Valuable for countless reasons, our memories allow us to learn, correct, progress, bond, and cherish, facilitating forward momentum rather than stagnation, or worse, regression. If we could not remember anything…. We’d be lost.
Our reliance upon memory is not limited to our ability to remember where we put our car keys or where we live, but rather is a phenomenon that occurs throughout our bodies in various contexts. For example, the ability of our immune systems to remember infections that we’ve encountered in the past is the reason that we do not get chicken pox twice, as well as the basis for vaccination. If the immune system lost its memory, our bodies would be susceptible to re-infection with a myriad of disease-causing pathogens, representing a serious health risk.
So what could cause this debilitating memory loss? New evidence points to the immune system’s equivalent of a concussion-causing blow to the head: the measles virus.
Measles and Immune Suppression
Measles, caused by infection with the measles virus (MeV), is a highly contagious disease that can cause cold-like symptoms, fever, rash, and death. Before the widespread administration of the measles vaccine in 1963, MeV infection claimed an average of 2.6 million lives each year. Since then, MeV-associated deaths have dropped dramatically, but still as of 2017 over 100,000 people died from this disease. Further, since 2018, measles cases worldwide have increased by 300%, largely due to a reduction in MeV vaccination.
In addition to risks associated with the primary measles infection, studies have also suggested that those infected with measles have reduced immunity and higher risk of infection for many years afterwards. In fact, the majority of measles-related deaths have been attributed to secondary infections that become deadly due to impaired immune function.
Although this link between MeV and immune suppression has been hypothesized for years, the underlying reason has been elusive until recently. In November of this year, two independent studies presented evidence that MeV alters the composition of one of the immune system’s key populations: B-cells.
B-cells: the keepers of memory
The immune system is composed of many different types of cells, each with specialized functions. One of these flavors of immune cell is the B-cell, which protects the host against disease by producing proteins called antibodies (Figure 1). Antibodies are specialized proteins that, in a lock-and-key fashion, attach themselves to disease-associated molecules in a lock-and-key fashion such as those made by viruses or bacterial cells. When an antibody recognizes and binds to one of these disease-associated molecules, it kickstarts a cascade of events intended to rid the body of the invader. For example, one role of an antibody is to mark the dangerous cells for destruction by other members of the immune system, such as phagocyte macrophages. By flagging bacteria or virus-infected cells and marking them for death, antibodies prevent the pathogen from replicating and spreading throughout the body.
In addition to protecting us against acute infections, B-cells and their antibodies are also vital for protecting us from re-infection by the same pathogen. Each B-cell, termed a B-cell clone, produces a unique antibody that specifically binds to only one or a couple of molecules, like two puzzle pieces fitting together. This means that, out of all of the B-cells in the body at a given time, only a small handful might be capable of making antibodies that recognize a certain pathogen. For example, some might recognize measles virus while others might recognize E.coli and still others might bind to hepatitis B virus. When we get infected with a new pathogen, say the influenza virus for example, the different B-cell clones capable of recognizing this virus will become activated and divide, eventually generating a much larger army of antibody-secreting cells to eliminate the flu. But, this process takes time, which is why it can take day or even weeks to get over the flu.
Once the body knows that that particular flu virus is around and is a threat, it maintains a larger pool of virus specific B-cells, termed memory B-cells. These cells are then ready to re-mount an attack should you get infected with the same virus again, eliminating it swiftly and effectively and explaining why we generally do not come down with the same sickness twice.
Given the pivotal role of B-cells and their antibodies in protecting us against both new and old pathogens, Measles is a particularly threatening disease. You see, MeV does not attack just any cells indiscriminately, but rather has a penchant for infecting B-cells.
Measles: the erasers of memory
Two independent studies, out of Harvard and Cambridge, recently investigated the implications of MeV’s ability to infect and kill B-cells. Both studies followed children in communities with a low MeV immunization rate, taking blood samples before any sign of infection and then again after the children naturally caught the virus.
The Harvard group tracked the antibody repertoire before and after MeV infection and reported a significant reduction in antibody diversity, indicating that MeV infection diminished the pool of B-cell clones capable of producing unique antibodies. The average loss of diversity among the MeV infected children was 20% , but about 12% of the group lost over 40% of their antibody repertoire (Figure 2). Importantly, similar effects were not seen in children who had received the measles vaccine.
Using a complementary strategy, the Cambridge group studied the genes that provide the instructions for making antibodies, investigating how the diversity of these genes changed following MeV infection. They report that, following MeV infection, some individuals showed evidence of an immature immune system — one that does not contain as many different antibody genes. Because we rely on a diverse antibody repertoire to fight off new infections, having a restricted pool of antibodies could make these children more susceptible to new infections after recovering from measles.
The group from Cambridge also looked at the antibody genes in memory B-cell compartment, reporting a restructuring in these genes as well. Further, after tracking the frequency of pathogen-specific B-cell clones before and after MeV infection, they report that the majority of infected individuals experienced a significant reduction in memory B-cells.
In combination, these findings indicate that measles infection can launch a three-pronged attack on the immune system: First, it attacks immune cells and damages immune cells in the primary infection. Second, by attacking B-cells in general, it reduces the number of unique B-cell clones and thus the number of unique antibodies that a person can make. This reduced antibody repertoire leaves gaps in a person’s immune protection, potentially rendering them vulnerable to attack by new pathogens not well recognized by the remaining antibodies. Third, by attacking memory B-cells, MeV can erase the body’s memory of previously encountered infections, thereby opening a pathway for re-infection by harmful pathogens. This multifaceted assault on the immune systems makes MeV a formidable opponent, one that is best stopped in its tracks by vaccination before its path of destruction can begin.