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baff

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Official Full Name
tumor necrosis factor (ligand) superfamily, member 13b
Synonyms
BAFF; BLyS; TALL1; THANK; zTNF4; TALL-1; TNFSF20; D8Ertd387e

B-cell activating factor (BAFF), a member of the family of TNF-like cytokines, supports the survival and differentiation of B cells. In myeloid cells, BAFF is expressed in a membrane-bound form on the cell surface (mBAFF) and can then be released as a soluble form after cleavage by furin protease. BAFF is an active ligand as a homotrimer, which is the main form of BAFF found in the circulation, however, unlike other TNF family cytokines, a 60-mer form of BAFF was obtained at physiological pH, which is also capable of binding to its receptor. Although this form has been described in a mouse model, it is still unclear whether it can be detected in humans.

The role of BAFF in promoting survival and selection of autoreactive B cells

BAFF binds to three receptors, BAFF-R, TACI transmembrane activator and calcium modulator host interactor (TACI) and B cell maturation antigen (BCMA), which are expressed by B cells at different times during the development of the individual. In humans, BAFF-R is widely expressed by all B cells except for bone marrow plasma cells. TACI is expressed by CD27+ memory B cells, by plasma cells, and by certain subsets of naive and activated B cells. BCMA is expressed by tonsillar memory B cells, GC B cells and plasma cells. BAFF-R is specific for BAFF, whereas TACI and BCMA also bind APRIL (a protein of the TNF superfamily recognized by the cell surface receptor TACI). BAFF-R signaling activates the alternative NF-κB pathway, and Akt mTOR and Pim2, and also weakly stimulates the classic NF-κB pathway, enhancing B cell survival, growth and metabolic fitness. TACI and BCMA signal through the classical NF-κB pathway and through other pathways to counteract apoptosis and promote class switching. BAFF does not work in central B cell selection in BM because immature B cells have very low BAFF-R expression.  

After their exit from the BM, B cells that encounter self-antigens in the periphery face a stringent tolerance checkpoint at the transitional stage. Strong BCR signaling allows cells to be deleted or unresponsive during early transitional stages, but improves the survival of late transitional and mature follicular B cells; at the same time, these cells also compete for survival signals transmitted by BAFF and BAFF-R interactions. BCR and BAFF-R mediated signals work in multiple ways. First, BCR crosslinking in naive cells triggers the expression of BAFF-R via the PI3K signaling pathway. Second, the alternative NF-κB pathway activated by BAFF-R requires the substrate p100, which is transcribed after BCR-mediated activation of the classical NF-kB pathway. BAFF-R is involved in up-regulating CD19 expression by regulating the transcription factor PAX5, thus enhancing BCR signaling and presumably increasing p100 production. Finally, BCR and BAFF-R inhibit the apoptotic pathway by altering the expression of different pro-survival and pro-apoptotic proteins. The effect of BAFF on the survival of naive B cells may be as early as the immature start of the T1 transition, as the amount of BCR expressed regulates the expression of BAFF-R in these cells.

These studies in sum show that supraphysiologic BAFF excess does not alter negative selection that occurs before or at the T1 stage but rescues autoreactive cells that are anergized after the T1 stage and promotes their maturation into follicular and or marginal zone cells. Conversely, BAFF inhibition preferentially depletes anergic autoreactive transitional B cells compared with non-autoreactive cells and self-reactive B cells with higher affinity receptors are more readily eliminated than ones with lower affinity BCRs. Importantly, if competition is provided by non-self-reactive B cells, BAFF excess has a much smaller effect on B cell selection.

Fig. 1. Effects of BAFF/APRIL on various immune cells in SLE. (Liu et al. Experimental cell Research. 2011).

References:

  1. Liu Z, Davidson A. BAFF and selection of autoreactive B cells. Trends in immunology. 2011;32(8):388-394.
  2. Fabien B. Vincent, Damien Saulep-Easton, William A. Figgett, Kirsten A. Fairfax, Fabienne Mackay. The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity. Cytokine & Growth Factor Reviews. 2013.
  3. Zheng Liu, Anne Davidson. BAFF inhibition: A new class of drugs for the treatment of autoimmunity. Experimental cell Research. 2011.
  4. Xu H, He X, Xu R. B Cell Activating Factor, Renal Allograft Antibody-Mediated Rejection, and Long-Term Outcome. Journal of Immunology Research. 2018; 2018:5251801.
  5. Musumeci G, Castrogiovanni P, Trovato FM, et al. Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis. Malemud CJ, ed. International Journal of Molecular Sciences. 2015;16(9):20560-20575.