Tuesday, September 6, 2011

A New Take on the Importance of Memory

When you hear the word memory your initial thought may be to think of your brain.  However, the memory of cells plays an integral role in other systems of our bodies as well. Memory is crucial to the immune system’s ability to efficiently fight off infections.  Our bodies are miraculously able to generate antibodies against viruses while maintaining anti-viral antibody secreting cells to protect us from future attack by the same virus. While antibodies we make span a month, they retain the means of reproducing them for a lifetime (3).
In 1796, Edward Jenner’s noted that dairymaids and farmers lacked the smallpox that was disfiguring and killing whole villages. Cowpox during this time suffered from a similar disorder, cowpox, in which cattle experienced similar but less severe symptoms than humans (3). He exposed an 8-year-old boy first with fluid from an infected cow then two months later he inoculated the boy with smallpox. Sure enough, the boy’s immune system was able to remember how to fight the infection (3). This experiment, although clearly unethical, proved to be the first successful vaccination that would lead to the development of future vaccinations for a plethora of viruses. Jenner paved the way for future scientists to build off his idea of weakening pathogens in the laboratory to inoculate patients with in order to protect them from future exposure to that pathogen.  Today scientists continue to build off of this demonstration with the intent to better understand the cellular and molecular mechanisms governing this profound observation and experiment. 

Until recently, the exact mechanism for this profound feat was not well understood. Recently, however, researchers at the Wistar Institute have discovered some of the protein signals involved in maintaining the memory of previous viral infections. The aim of the study is to reduce the nearly Influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 250,000 and 500,000 people annually while reaching extremes of millions of deaths in some pandemic years (2). Regardless of the annual vaccines against the disease, the influenza virus continues to cause unnecessary deaths each year. Researchers at the Wistar Vaccine Center hope to discover a universal flu vaccine to replace the annual flu shot.
             The thought behind their study is based off of basic immunology.  Antibodies (Abs) are highly variable proteins that bind to portions of the infectious agent creating a target for the immune system cells to attack and remove the disease. Although our immune system casts out a broad mass of antibodies, when we become infected with a virus, the immune system rewires to allow for the main production of antibodies to be those specifically targeting the virus. Cells making these antibodies are preserved. Antiviral Abs are crucial for this process of protection. In response to influenza, the body produces Abs, which are important for viral neutralization and defense in a secondary viral infection. Interestingly long-lived Ab-secreting cells (ASCs) and memory B cells which maintain Abs last for years even though the half-life of serum lasts a few weeks (1).
            According a study by Wolf et al (2011) Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI , the step of preservation depends on signals sent out by proteins called BLyS and APRIL. Researchers identified TACI, a receptor on ASCs, and its ligands BLyS and APRIL as key players in the maintenance of protective antiviral ASCs. Mice exposed to influenza must have these proteins in order to prolong anti-influenza ASCs in their lungs. After infecting the mice with influenza, they found ASCs augment at various sites including the RT where they remained elevated for several months. They discovered that neutralizing BLyS and APRIL lowered the numbers of anti-viral ASCs produced in the lungs and bone marrow. Oddly enough however, this did not affect the ASCs counted in the spleen or in lymph nodes neighboring the lungs. The anti-viral ASCs in the lungs were found to live short-term and need both BLyS and APRIL for their immediate survival. In addition the production of longer-term ASCs in the bone marrow also required these signals. TACI hypothesize must serve to mark the ASCs that will become long-lived. Mice that lacked the TACI gene have an initial B cell response to viral infection as well as produce antibodies against the flu but eventually fail to maintain long surviving ASCs. This results in lower antibody titers, which translates to mice that are less protected with second exposures to the viral attack (1). 
Researchers theoretically hope to create Drugs that enhance the targeted production of ASC survival factors such as BLyS and APRIL as well as the transduction of their signals through their receptor TACI that could help sustain specific antibodies. With the flu constantly mutating, the desire to find an annual vaccine is becoming heightened because even weakly reactive antibodies could solve the problem if enough of them are produced or sustained. Future research needs to be conducted since the persistence of ASCs appears to be regulated differently in tissues implying multiple pathways are involved.   However this new research shows promise in developing a vaccine because with this new knowledge about the importance of signaling from TACI ligands BLyS and APRIL for the longevity of humoral immunity and safeguard against influenza virus. Hopefully this new work will lead to the prevention of many premature deaths around the world (1).    

1. Wolf, A.I., Mozdzanwoska, K., Quinn, W.J., Metzgar, M., Williams, K.L., Andrew, J.C.,            Meffre, E., Bram, R.J., Erickson, L.D., Allman, D., Cancro, D.A., and Erikson, J. 2011. Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI. Proceedings of the Journal of Clinical Investigation, U.S.A. doi:10.1172/JCI57362

2. Influenza. Retrieved on 01 September 2011 from http://en.wikipedia.org/wiki/Influenza.

3. Mak, Tak & Saunders, Mary. Primer to the Immune Response. California: Elsevier, 2011. Print.


  1. Thanks for the post, Addie. Did the authors mention which cells produce BLyS and APRIL to stimulate the antibody secreting cells?

  2. Wow! I never studied biology in college but this model for a way to vaccinate someone by taking advantage of the body's ability to remember a pathogen it was exposed to is fascinating. I hope they are able to eventually create a vaccine!

  3. Did you learn about any other pathways that could be responsible for how the flu is constantly mutating?

  4. That's interesting that the spleen and lymph nodes are more conducive to the ASC's with BLyS and APRIL, maybe we just need a flu that lasts shorter than the ASC's ability to survive in the lungs and bone marrow!

  5. We are starting to learn about memory and the processes of memory in the brain in Human Cognition class. Reading about how memory also plays a role at the cellular level is extremely interesting and something I was not at all aware of. I know very little about how the immune system works, so keep blogging!

  6. Thanks for all your comments. I think the paper says more about how our cells maintain memory than it does, necessarily, about influenza infection. The authors were using flu as a "model" virus to study, not necessarily focusing on how to generate a better immune response specifically to flu. But, your points are well taken in that by determining ways to manipulate ASCs, vaccine designers will be able to add components to vaccines that can help facilitate longer-lasting immunity (= fewer booster shots! Yay!)