A New Understanding of Memory B Cell Generation in Bacterial Infections

We all know that when we’re sick, our immune system launches a response to help rid our bodies of the invading pathogen. But in addition to the cells generated for immediate pathogen elimination, our immune system also generates a set of cells that stick around for months to years; these cells are called memory cells¹. These long-lasting memory cells that are generated during an infection are specific for a particular pathogen, so if that same pathogen tries to invade months later, your memory cells will immediately recognize it. Once the memory cell recognizes that pathogen it can mount a robust immune response, hopefully before you even begin to feel sick. These memory cells are what mediate the protection against pathogens that is generated by vaccination¹.

There are two main types of memory cells: memory B cells and memory T cells. Memory T cells are derived from activated T cells during infection, which are responsible for cell-mediated immunity. T cells activate other immune cells upon infection, and kill cells that are infected with a pathogen. Memory B cells are derived from activated B cells, and are important for antibody secretion. Therefore B cells function as a vital part of humoral immunity, or immunity derived form macromolecules in fluid, in this case our bodily fluids. Antibodies bind pathogen to prevent it from entering your own cells, and to signal phagocytic cells (or “eater cells”) to destroy the pathogen by ingestion. When a memory B cell encounters its cognate pathogen upon secondary infection, it divides to form more B cells that begin to secrete antibodies to fight the pathogen.

There are many types of memory B cells, which differ in the type of antibody they produce. When a B cell is fighting an infection, it can undergo something called a class switch, which changes the type of antibodies it secretes. There are five main types of antibodies, aptly name isotypes, and each has a specific function. The IgG memory B cell, which secretes the IgG antibody isotype, has long been thought to be the primary contributor to our memory B cell populations. However in the past few years scientists have found that our memory B cell populations are actually more diverse than originally thought. In one recent study, scientists established an important role for another type of memory B cell generated after bacterial infection, the IgM B cell.

IgM B cells are the first B cells generated during an immune response for a specific pathogen. While some IgM B cells produce antibodies to begin to target the pathogen for destruction, other B cells begin to undergo class switching to produce other types of antibodies, like IgG. These B cells also undergo mutations in the DNA region that codes for the pathogen-binding domain on the antibody so that the pathogen can bind the antibody with a better fit; this is called affinity maturation. Therefore, it has long been thought that memory B cells that have undergone class switching and affinity maturation, like IgG memory B cells, are better suited for response to secondary infection since they bind the pathogen with higher affinity². But a study published by Yates and colleagues showed that IgM memory B cells, which don’t undergo affinity maturation, are actually a large proportion of our memory B cells generated during a bacterial infection. Furthermore, these IgM cells are required for the generation of IgG responses during secondary antigen challenge.

You Are What You Eat: A New Therapeutic Approach to IBD

Virulent fimbria expression on bacterial mats in the absence and presence of Phloretin (Lee et al., 2011)

Many inflammatory bowel diseases (IBD) such as Chron's (CD) or ulcerative colitis (UC) are considered autoimmune diseases caused by the body's immune system attacking the gastrointestinal tract. This is thought to trigger colitis, the medical term used to describe colonic and often intestinal inflammation. Specifically, a failure to regulate T cell responses are believed to trigger the inflammation of the intestinal or colonic mucosa in these disorders.

Researchers have begun to suspect intestinal microflora inhabiting the mucosae play a significant role in the development of IBD and colitis. Patients suffering from IBD have been shown to have higher concentrations of mucosal bacteria that increase progressively with symptom severity. The mucosae are thin membranes that are found throughout the body in areas where internal organs and tissues are exposed to external environments. They possess unique immune systems that are tightly regulated and hyporesponsive, or unresponsive to most antigens, due to the high antigen loads they come into contact with (Neurath et al., 2007). Because the mucosae are so sensitive to inflammatory damage, disruption of the hyporesponsive state can have devestating effects.

Phloretin is a type of flavonoid found mainly in apples and strawberries that has antioxidative and anticarcinogenic properties, as well as biological roles in estrogen hormonal activity and cardiovascular disease prevention. If the roles of phloretin weren't already diverse enough, researchers have also recently found flavonoids can inhibit the biofilm formation of pathogenic E. coli O157:H7. Bacterial biofilms are aggregates of bacteria that aggregate together and adhere to a surface. This might explain another recent study that found phloretin is capable of reducing the expression of many inflammatory proteins and receptors in human colon epithelial cells.

Recently, this relationship between phloretin and biofilm formation was further investigated by a team of researchers hoping interested in whether phloretin's inhibitory effect on biofilm formation could have a therapeutic effect on patients of IBD (Lee et al., 2011).

Vaccinating by Proxy: Preventing Neonatal Infection by GBS

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a commensal bacteria that is commonly found in the vagina of approximately 30% of healthy women. While GBS does not normally pose a health risk to humans, GBS infection is a serious risk for neonatal infants. This otherwise innocuous bacterium is the leading cause of neonatal septicemia, pneumonia, and meningitis. Neonatal GBS infection carries with it a 10% mortality rate, and meningitis caused by GBS leaves 25 to 35% of survivors with permanent neurological damage. Current treatment of GBS is focused on the identification of “at-risk” mothers and the prevention of mother-infant transmission through intrapartum antibiotic prophylaxis (IAP). In IAP, a mother who has been identified as a GBS carrier is treated with antibiotics during her pregnancy, particularly during the third trimester. While this preventative treatment has been effective in reducing the incidence of early-onset disease (EOD), it is not without its problems. IAP has been unable to prevent a rise in infant mortality in the last decade due to late-onset disease (LOD), which occurs after the first week of life. Unfortunately, LOD is the most damaging form of GBS infection, as it tends to cause meningitis. At the same time, the rise of antibiotic-resistant strains of GBS has been linked to the widespread use of IAP as a preventative measure (11, 12).

Due to the problems with current GBS treatments, current research is focused on the development of an effective vaccine. While the fragility of the fetal and neonatal immune system makes immunizing the fetus itself impractical, neonates may develop immunity to diseases against which their mother has been vaccinated. This occurs through a phenomenon known as passive immunity, in which antibodies produced by the mother cross the placenta and enter the fetal bloodstream. Previous attempts to design vaccines for GBS have been met with difficulty due to the wide variety of infectious GBS strains. Ideally, a vaccine would target a protein that is both required for infection – also known as a virulence factor – and that is shared by all infectious strains of GBS. A second difficulty with promoting GBS immunity in infants is that the reasons for neonatal susceptibility to GBS have not previously been well-understood. While it is clear that GBS is able to prevent an effective immune response, the methods by which it does so had not been characterized.

A Chronic Viral Infection May Affect Ability to Fight Off Bacteria

The prevalence of viruses like HIV and Hepatitis C, which cause chronic infections, raises questions about the long-term effects of infection on the immune system. These questions include: How does the immune system’s composition change in response to a chronic infection? How do the immune system’s effector functions change? How is a defense mounted against other simultaneous infections? In a recent PLoS Pathogens article, Zajac and coworkers address some of these questions. They describe a population of cells, called exhausted T cells, which develop from chronic viral infection and have a reduced ability to fight bacteria.

The presence of an intracellular pathogen, like a virus, rallies a population of T cells to combat the virus. Among the cells produced are effector and memory CD8+ T cells. Effector CD8+ T cells are capable of lysing (killing) cells infected with the same virus that induced their production. Memory CD8+ T cells, on the other hand, wait for further stimulation (a second infection with the same virus) to proliferate and produce the next generation of effector cells. These functions constitute an adaptive response, where T cells respond to one antigen (the virus) specifically.

In addition, effector and memory CD8+ T cells can mount a broader innate-like response that does not require the presence of the specific antigen that induced their production. For example, if effector or memory CD8+ T cells receive cytokines (molecular signals) IL-12, IL-18, and IL-21, produced in response to an infection, they can secrete a cytokine called IFN-gamma that helps other cells take action against the infection. Here the memory and effector cells are responding not to one antigen, but any antigen that induces production of IL-12, IL-18, and IL-21.

While it was already known that exhausted T cells, produced from persistent viral infection (think: less effective versions of effector/memory cells), mount weaker adaptive responses than normal effector or memory T cells (2), Zajac and coworkers found that exhausted T cells mount weaker innate-like responses, as well.