Biology:B-cell activating factor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

B-cell activating factor (BAFF) also known as tumor necrosis factor ligand superfamily member 13B and CD257 among other names, is a protein that in humans is encoded by the TNFSF13B gene.[1][2] 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.[3]

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[2] 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.[4] BAFF is the natural ligand of three nonconventional 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.[5] 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,[6] 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).[7]

Interactions

B-cell activating factor has been shown to interact with TNFRSF13B,[8][9] TNFSF13,[10] TNFRSF13C,[11][12] and TNFRSF17.[13][14]

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.[4]

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.[15]

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 erythematosus, rheumatoid arthritis, and many other autoimmune diseases.[16] Overexpression of BAFF also correlates with enhanced humoral immunity against malaria infection.[17]

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 autoimmune diseases.[18]

BAFF has been found in renal transplant biopsies with acute rejection and correlate with appearance C4d.[19] Increased levels of BAFF may initiate alloreactive 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.[20] 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.[21]

BAFF may also be a new mediator of food-related inflammation.[22] 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.[23] In patients with celiac disease, serum BAFF levels are reduced after a gluten-free diet.[24] The same reduction could 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.[25][26]) BAFF is also a specific inducer of insulin resistance and can be a strong link between inflammation and diabetes or obesity.[27][28] 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) and they are both markers of non-IgE-mediated reactions in food-reactivity.[23]

References

  1. ↑ "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". Journal of Leukocyte Biology 65 (5): 680–3. May 1999. doi:10.1002/jlb.65.5.680. PMID 10331498. 
  2. ↑ 2.0 2.1 "BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth". The Journal of Experimental Medicine 189 (11): 1747–56. June 1999. doi:10.1084/jem.189.11.1747. PMID 10359578. 
  3. ↑ "Entrez Gene: tumor necrosis factor (ligand) superfamily". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10673. 
  4. ↑ 4.0 4.1 "Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors". Journal of Immunology 188 (1): 497–503. January 2012. doi:10.4049/jimmunol.1102321. PMID 22124120. 
  5. ↑ "BAFF and BAFF-R levels are associated with risk of long-term kidney graft dysfunction and development of donor-specific antibodies". American Journal of Transplantation 12 (10): 2754–62. October 2012. doi:10.1111/j.1600-6143.2012.04194.x. PMID 22883025. 
  6. ↑ "Structural basis of BLyS receptor recognition". Nature Structural Biology 9 (4): 288–92. April 2002. doi:10.1038/nsb769. PMID 11862220. 
  7. ↑ "BAFF, APRIL, TWE-PRIL: who's who?". Autoimmunity Reviews 7 (4): 267–71. February 2008. doi:10.1016/j.autrev.2007.05.002. PMID 18295728. 
  8. ↑ "Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity". Nature Immunology 1 (1): 37–41. July 2000. doi:10.1038/76889. PMID 10881172. 
  9. ↑ "TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation". The Journal of Experimental Medicine 192 (1): 137–43. July 2000. doi:10.1084/jem.192.1.137. PMID 10880535. 
  10. ↑ "BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases". Journal of Immunology 169 (8): 4314–21. October 2002. doi:10.4049/jimmunol.169.8.4314. PMID 12370363. 
  11. ↑ "BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF". Science 293 (5537): 2108–11. September 2001. doi:10.1126/science.1061965. PMID 11509692. Bibcode: 2001Sci...293.2108T. 
  12. ↑ "Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency". Current Biology 11 (19): 1547–52. October 2001. doi:10.1016/S0960-9822(01)00481-X. PMID 11591325. 
  13. ↑ "Ligand-receptor binding revealed by the TNF family member TALL-1". Nature 423 (6935): 49–56. May 2003. doi:10.1038/nature01543. PMID 12721620. Bibcode: 2003Natur.423...49L. 
  14. ↑ "B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1". Proceedings of the National Academy of Sciences of the United States of America 97 (16): 9156–61. August 2000. doi:10.1073/pnas.160213497. PMID 10908663. Bibcode: 2000PNAS...97.9156S. 
  15. ↑ "[The immunopotentiation of human B lymphocyte stimulator C-terminal peptide]". Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica 35 (12): 1128–32. December 2003. PMID 14673506. 
  16. ↑ "Overexpression of the Cytokine BAFF and Autoimmunity Risk". The New England Journal of Medicine 376 (17): 1615–1626. April 2017. doi:10.1056/nejmoa1610528. PMID 28445677. 
  17. ↑ "A BAFFling Association between Malaria Resistance and the Risk of Multiple Sclerosis". The New England Journal of Medicine 376 (17): 1680–1681. April 2017. doi:10.1056/nejme1700720. PMID 28445672. 
  18. ↑ "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial". Lancet 377 (9767): 721–31. February 2011. doi:10.1016/S0140-6736(10)61354-2. PMID 21296403. 
  19. ↑ "Elevated pretransplantation soluble BAFF is associated with an increased risk of acute antibody-mediated rejection". Transplantation 96 (4): 413–20. August 2013. doi:10.1097/TP.0b013e318298dd65. PMID 23842189. 
  20. ↑ "Mechanisms involved in antibody- and complement-mediated allograft rejection". Immunologic Research 47 (1–3): 25–44. July 2010. doi:10.1007/s12026-009-8136-3. PMID 20135240. 
  21. ↑ 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. http://clinicaltrials.gov/ct2/show/NCT01162681. 
  22. ↑ "Functional and clinical aspects of the B-cell-activating factor (BAFF): a narrative review". Scandinavian Journal of Immunology 73 (1): 1–7. January 2011. doi:10.1111/j.1365-3083.2010.02470.x. PMID 21128997. 
  23. ↑ 23.0 23.1 "Double outlet right ventricle and left-sided aorta. A previously undescribed association with cor triatriatum and double right ventricular chamber". Japanese Heart Journal 27 (1): 117–22. January 1986. doi:10.1186/2045-7022-3-S3-O5. PMID 3723786. 
  24. ↑ "Elevated B cell-activating factor of the tumour necrosis factor family in coeliac disease". Scandinavian Journal of Gastroenterology 42 (12): 1434–9. December 2007. doi:10.1080/00365520701452225. PMID 17852877. 
  25. ↑ "Spectrum of gluten-related disorders: consensus on new nomenclature and classification". BMC Medicine 10: 13. February 2012. doi:10.1186/1741-7015-10-13. PMID 22313950. 
  26. ↑ "Does gluten sensitivity in the absence of coeliac disease exist?". BMJ 345: e7907. November 2012. doi:10.1136/bmj.e7907. PMID 23204002. 
  27. ↑ "B cell activation factor (BAFF) is a novel adipokine that links obesity and inflammation". Experimental & Molecular Medicine 41 (3): 208–16. March 2009. doi:10.3858/emm.2009.41.3.024. PMID 19293640. 
  28. ↑ "B cell-activating factor controls the production of adipokines and induces insulin resistance". Obesity 19 (10): 1915–22. October 2011. doi:10.1038/oby.2011.165. PMID 21701571. 

Further reading

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