B-cell activating factor (BAFF) also known astumor necrosis factor ligand superfamily member 13B andCD257 among other names, is aprotein that in humans is encoded by theTNFSF13Bgene.[5][6] 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).
BAFF is a 285-amino acid long peptideglycoprotein which undergoesglycosylation at residue 124. It is expressed as a membrane-bound type IItransmembrane protein[6] on various cell types includingmonocytes,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.[8] BAFF is the natural ligand of three nonconventionaltumor necrosis factor receptors namedBAFF-R (BR3),TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), andBCMA (B-cell maturation antigen), all of which have differing binding affinities for it. These receptors are expressed mainly on matureB lymphocytes and their expression varies in dependence of B cell maturation (TACI is also found on a subset ofT-cells and BCMA onplasma cells). BAFF-R is involved in the positive regulation during B cell development.[9] TACI binds worst since its affinity is higher for a protein similar to BAFF, calleda 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 counterapoptosis. All these ligands act as homotrimers (i.e. three of the same molecule) interacting with homotrimeric receptors,[10] 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).[11]
Interaction between BAFF and BAFF-R activates classical and noncanonicalNF-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.[8]
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.[19]
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.[20] Overexpression of BAFF also correlates with enhanced humoral immunity against malaria infection.[21]
BAFF has been found in renal transplant biopsies with acuterejection and correlate with appearanceC4d.[23] Increased levels of BAFF may initiate alloreactive B cell andT 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 vascularendothelium of graft and activatecomplement. This process result inneutrophils infiltration,hemorrhage, fibrin deposition andplatelet aggregation.[24] Targeting BAFF-R interactions may provide new therapeutic possibilities intransplantation.
BAFF may also be a new mediator of food-related inflammation.[26] 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.[27] In patients with celiac disease, serum BAFF levels are reduced after a gluten-free diet.[28] 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.[29][30]) BAFF is also a specific inducer of insulin resistance and can be a strong link between inflammation and diabetes or obesity.[31][32] 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.[27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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^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".Nature Structural Biology.9 (4):288–92.doi:10.1038/nsb769.PMID11862220.S2CID24498929.
^Yan M, Marsters SA, Grewal IS, Wang H, Ashkenazi A, Dixit VM (July 2000). "Identification of a receptor for BLyS demonstrates a crucial role in humoral immunity".Nature Immunology.1 (1):37–41.doi:10.1038/76889.PMID10881172.S2CID22957179.
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^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 (February 2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial".Lancet.377 (9767):721–31.doi:10.1016/S0140-6736(10)61354-2.PMID21296403.S2CID28952240.
^Fabris M, Visentini D, De Re V, Picierno A, Maieron R, Cannizzaro R, Villalta D, Curcio F, De Vita S, Tonutti E (December 2007). "Elevated B cell-activating factor of the tumour necrosis factor family in coeliac disease".Scandinavian Journal of Gastroenterology.42 (12):1434–9.doi:10.1080/00365520701452225.PMID17852877.S2CID44676344.
Nardelli B, Moore PA, Li Y, Hilbert DM (July 2002). "B lymphocyte stimulator (BLyS): a therapeutic trichotomy for the treatment of B lymphocyte diseases".Leukemia & Lymphoma.43 (7):1367–73.doi:10.1080/10428190290033297.PMID12389615.S2CID2521553.
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Treml LS, Crowley JE, Cancro MP (October 2006). "BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells".Seminars in Immunology.18 (5):297–304.doi:10.1016/j.smim.2006.07.001.PMID16919470.
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