By Uma Chandrasekaran
Ebola outbreak. SARS epidemic. Swine-flu pandemic. If these weren’t enough to claim our lives, re-emergence of measles, polio, whooping cough and, of course the ever-changing strains of flu always poses a threat.
In stark contrast, according to WHO, the global life expectancy at birth in 2013 has risen to 71 years from a mere 20-35 years at the turn of the century1,2. How do these two pieces of data fit together?
It turns out that we are not dead yet, because of the advancements in the field of medicine, specifically, the discovery of vaccines. Many of us would have received the kiss of death from small pox or rabies - if not for vaccines, well before we hit the five-year milestone. Despite coming out in the clear from the commonly afflicted childhood communicable diseases, human races’ ever-raging battles with the microbial and viral communities continue throughout our lifetime. Vaccines are the prime tried and tested arsenal for humans in this battle.
As the life expectancy increases and so does our encounters with these omnipresent ever-emerging foreign organisms. This heightens the need for the development of effective vaccines against life-threatening illnesses.
What do vaccines do, by the way?
Let me remind you of the Aesop’s fable about the boy who cried wolf3. In that story a shepherd boy repeatedly raises false alarm by tricking the villagers into believing that a wolf is attacking his flock of sheep. When the wolf actually does attack the shepherd, the villagers ignore his cry for help assuming it is another false alarm by the boy.
Vaccines behave very similar to the shepherd. They make the immune cells of our body to believe that a foreign organism is attacking. By raising a false alarm, vaccines trigger and prepare our immune cells in anticipation of a real attack. But unlike in the Aesop’s fable, when faced with the real onslaught of microbes and viruses, our well-trained army of immune cells is ready to attack and expel the intruder with little harm to the host. In essence, vaccination is akin to a boot camp for the immune cells of our body.
One of the key immune players in our bodies is called the B-cell. They secrete certain type of proteins called antibodies, when confronted with a foreign organism like virus. These antibodies attack and neutralize the virus thus protecting the host from infection and disease. One of the several ways through which vaccines prepare our body from a future attack of invading pathogens is to trigger the production of antibodies from B-cells. Presence of antibodies against pathogens in our blood thus indicates past history of infection. Some of these antibody responses can last for remarkably long periods thus providing life-long immunity. For e.g.: antibody response after a natural infection of measles and mumps were of the order of 3,014 years and 542 years respectively4. In contrast, the antibody response following vaccination for tetanus was of the order of 11 years, suggesting that perhaps vaccine-induced immunity is not as long-lived as a natural infection.
Immunologist like Rafi Ahmed of the Emory Vaccine Centre in Atlanta identified that a certain type of B-cell called long-lived plasma cells (LLPCs), found in the bone marrow were mainly responsible for the maintenance of the long-term antibody responses in mice7. However, the characterization of LLPCs in humans remained elusive for long.
Frances Eun-Hyung Lee, assistant professor of medicine at Emory University School of Medicine (and director of Emory Healthcare's Asthma, Allergy and Immunology program) is also interested in this inquiry. She thinks that understanding the function and maintenance of LLPCs in humans will enable us to generate long-lived protective responses following microbial and viral vaccinations.
In her recent work published in Immunity8, the authors examined the bone marrow samples of 11 individuals (aged 43 to 70) who had not been immunized against measles or mumps. In spite of not being vaccinated, these individuals carried antibodies in their blood against measles and mumps viruses indicating that these individuals had contracted the infection naturally during childhood.
In this study, the authors classified the B cells in the bone marrow of these individuals into 4 subsets, A-D (based on the expression of surface proteins equivalent to say, hair color, eye color and height of a person). Interestingly, they found that only cells in subset D produced antibodies that reacted against measles and mumps virus derived proteins. On the other hand, cells producing antibodies against influenza virus were distributed among subsets A, B and D. Since all the study subjects had received influenza immunization in the recent past, the authors concluded that short-lived newly developed antibody responses are found in subsets A, B and D and long-lived antibody responses are confined to subset D.
They also found that short-term antibody response against tetanus following recent vaccination was distributed in subsets A, B and D. As expected, over time long-lived antibody response against tetanus slowly shifted to subset D, thus confirming the identity of human LLPCs as subset D.
Dr. Lee in a press release stated5,6, “I like to call this group of cells (subset D) the ‘historical record’ of infection or vaccination.”
The perfectionists that these scientists are, Lee and her colleagues, using high-throughput sequencing technology, further characterized the specificity of the antibodies secreted by these LLPCs. LLPCs responded to a myriad of foreign organisms (antigens) consistent with their function as an immune archive. Using transcriptome and microscopy techniques, Dr. Lee’s research group identified the secret pathway to the longevity of LLPCs in bone marrow. LLPCs expressed many genes involved in a process called autophagy meaning “self-eating”. It is a recently recognized process that enables cells to survive stressful conditions like nutrient deprivation and antibody secretion, by recycling cell components from degraded cells.
Dr. Lee’s research outcome suggests targeting the LLPCs might be a smart strategy for vaccine developers when developing effective vaccines. Dr. Lee echoed similar thoughts and said, “If you're developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen."
The Roman philosopher Seneca once said, “Things that were hard to bear are sweet to remember.” This statement was true long before the discovery of vaccines. Once we survived the painful deadly childhood diseases our immune memory protected us for life. Vaccines make our lives even better by helping us bypass the painful road to immunity. They have made us believe, “Things that we experience are sweet to remember.”
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