It’s never lupus, but if it is… — #GeneOTW: TNFSF13B (aka BAFF)

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system erroneously attacks healthy, innocent tissues, including skin, joints, kidneys, the heart, and the brain.  The cause of SLE is unknown and a cure remains elusive.  (Fun fact: “lupus” is Latin for wolf, the bite of which was thought to have cause the rash we now associate with SLE.)

 

Symptoms_of_SLE

SLE symptoms differ widely. Symptoms are unpredictable and can affect multiple organs with varying severity. SLE is therefore often missed entirely or (as in House) overly diagnosed. Image from Wikipedia.

Last week, I went to the doctor for chronic hand pain.  After a half-hour long consultation, my doctor was mystified by my condition.  After dismissing typing and labwork (pipetting and playing with mice) as the cause of my pain, she assured me, “It’s probably not lupus.”

While I know she intended to comfort me, this was the first mention of lupus as a possibility, and though Dr. House says it’s never lupus, I got a little scared.  Admittedly, I didn’t know much about lupus.  All I knew was that SLE claimed the life of J Dilla and hospitalized Toni Braxton.  But now I know that the prognosis of the disease has improved greatly over the years, and the survival rate of patients with SLE is almost the same as that of those without SLE (see more stats here).  I also know that SLE research is progressing nicely, so even more effective treatments (and eventually a cure?) are on the way.

I know this not only because I immediately Googled “lupus” when I left the doctor’s office, but because our gene-of-the-week was coincidentally related to SLE.  This week’s long-named gene, tumor necrosis factor ligand super-family member 13 B (TNFSF13B), was perfectly timed to assure me that, even if it is lupus (and it’s probably not), I will probably be okay.

The Immune System 

Since I am being open with you today, I will admit now that when I started reading about SLE, I remembered approximately nothing about the immune system beyond the words “antibody” and “antigen.”  Therefore, before I talk a little more about the TNFSF13B, I am going to cautiously assume you remember approximately less than that (my apologies to the med students and immunologists I am about to insult and potentially infuriate).  Here are three extremely simplified key terms to catch you up to speed, at least for the duration of this article:

  • Antigens: molecules that the body recognizes as foreign (even if, as in SLE, they’re innocent natives of your body!)
  • Antibodies: Y-shaped proteins produced by white blood cells that bind antigens and neutralize them or tag them for destruction; antibodies are sometimes attached to B-cells
  • B-cells: lymphocytes (white blood cells) that produce antibodies and present antigens; see below for an example of how the different types of B-cells operate
series

I love this adorable illustration of the immune system at work. Does any of this ring a bell? From the Nobel Prize website, which is a pretty cool resource!

BAFF and Belimumab 

TFNSF13B encodes B-cell activating factor (BAFF, also known as B-lymphocyte stimulator or BLyS).  In 1999, Mackay et al., who discovered BAFF, found that mice with dysregulated BAFF expression had increased levels of B-cells and developed autoimmune-like symptoms.1  In 2011, belimumab (aka Benlysta),  a human monoclonal antibody targeting BAFF, was approved for the treatment of SLE.2  The discovery of belimumab was exciting, because it was the first treatment approved specifically for SLE in over 50 years.

BLyS belimumab

Belimumab prevents BAFF (labeled ‘BLyS’) from binding BAFF-receptor (BAFF-R, labeled ‘BR3’), which promotes immature B-cell survival and maturation. Image from Stohl et al. (2012).

Neutralizing BAFF with belimumab decreases the overall amount and regulatory control of B-cell activation.  BAFF can exist as a transmembrane protein, in trimers, and as 60-mers.  Current studies are investigating how each different form of BAFF may contribute to SLE.3  Perhaps targeting a specific subset of BAFF proteins will be more effective in the treatment of SLE.  Currently, several new BAFF-targeting treatments are in clinical trials.4 There may also be subsets of SLE, some of which are more effectively treated by belimumab.5  Finally, it is unclear now whether or not BAFF can be used as a diagnostic marker for SLE, but more specific reports on the presentation of BAFF in SLE are imminent.

variants of BAFF

There is a lot going on here. Importantly, BAFF is not a simple protein and the BAFF pathway is not straightforward. The dashed lines represent potential SLE pathways that require further investigation. These future studies make me hopeful for the future of SLE treatment and also curious as to how many PhDs-worth of work this will create. Figure from Vincent, et al. (2014).

In the meantime, patients treated with belimumab have reported better quality of life, with lower autoantibody levels and normal levels of memory B- and T-cells.  The state of SLE research is encouraging and improving rapidly, so if my hand pain is due to SLE, I don’t feel so bad.  Thank you, science.

BAFF popularity

In addition to two recent reviews on BAFF in SLE pathogenesis67, mouse8 and patient9 studies have been published recently, further investigating the role of disrupted BAFF in the pathogenesis of lupus.  Progress!

References 

  1. Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190(11):1697-710. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2195729&tool=pmcentrez&rendertype=abstract. []
  2. Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol. 2012;30(1):69-77. doi:10.1038/nbt.2076. []
  3. Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10(6):365-73. doi:10.1038/nrrheum.2014.33. []
  4. Sanchez-Niño MD, Ortiz A. “That Obscure Object of Desire”: in systemic lupus erythematosus B-cell activating factor/B-lymphocyte stimulator is targeted both by the immune system and by physicians. Nephrol Dial Transplant. 2014:1-7. doi:10.1093/ndt/gfu213. []
  5. Chong BF, Tseng L-C, Kim A, Miller RT, Yancey KB, Hosler GA. Differential expression of BAFF and its receptors in discoid lupus erythematosus patients. J Dermatol Sci. 2014;73(3):216-24. doi:10.1016/j.jdermsci.2013.11.007. []
  6. Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10(6):365-73. doi:10.1038/nrrheum.2014.33. []
  7. Sanchez-Niño MD, Ortiz A. “That Obscure Object of Desire”: in systemic lupus erythematosus B-cell activating factor/B-lymphocyte stimulator is targeted both by the immune system and by physicians. Nephrol Dial Transplant. 2014:1-7. doi:10.1093/ndt/gfu213. []
  8. Coquery CM, Wade NS, Loo WM, et al. Neutrophils Contribute to Excess Serum BAFF Levels and Promote CD4+ T Cell and B Cell Responses in Lupus-Prone Mice. PLoS One. 2014;9(7):e102284. doi:10.1371/journal.pone.0102284. []
  9. Chong BF, Tseng L-C, Kim A, Miller RT, Yancey KB, Hosler GA. Differential expression of BAFF and its receptors in discoid lupus erythematosus patients. J Dermatol Sci. 2014;73(3):216-24. doi:10.1016/j.jdermsci.2013.11.007. []

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