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Monday, December 5, 2011

CaMKIV: A Potential Target for a Treatment for Lupus Nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disorder that currently has no cure (PubMed Health, 2011). SLE may result in abnormal deposits in kidney cells, which leads to complications in the kidneys. This results in the condition lupus nephritis, in which extensive damage to the kidney occurs and ultimately results in kidney failure (PubMed Health, 2011). There has been much speculation that Calcium/calmodulin-dependent protein kinases (CaMKs) is a factor in the progression of SLE, for it has previously been demonstrated that CaMKIV contributes to decreased IL-2 production in SLE T cells (Karin, 1995). CaMKIV may also play a role in the production of IL-6, for it has been demonstrated that just before the age when lupus nephritis is developed, spleen cells of mice contain a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA and double-stranded DNA (Datta, 1987). This may be of critical importance, for it has also been shown that IL-6 is a feed forward process in which macrophages respond to IgG to support further B-cell production of IgG (Maeda, 2010).
It has previously been demonstrated that inhibiting CaMKIV in lupus-prone MRL/lpr mice mitigates disease pathology (Karin, 1995). Ichinose et al. have recently elaborated on the cellular abnormalities that may be controlled by CaMKIV (2011). These results have helped to clarify the cellular processes that result in the damage of kidneys in lupus nephritis by producing large amounts of autoimmune mesangial cells and increasing production of IL-6 and have shown that CaMKIV may be a critical target in developing treatments for lupus nephritis.
Ichinose et al. have recently proposed a critical functioning of CaMKIV in the progression of SLE and lupus nephritis (2011). To first test this hypothesis, Camkiv null locus was transferred into lupus-prone mouse strain MRL/lpr. However, it was found that there was no difference in number of splenocytes, peripheral lymph node cells, and major B and T cell compartments amounts between MRL/lpr and mice lacking the CaMKIV gene, MRL/lpr.Camkv-/- mice.
However, after 16 weeks of development, the kidney was considerably less damaged in MRL/lpr.Camkiv-/- mice compared to MRL/lpr mice. Even though immune cell levels remained comparable, mice without functional CaMKIV developed significantly less glomerular, tubulointerstitial, and pervascular lesions as well as decreased proteinuria and serum titers of anti-dsDNA antibodies. From these results, it was concretely determined that the presence of CaMKIV was responsible for kidney damage, but not from the functioning of the major immune cells.
KN-93 is a known inhibitor of CaMKIV, therefore treatment with KN-93 will diminish the function of CaMKIV. To test the function of CaMKIV on the number of mesangial cells, MRL/MPJ and MRL/lpr mice were pretreated with KN-93 to assess the differences in mice when CaMKIV is blcoked. Treatment with KN-93 was found to suppress levels of mesangial cells. Therefore, inhibition of CaMKIV in lupus-prone MRL/lpr mice results in decreased mesangial cell proliferation.
Cell division was monitored in order to determine the rates of cell prliferation. Cells undergoing division were synchronized by serum starvation for 24 hours and labeled with propidium iodide in order to observe their proliferation capabilities by flow cytometry. It was found that the percentage of cells actively commencing the cell cycle in order to divide and multiply was much higher in lupus prone MRL/lpr mice compared with the control MRL/MPJ mice. This indicates that mesangial cells in MRL/lpr mice actively divide, even in the absence of exogenous stimuli. However, upon treatment with KN-93, cells were arrested in the cell cycle and the percentage of mesangial cells dividing and proliferating was clearly diminished.
Mice were then genetically depleted of CaMKIV in MRL/lpr.Camkiv-/- mice in order to determine the impact of the absense of CaMKIV. Mesangial cells in mice without functional CaMKIV were then measured. It was found that large percentages of mesangial cells from MRL/lpr.Camkiv-/- mice were arrested in the cell cycle and not actively dividing compared with control MRL/lpr and MRL/MPJ mice. PDGF-BB, which acts as a stimulus to promote cell proliferation, was not able to overcome the block imposed by the genetic deletion of CaMKIV, demonstrating that CaMKIV plays an important role in mesangial proliferation, with an intrinsic ability to proliferate without exogenous stimulation.
IL-6, a product of mesangial cells, was then measured to determine what the influence of mesangial cells have on the progression of kidney failure. It was found that cells with genetic deletions of CaMKIV had lower levels of IL-6. IL-6mRNA expression in activated splenocytes was significantly decreased in MRL/lpr.Camkiv-/- mice. Furthermore, mice treated with KN-93 also had suppressed levels of IL-6 in MRL/lpr mesangial cells at mRNA and protein levels. These results indicate that either the genetic deletion or inhibition of CaMKIV will not only decrease the proliferation of mesangial cells, but will also decrease the production of IL-6.
Ichinose et al. further delved into the transcriptional mechanisms underlying IL-6 expression. It was found that IL6 promoter activity in MRL/lpr.Camkiv-/- mesangial cells decreased compared with MRL/lpr mesangial cells. Mutating AP-1 resulted in limited promoter activity, demonstrating that AP-1 is involved in IL-6 gene transcription. AP-1 member c-jun was also found in increased levels in MRL/lpr.Camkiv-/- mesangial cells compared with MRL/lpr mesangial cells. This was further confirmed using DNA binding assays, demonstrating that the AP-1 motif showed an increased binding of nucleoprotein from MRL/lpr mesangial cells stimulated with PDGF-BB, which was diminished when nucleoprotein lysates from MRL/lpr.Camkiv-/- mesangial cells were used.
This study elaborated on the mechanisms that potentially influence the progression of lupus nephritis. Ichinose et al. provide concrete evidence that mesangial cells from MRL/lpr mice are able to proliferate in vitro in the absence of exogenous stimuli, along with increasing IL-6 production. Ichinose et al. were able to convincingly link these cellular abnormalities to CaMKIV, for the genetic absence or the blocking of function of CaMKIV resulted in the suppression of mesangial cell proliferation. CaMKIV has been identified as an important regulator of cellular abnormalities that are observed in lupus nephritis, suggesting it as a potential target in the mitigation of autoimmunity and suppression of kidney inflammation. These results should be elaborated on by assessing the effects of CaMKIV on the functioning of macrophages and the production of IgG to further understand the effects of IL-6 on the immune system and progression of lupus nephritis. Further research may also be required to assess the practicality of blocking CaMKIV in lupus nephritis treatment. Even though inhibiting the function of CaMKIV may help regulate cell abnormalities in lupus nephritis, CaMKIV has been shown to have neuroprotective effects, and its inhibition may potentially prove to be disastrous in other body functions (Sée et al., 2001). Ichinose et al. have made much progress on targeting a potential controller of lupus nephritis. This lead should be followed in order to advance the understanding of SLE and potentially propose the first successful treatment for this autoimmune disease.


Works Cited:
Datta, S. K., Patel H., Berry D. Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. (1987). J. Exp. Med. 165, 1252-1268.
Ichinose K., Rauen T., Juang Y., Kis-Toth K., Mizui M., Koga T., Tsokos G. C. Cutting Edgue: Calcium/Calmodulin-Dependent Protein Kinase Type IV is Essential for Mesangial Cell Proliferation and Lupus Nephritis. J. Immunol. 1102357.
Karin M. 1995. The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270: 16483-16486.
Maeda K., Mehta H., Drevets D. A., Coggeshall K. M. IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production. (2010). Blood 115: 4699-4706.
PubMed Health, A.D.A.M. Medical Encyclopedia. Systemic lupus erythematosus. (2011). National Center for Biotechnology Information.
Sée V., Boutillier A. L., Bito H., Loeffler J. P. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons. FASEB J. 2001 Jan;15(1):134-144. PubMed PMID: 11149901.

145 comments:

  1. Great job Allison! You really nailed this one!

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  2. I concur, Allison. You really did a great job illuminating this horrible disease.

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  3. Allison, a job well done. I've learned a lot and I never thought I could process such intense scientific material.

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  4. My aunt had SLE. I wish the public was as educated on how horrible it as, as you now are.

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  5. I think you hit it right on target with your assessment of the deletion of CaMKIV. This could really do wonders

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  6. Do you really think that this disease could be wiped out soon?

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  7. Do you believe that the scientific community needs to be more aggressive in clinical trials for this?

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  8. Great job for such a complicated topic Allison!

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  9. You lost me a little in all the acronyms, but I caught it on the reread.

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  10. Is this what you think you want to focus on after graduation? For research?

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  11. I was doing some research on different lupus treatments in New York a few years back after I decided to take some time off from med school. You should look into that perhaps if that is up your alley

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  12. The treatment of mice shows promise. Maybe it just needs to be taken up a step!

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  13. I think we definitely need further research! I'm with you on this one

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  14. I don't know if I believe this is making much progress. I may be pessimistic, but I think its a bit too hopeful

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  15. Great job! No way I could summarize all this information so concisely!

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  16. This is a very confusing topic with so many facets to cover! Wow, what a challenge!

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  17. Having had a family member who suffered from lupus and knowing a dear friend who did as well, I definitely see a lot of promise in the innovations that are taking place

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  18. This is really intense stuff!

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  19. Wow! Now that's revealing! Definitely didn't know all that!

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  20. Your level of detail is really amazing. Definitely not a half-effort here Allison

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  21. Have you read this research that was posted from the University of Toronto? I found it most revealing http://www.molecularpain.com/content/1/1/10

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  22. Do you think the chances of this not being a correlation are possible?

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  23. I wholeheartedly agree with Elizabeth and others, this is some very complicated material to process. Hats off to you for your successful attempt

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  24. All of the posts on this blog deal with such delicately intricate conditions and science, yet you chose to investigate an issue that would scare off the common man

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  25. This is just like an episode of House that I saw!

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  26. I didn't really believe that CaMKIV was that much of a key component in this battle against lupus. I'm still skeptical

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  27. IL-6 doesn't seem to be the most efficient means to measure kidney failure. It seems a bit presumptuous don't you think

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  28. Great job on your composition of correlating factors. Everything ties in well

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  29. The future is bright with scientists like you

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  30. I found this while I was googling for my own project on lupus nephritis. Thanks for the help

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  31. Touche Allison, touche

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  32. I learned a lot for a liberal arts student that understands barely any science at all. Thank you

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  33. Have you ever taken a journalism class before because it seems like you have from your crisp writing skills

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  34. I'm really impressed

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  35. You seem pretty knowledgeable in this field. Nicely done.

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  36. You really articulate this complex material clearly

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  37. I am impressed that an undergrad student can handle keeping all this in order

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  38. Allie, a wonderful Job!!!! It was so interesting. I got lost here and there, but that was because of my own ignorance about the subject.

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  39. Thanks for helping me understand science.

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  40. So good. You really know your stuff!!

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  41. I don't know how you do it girl

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  42. Wow, you really did your research thoroughly and did an incredible job reporting it! Good Job Allie!

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  43. Great job explaining such a complicated topic!

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  44. You seem so informed to keep all this information in order

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  45. Excellent! Just excellent!

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  46. Wow. Thanks for explaining!

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  47. Dr. Rabinowitz anyone?

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  48. Are you sure this wasn't written by a professor?

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  49. This is really excellent work!

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  50. Wow! This stuff looks tough! Great job though!

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  51. Wow Allie this blog is amazing!

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  52. Great blog! You must have a really high GPA........

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  53. Great job Allie! Really!

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  54. This is so interesting! Great job!

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  55. Wow, this is fascinating. I had never heard of SLE before and you did an excellent job of explaining it!

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  56. I was wondering what you thought of the likelihood of eliminating this disease? Soon? Or not for a while?

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  57. I can't believe I didn't even know what this was until you told me!

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  58. Lupus is always the diagnosis on House. Maybe if this cure is discovered, they'll have to rewrite most of their shows!

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  59. This is some really interesting stuff!

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  60. Wow! I don't know how you keep all your acronyms straight

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  61. Awesome job Allie! Very informative! :)

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  62. You sound so smart!! Great job Girl!

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  63. You absolutely killed this post girl!

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  64. fascinating research!

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  65. Nice work Allie! This stuff is really difficult and you made it look like cake

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  66. Mesangial cells are totes the worst!!!!!

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  67. wow ally you are so smart and i am loving your scientific looking blog background

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  68. Amazing job, Allie! you blew my mind.

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  69. Whoa! Allie - so cool!

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  70. Very interesting!! Would love to learn more about this topic!

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  71. Great job Allie!!! Top notch! Cherio!

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  72. YOU ARE A GENIUS.

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  73. Great job! Interesting stuff!

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  74. This is so great, Allie! Learned a lot.

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  75. You're so smart, Allie!

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  76. I never thought I could learn so much from a blog. You da bomb chicky!

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  77. I feel so inadequate in comparison. THIS IS GENIUS!

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  78. I like the color scheme you used for your blog - it made a complicated topic inviting even to someone like me who knows very little about it!

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  79. So interesting! Way to go, Allie

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  80. This is so good! The best blog by far!

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  81. Really cool stuff Allie! I like

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  82. You're number 1 in my book for this blog post

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  83. How do you do it Rabinowitz!?!

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  84. Pretty nice science-ing there Allie!

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  85. I don't think you could have impressed me more if you had tried

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  86. You explained it all so well!! I did learn something....great finals procrastination

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  87. Its good to see that the future looks so promising

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  88. I loved your optimism throughout the post on such a serious topic

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  89. Allison, your piece was very interesting. I did not know much about SLE before your post. Actually, I didn't know anything. I would classify myself as someone who is new to all things science, so some of the terms flew over my head, but ultimately I learned a lot.

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  90. Very good job explaining this very complex topic. You feel very proud of yourself

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  91. this is truly a heartbreaking work of staggering genius.

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  92. Hey now, is this a great blog post or is this a great blog post? Am I right?

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  93. Great work allie!!

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  94. Can we get this published?

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  95. Did you know that Michael Jackson had SLE? He was diagnosed with it in 1986! (FUN FACT)

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  96. ¡Qué interesante! Me encanta tu artículo, Allison.

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  97. Wow, this is so interesting. You did a great job explaining SLE.

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  98. Estoy de acuerdo con mi amigo, Juan. Su artículo es informativo e interesante. Su habilidad con el idioma Inglés es una maravilla. Felicitaciones por el trabajo bien hecho. Espero que algún día conocerlo en persona. Besos

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  99. Michael Jackson wasn't the only one! Lady Gaga tested positive for SLE. She spoke about it while being interviewed by Larry King. As a huuuuuge fan of hers, I was deeply upset and worried, but she said that she has not been affected by the symptoms yet and hopes to maintain a healthy lifestyle to further combat the disease.

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  100. Is it sad that feel bad for the poor mice that are being experimented on?

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  101. Is it sadder that I don't feel bad for Lady Gaga?

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  102. Wow Nathan. That's not cool. No need to be such a jerk

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  103. Sorry, Sorry. Didn't mean to come off like that.
    ...I'm just saying...have you seen her videos? Those things are crazy! They ACTUALLY give me nightmares. They're scary and freaky and half the time I don't even know what I'm looking at! Or what it is supposed to mean!

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  104. YOU MUST BE THE SMARTEST PERSON ON EARTH!!!!!!

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  105. Guys, guys, guys. Please stop your bickering. Your taking away from the lively discussion we should be having about this post and this disease that Allison has shed light on so well. Please take your back and forth attacks elsewhere. The focus on here should be science! And Allison's great effort, of course!

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  106. This is fantastic Allie, GREAT JOB!

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  107. Reginald Warston IVDecember 6, 2011 at 6:12 PM

    Bloody Hell this is a great post! First-rate effort Allison! You really gave it 110%!

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  108. wowza. what a smarty pants.

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  109. Are there many celebrities that have had this disease? I didn't even know about Lady Gaga or Michael Jackson having it until today.

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  110. Apparently Seal and Toni Braxton have it too

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  111. Wow Allie, talk about picking a disease that is pretty relevant and prevalent, yet no one seems to know about it. Nice move!

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  112. I think this blog post is very informative for a disease that has a lot of promise of being stopped. Just this past March the FDA approved Benlysta, a drug that has the potential to treat SLE. Unfortunately, even the FDA acknowledged that it may not work in all cases. Hopefully, one day we can figure out a way to make it successfully eliminate SLE for all those who suffer from it.

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  113. Wow this was really informative!

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  114. This is great research! And a really well designed blog! Nice work Allie.

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  115. Allie, maybe you should take a look at the research that is currently taking place at Stanford. You might find it very interesting that their Med School is currently testing a treatment for SLE. Great work though!

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  116. This is so cool! I feel like you made this a lot less confusing than what you probably had to read! :)

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  117. This sounds really interesting, which is impressive!

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  118. I never knew about the presence of antibodies that only exist in the brain of individuals affected by lupus! I guess you do learn something new every day

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  119. I can't believe you handle all these scientific terms with such ease. Truly unbelievable!

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  120. Amazing work Allison! Reading this blog post made my week

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  121. Two thumbs up Allison on your great job!

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  122. Good Job Allie! I learned so much!!

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  123. Great job Allie synthesizing all of this difficult and technical information. You've accomplished your task of teaching many different people a great deal about SLE and the innovations that are currently taking place in the scientific community to attempt to rid the world of it forever. Very impressive!

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  124. Oh Allison, this is wonderfully written. Just absolutely wonderful! I'm so proud of you bubbala

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  125. This is great Allie! A very interesting read!

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  126. I'm really impressed by this. You show such a command of the material (and it doesn't seem like very easy material).

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  127. This is fantastic! You go girl!

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  128. This blog entry is really good work. I'm curious what led you to this topic. Do you have a particular personal interest?

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  129. Oh allie you're such a smart cookie!

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  130. This is so well-written allison. Do you know if CaMKIV is really a viable option or might it have terrible side effects?

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  131. You really did a bang up job on this Allison! I can see how hard you worked on it. I hope it pays off!

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