "A therapeutic role for BLyS antagonists.". Lupus 13 (5): 317–22. doi:10.1191/0961203304lu1019oa. PMID 15230285.
- Quartuccio L, Fabris M, Ferraccioli G (2004). "[B lymphocyte stimulator (BLyS) and monocytes: possible role in autoimmune diseases with a particular reference to rheumatoid arthritis]". Reumatismo 56 (3): 143–6. doi:10.4081/reumatismo.2004.143. PMID 15470519.
- Sutherland AP, Mackay F, Mackay CR (2007). "Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas.". Pharmacol. Ther. 112 (3): 774–86. doi:10.1016/j.pharmthera.2006.06.002. PMID 16863659.
- Bossen C, Schneider P (2007). "BAFF, APRIL and their receptors: structure, function and signaling.". Semin. Immunol. 18 (5): 263–75. doi:10.1016/j.smim.2006.04.006. PMID 16914324.
- Brink R (2007). "Regulation of B cell self-tolerance by BAFF.". Semin. Immunol. 18 (5): 276–83. doi:10.1016/j.smim.2006.04.003. PMID 16916609.
- Tangye SG, Bryant VL, Cuss AK, Good KL (2007). "BAFF, APRIL and human B cell disorders.". Semin. Immunol. 18 (5): 305–17. doi:10.1016/j.smim.2006.04.004. PMID 16916610.
- Treml LS, Crowley JE, Cancro MP (2007). "BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells.". Semin. Immunol. 18 (5): 297–304. doi:10.1016/j.smim.2006.07.001. PMID 16919470.
- Woodland RT, Schmidt MR, Thompson CB (2007). "BLyS and B cell homeostasis.". Semin. Immunol. 18 (5): 318–26. doi:10.1016/j.smim.2006.06.001. PMID 16931037.
- Kalled SL (2007). "Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production.". Semin. Immunol. 18 (5): 290–6. doi:10.1016/j.smim.2006.06.002. PMID 16931038.
- Mackay F, Leung H (2007). "The role of the BAFF/APRIL system on T cell function.". Semin. Immunol. 18 (5): 284–9. doi:10.1016/j.smim.2006.04.005. PMID 16931039.
- Bosello S, Pers JO, Rochas C et al. (2007). "BAFF and rheumatic autoimmune disorders: implications for disease management and therapy.". International journal of immunopathology and pharmacology 20 (1): 1–8. PMID 17346422.
- Mukhopadhyay A, Ni J, Zhai Y et al. (1999). "Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase.". J. Biol. Chem. 274 (23): 15978–81. doi:10.1074/jbc.274.23.15978. PMID 10347144.
- Moore PA, Belvedere O, Orr A et al. (1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator.". Science 285 (5425): 260–3. doi:10.1126/science.285.5425.260. PMID 10398604.
- Tribouley C, Wallroth M, Chan V et al. (2000). "Characterization of a new member of the TNF family expressed on antigen presenting cells.". Biol. Chem. 380 (12): 1443–7. doi:10.1515/BC.1999.186. PMID 10661873.
- Gross JA, Johnston J, Mudri S et al. (2000). "TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.". Nature 404 (6781): 995–9. doi:10.1038/35010115. PMID 10801128.
- Shu HB, Johnson H (2000). "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1.". Proc. Natl. Acad. Sci. U.S.A. 97 (16): 9156–61. doi:10.1073/pnas.160213497. PMC 16838. PMID 10908663.