Cells in our bodies communicate by releasing signals
Our bodies are made up of organ systems, each made in turn of tissues and cells. Our heart is a collection of cells that work together to pump blood through our arteries and veins, our muscles are collections of cells that can contract in response to nerve impulses, and our nervous system is a collection of cells that act like a series of wires running from a central control center to targets throughout the body. Getting individual cells to work in a coordinated way requires communication. That communication takes the form of chemicals released into the spaces between our cells. While we think of our bodies as being solid, the truth is that we are mostly water. Each of our cells is embedded in a complicated mix of water and materials made by our cells themselves, including collagen (a fibrous protein), hyaluronic acid (a type of sugar), hormones, enzymes, and salts. Individual cells send signals to other cells by making and releasing chemicals into the liquid between cells. If a signal molecule is released into the blood, it is called a ‘hormone’. If a signal molecule is released into the tiny spaces between nerve cells, or neural synapses, it is called a ‘neurotransmitter’. Some signals are released more generally into the spaces between cells, the ‘interstitial’ spaces, where they diffuse out from their source cell like dye dissolving off the surface of candy (for a fun visual, follow this link)
While the immune system does include some solid, organized organs (lymph nodes, bone marrow, the spleen, the thymus), the majority of immune cells are solitary, moving in and out of blood, lymph and tissues, or even setting up residence in other organ systems. Because the immune system is diffuse (spread throughout the body), coordinating its overall function relies heavily on signal molecules released by immune cells into interstitial fluid and/or blood and lymph. Signal molecules that are released by immune cells or are heard by immune cells are called ‘cytokines’. Our immune cells produce a dizzying number of cytokines, and scientists have found that predicting exactly which cytokines are made and when, and how an immune cell will respond to those cytokine, is very challenging. If we are ever feeling too comfortable in our understanding of how our bodies work, the immune system will be sure to remind us we have much yet to learn.
What are antibodies?
Antibodies are another kind of molecule made by immune cells that are released into the blood, lymph and interstitial spaces. While antibodies can act as signal molecules, their main function is to bind foreign or damaged materials in the body. Antibodies are large complicated proteins that are overall shaped like the letter “Y”. They bind their targets at each tip of the Y, and then their ‘stem’ regions can be recognized and bound by proteins on the surfaces of immune cells. Antibodies therefore act as a ‘handle’ that immune cells can use to grab and pick up whatever target the antibody has bound. Antibodies are made and secreted by a type of cell called a B-cell. We have over a trillion different B-cells circulating in our blood; every day roughly 1-2% of those B-cells die and are replaced by new B-cells emerging from our bone marrow. While all B-cells make antibodies with pretty much the same stem region, each B-cell goes through a remarkable process during its maturation that essentially randomizes the genetic material that codes for the tips of the Y of the antibody. This means that each new B-cell our bodies have made or will ever make produces antibodies that are unique in what they can bind.
While each B-cell can only make antibodies with one version of the ‘tip’ region, they have several options for which ‘stem’ region to use. Because antibodies are immunoglobulin molecules (or “Ig” for short), antibodies with these different stems are named IgA, IgD, IgE, IgG and IgM. The different stem regions give the immune system a way to choose the best response to a pathogen, whether it be a virus, a bacteria, a fungus or a parasite, because each antibody stem type has different functions:
- IgM and IgD antibodies can be B-cell receptor, remaining attached to the surface of the B-cell, alerting it when it binds something its antibodies recognize.
- IgM antibodies can also be secreted out of the cell, and are the first antibody type made in an immune response. They are less effective, however, at removing pathogens than antibody types made later in an immune response.
- IgG antibodies are the ‘go-to’ antibody type for immune responses to viruses and bacteria, which are small and can be cleared by individual immune cells which phagocytose, or ‘eat’, targets covered in IgG antibodies. IgG antibodies last the longest. With a half-life of as much as 21 days, they circulate in the body for up to about three months after they are released.
- Targets that are too large to be phagocytosed, like fungi or parasites, must be attacked with another type of immune cell, the granulocytes, which release toxic compounds at the location of targets covered in IgE antibodies.
- IgA antibodies are an interesting class – they are secreted at body surfaces such as skin and mucous membranes, where they bind up pathogens before they even have a chance to enter host cells at those surfaces.
When and how are antibodies made?
If a B-cell binds a target with its receptor, and gets additional signals from stimulating cytokines and helper T-cells, it will activate. An activated B-cell starts to rapidly divide, making many identical daughter cells that all make the same antibody as each other. Note that while our bodies never generate two identical B-cells in our bone marrow, an already-made B-cell can make hundreds of identical copies of itself. This process of ‘clonal expansion’ rapidly increases the immune system’s ability to make antibodies that will bind whatever pathogen first triggered the immune response. These daughter cells are now free to follow their own paths in the immune response. Some rapidly convert to plasma cells which produce massive amounts of IgM antibodies but can’t divide to make daughter cells of their own and will die after just a few days. Other daughter cells keep interacting with helper T-cells in lymph nodes, honing their ability to recognize and respond to the pathogen that activated them by improving on their binding sites (the ‘tips’ of the Y) and switching to more effective antibody classes (the ‘stem’ of the Y). These cells continue to divide, making their own daughter (granddaughter?) cells which then convert to short-lived antibody producing plasma cells. And still others of these daughter/granddaughter cells stop dividing but don’t become plasma cells, and don’t produce antibodies. These immune ‘memory’ cells survive much longer than newly made, never activated B-cells (years rather than weeks), and can reactivate, with the help of T-cells, much more quickly than new, naïve B-cells when they are exposed to a pathogen similar to the one that first triggered their production. Because of these memory cells, our immune system responds both faster and more strongly the second time we encounter a pathogen. Only three to five days after a second exposure to a pathogen, our bodies are making antibodies at levels 100-1000x greater than during the peak of our first response.
Persistent antibodies protect against reinfection
So, can we be re-infected by this coronavirus? Or are we immune ‘for good’ after the first infection, like we are to chicken pox or measles after infection or vaccination? Well, we don’t know. While our immune systems run through basically the same program in response to any viral infection, each response differs in the details. The overall process of mobilizing an immune response to a brand new, never-before-seen virus takes 7-10 days. After about 7 days, our bodies start making and releasing IgM antibodies, and then within about 10 days most of us will begin producing the more effective, longer lived IgG antibodies. Whether each of us in fact goes on to produce IgG antibodies depends on how much virus is present in our bodies at peak infection, how fast we clear the virus and individual variations in our immune responses.
Once our immune systems are no longer being actively stimulated by virus (in other words, all or most viral particles have already been cleared), the activation and clonal proliferation of B-cells ends and plasma cells made during the active immune response die off. If we have made IgG type antibodies in the course of the infection, those can persist for weeks to months after an immune response is completed, protecting us against reinfection. The IgG antibodies made during the initial immune response will eventually fall apart, which may leave us open to reinfection. I say “may” because some pathogens (and vaccines) trigger the formation of a small population of long-lived plasma cells, which can churn out low levels of protective antibodies for months or even years after infection.
Does SARS-CoV-2 infection promote the formation of long-lived plasma cells? We don’t know, but a study showed that 6 of 7 people infected with the related MERS virus still had detectable antibody levels nearly three years after infection, and an as yet unpublished study of healthcare workers infected with SARS (SARS-CoV-1, 2002/2003) showed measurable levels of anti-SARS antibodies even 12 years later. But both of MERS and SARS had a more severe disease course than the current coronavirus (34% and 10% fatality rates, respectively), and these studies have very small sample sizes. We can’t assume from these data that SARS-CoV-2 infections will also result in persistent antibodies. The truth is, with so many infections occurring in March or later, we haven’t had enough time to find out if antibodies persist past three months or so (see this link for more detail).
Immunological memory can provide long term protection
If we slowly lose our ‘protective coat’ of antibodies, then yes, it is definitely possible for SARS-CoV-2 to infect us again. But before you panic, remember that immune responses generate memory cells. Memory cells respond much more quickly and more intensely than the original naïve immune cells that first encountered SARS-CoV-2. If our immune response to that first infection left behind a solid population of memory B-cell (and memory T-cells), we can expect that our bodies will respond to and clear a new infection within a few days rather than the 2 weeks or more it took the first time around. But not all immune responses are the same, and not all infections (and vaccinations) generate a durable population of memory cells. It is possible that a SARS-CoV-2 infection does not always generate a persistent population of memory cells, in which case any immune memory we have for this virus may degrade over time.
How do we know if we have an immune memory for SARS-CoV-2? Unlike testing for pathogen-specific antibodies, finding and counting the number of memory B-cells we have that recognize a specific pathogen is not something that can be done with a simple blood test. While tests can measure the number of the different types of immune cells are present in the blood, including memory B-cells, they can’t easily identify what pathogen each of those cells will respond to. In laboratory experiments like those conducted during vaccine development, B-cells are isolated from animals (usually a mouse) previously exposed to a pathogen. Those cells are then exposed to the same pathogen a second time and their response is compared to that of B-cells isolated from an animal that has never been exposed to the pathogen before. If the previously exposed cells respond faster and stronger than the newly exposed cells, the animal has memory B-cells to that pathogen in its blood. It is possible to isolate B-cells from human blood and test their responses to a pathogen of interest, though due to cost and the complexity of the test this is not something that can be done for a large number of samples. Not enough time has passed since initial infections for this type of test to be useful for SARS-CoV-2, but a study of people infected with the related virus that caused SARS in 2002/2003 (SARS-CoV-1) found that none of the 23 people tested had memory B-cells to SARS-CoV-1 antigens circulating in their blood six years after their initial infection.
And so I come back to the same question again – can we be re-infected by this coronavirus, or do we have a lasting ‘memory’ of this pathogen? The answer is still “we don’t know”, which is frustrating to be sure. Studies to address these question will take months or even years, while by their nature viral infections move through populations on a much shorter time scale. For more sources that address that particular question, please see these excellently written articles:
- Can You Get Covid-19 Again? It’s Very Unlikely, Experts Say (published in the New York Times, July 23, 2020)
- Six months of coronavirus: the mysteries scientists are still racing to solve (published in Nature, July 3, 2020)
- Long-term and herd immunity against SARS-CoV-2: implications from current and past knowledge (published in Pathogens and Disease, June 8, 2020)
Will we need boosters or annual vaccinations for this virus?
If at some point we no longer have memory cells for the virus, then we will respond to a new infection as if it were the first time we were seeing the virus. The likelihood of this is very low, however, for anyone with a moderately well-functioning immune system. And during those months to years it takes for our immune system to lose its memory, the virus that initially infected us is changing, accumulating mutations in its genetic material that affect how it looks and acts. Some viruses mutate quickly, acquiring changes that make them look ‘new’ to our immune systems, so much so that memory cells won’t respond to them. Flu viruses are like that, which is why we need a new vaccine every year in order to keep our immune system up to date with the current ‘model’, as it were. Cold viruses (rhinoviruses) actually mutate relatively slowly. How is it, then, that we all catch cold after cold? It isn’t because the virus changes so fast our immune system can’t recognize it, but rather that there are so many kinds of rhinovirus, so many versions and variants, that we are rarely exposed to the same one twice. SARS-CoV-2 actually mutates relatively slowly, which means that any memory immune cells we generate in the first infection will most likely be able to recognize and respond to later version of the virus. This slow mutation rate also is a very good thing in terms of vaccine development. Any vaccine we develop now, if it triggers the formation of persistent memory cells, will most likely be effective against the version of SARS-CoV-2 present next year, and probably also in five years.
Science in Translation 