APRIL and BAFF connect autoimmunity and cancer

CF Ware - The Journal Of Experimental Medicine, 2000 - rupress.org
CF Ware
The Journal Of Experimental Medicine, 2000rupress.org
Recent studies of two newcomers to the TNF cytokine family have revealed an unsuspected
link between autoimmunity and cancer. In this issue, Rennert et. al.(1) define the specific
receptors for the orphan ligand known as APRIL (a proliferation-inducing ligand), which was
previously recognized for its growth stimulating activity for tumors of lymphoid, colon, and
thyroid origin (2). APRIL binds cell surface receptors B cell maturation antigen (BCMA) and
transmembrane activator and CAML interactor (TACI)(see also reference 3); a soluble decoy …
Recent studies of two newcomers to the TNF cytokine family have revealed an unsuspected link between autoimmunity and cancer. In this issue, Rennert et. al.(1) define the specific receptors for the orphan ligand known as APRIL (a proliferation-inducing ligand), which was previously recognized for its growth stimulating activity for tumors of lymphoid, colon, and thyroid origin (2). APRIL binds cell surface receptors B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI)(see also reference 3); a soluble decoy form of BCMA that antagonizes APRIL’s activity inhibits the growth of tumors that naturally overexpress APRIL. What makes this observation biologically intriguing is that the two receptors, BCMA and TACI, were just very recently recognized as receptors for another TNF family member, BAFF, a B lymphocyte activating factor. BAFF is implicated as a key cytokine sustaining B cell survival and may play a significant role in lupus-like autoimmune nephritis observed in NZB/WF1 mice. The definition of BAFF and APRIL cytokine systems establishes a connection between autoimmunity and cancer that is poised for detailed exploration.
Ligands related to TNF are type 2 (NH2 terminus inside the cell) single transmembrane proteins that assemble in their biologically active form as trimers. In either membrane-anchored or secreted states, the trimeric ligands bind and aggregate their specific cell surface receptors, activating cell death or survival signals (4, 5). The amino acid sequence homology that defines the TNF family is limited to the receptor-binding domain, which between APRIL and BAFF (also known as BlyS, THANK, TALL, zTNF4; references 6–9) is only 33% identical, an insufficient clue as to their closer functional ties. Both ligands are similarly processed by a furin-like proteinase that releases biologically active soluble trimers, which circulates in serum and thus may act systemically (10).
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