B-cell activating factor explained

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.

Further reading

Notes and References

  1. Shu HB, Hu WH, Johnson H . 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 . 10331498 . 10.1002/jlb.65.5.680. 1498303 .
  2. 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 . 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 . 10359578 . 2193079 . 10.1084/jem.189.11.1747 .
  3. Web site: Entrez Gene: tumor necrosis factor (ligand) superfamily.
  4. Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H . 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 . 22124120 . 10.4049/jimmunol.1102321 . free .
  5. Thibault-Espitia A, Foucher Y, Danger R, Migone T, Pallier A, Castagnet S, G-Gueguen C, Devys A, C-Gautier A, Giral M, Soulillou JP, Brouard S . 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 . 22883025 . 10.1111/j.1600-6143.2012.04194.x . 29060390 . free .
  6. Oren DA, Li Y, Volovik Y, Morris TS, Dharia C, Das K, Galperina O, Gentz R, Arnold E . Structural basis of BLyS receptor recognition . Nature Structural Biology . 9 . 4 . 288–92 . April 2002 . 11862220 . 10.1038/nsb769 . 24498929 .
  7. Daridon C, Youinou P, Pers JO . BAFF, APRIL, TWE-PRIL: who's who? . Autoimmunity Reviews . 7 . 4 . 267–71 . February 2008 . 18295728 . 10.1016/j.autrev.2007.05.002 .
  8. Yan M, Marsters SA, Grewal IS, Wang H, Ashkenazi A, Dixit VM . Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity . Nature Immunology . 1 . 1 . 37–41 . July 2000 . 10881172 . 10.1038/76889 . 22957179 .
  9. 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 . 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 . 10880535 . 1887716 . 10.1084/jem.192.1.137 .
  10. Roschke V, Sosnovtseva S, Ward CD, Hong JS, Smith R, Albert V, Stohl W, Baker KP, Ullrich S, Nardelli B, Hilbert DM, Migone TS . 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 . 12370363 . 10.4049/jimmunol.169.8.4314 . free .
  11. Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID, Mullen C, Strauch K, Zafari M, Benjamin CD, Tschopp J, Browning JL, Ambrose C . BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF . Science . 293 . 5537 . 2108–11 . September 2001 . 11509692 . 10.1126/science.1061965 . 2001Sci...293.2108T . 42673198 . free .
  12. Yan M, Brady JR, Chan B, Lee WP, Hsu B, Harless S, Cancro M, Grewal IS, Dixit VM . 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 . 11591325 . 10.1016/S0960-9822(01)00481-X . 13925100 . free . 2001CBio...11.1547Y .
  13. Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, Pan CH, Martin WE, Murphy RC, Shu HB, Dai S, Zhang G . Ligand-receptor binding revealed by the TNF family member TALL-1 . Nature . 423 . 6935 . 49–56 . May 2003 . 12721620 . 10.1038/nature01543 . 2003Natur.423...49L . 4373708 . free .
  14. Shu HB, Johnson H . 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 . 10908663 . 16838 . 10.1073/pnas.160213497 . 2000PNAS...97.9156S . free .
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  18. 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 . 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 . 21296403 . 10.1016/S0140-6736(10)61354-2 . 28952240 .
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