Reading an interesting post on the tree of life reminded me that today is April 1st. I will seize this opportunity to make you familiar with an interesting protein that had been discovered in – you might have guessed it – April, exactly 10 years ago. In reality, the name APRIL has nothing to do with the month but rather means “A PRoliferation Inducing Ligand”. You can look it up somewhere in JEM.
APRIL is a member of the TNF family, which also contains proteins such as TRAIL and Fas-ligand. Unlike many other TNF family proteins, APRIL does not induce apoptosis, quite to the contrary: By a mechanism that is still very incompletey understood, APRIL upregulates the anti-apoptotic members of the Bcl2 family, most likely by way of NF-kB. Initially, we thought that APRIL had a connection to tumor-specific proliferation events. We had seen APRIL message and protein predominantly in tumors and only very little in normal tissues. Moreover, when various tumor cells were treated with APRIL, their proliferation rate was enhanced. I haven”t followed this field very closely, but I am under the impression that this tumor connection is shaky at best. A quickPubmed scan even found several reports of APRIL being stronger expressed in normal tissue as compared to a matched tumor.
Nowadays, it seems that APRILs role is mainly in B-cell biology, similar to its younger (but better-known) brother BAFF (some people call this protein BLyS, but I won”t). One of the more intriguing features of BAFF is its name. My initial choice was BPRIL (leaving room for CPRIL, DPRIL and so on), obstensibly an acronym for “B-cell proliferation inducing ligand”. As usually, nobody cared for my name choice, and in the end we “agreed” on BAFF (for B-cell Activating Factor – can”t remember where we got the 2nd F from.). At some point in time, when a patent application on this protein had to be filed, we had a name vacuum, resulting in an obscure application with the even more obscure title “Kay – A NOVEL IMMUNE SYSTEM PROTEIN”. As you would expect, this application was rapidly superseded by something more decent, but it can still be accessed at freepatentsonline.com. I just love the claim on “modified Kay-ligands and pharmaceutical compositions comprising them”. In the meantime, there is no shortage for names to choose from: BAFF is also known as BLyS, CD257, TALL, TALL-1, THANK, UNQ401, ZTNF4, TNFSF20 and TNFSF13B.
So, what does BAFF, the B-cell activating factor, do? Right. APRIL seems to work similarly, which is maybe not too surprising, given that the two ligands are relatively similar and share the two receptors BCMA and TACI. A third receptor, BAFF-R, seems to be specific for BAFF, while BCMA has been reported to prefer APRIL over BAFF. Nevertheless, BAFF/BlyS is better known, as it is the target of Belimumab (Lymphostat-B), a monoclonal antibody which is being developed by HGS as a therapy for rheumatoid arthritis (RA) and possibly other auto-immune diseases. As far as I know, APRIL has not specifically been targeted for drug development, although there are early clinical studies of Atacicept, a TACI-Ig fusion that would be expected to inhibit both APRIL and BAFF.
What is even worse, the drug people tend to use the ‘wrong’ name for BAFF/BlyS: Instead of writing reviews with titles like “A BLySful end to autoimmune disease”, people should think about “A BAFFling success in autoimmune therapy”.
Before I forget: To properly celebrate April 1, I have included one factual error in the above text. Spot it and earn an (BlySful, BAFFling, extra-TALL) beer at the next conference. At the moment, this post does not include any links, they will be added later.