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.
The researchers first wanted to
show that memory IgM B cells are truly generated during a bacterial infection.
They infected mice with ehrlichiae, a tick-borne bacterium, and analyzed the
immune cells that were generated in response to the ehrlichiae (E. muris)
infection. Each type of immune cell has a unique set of cell surface proteins
that distinguish it from another type of cell. Therefore the researchers
analyzed the cell surface markers on the immune cells generated in response to
E. muris infection to identify different populations of immune cells. They
identified the cell surface markers by flow cytometry. In flow cytometry, cells
are treated with a fluorescing molecule that binds to a cell surface molecule
of interest. The cells are then run through a flow cytometer, which quantifies
the amount of the fluorophore on the cell, indicating how much of the molecule
of interest is present on the cell. Using flow cytometry, the researchers
identified a population of cells with a unique cell marker, CD11c, which secretes
IgM antibodies. They isolated these cells, and using flow cytometry established
that the CD11c-positive cells also expressed known markers of memory B cells. These
CD11c-positive IgM-secreting cells were further proven to be true memory cells
by showing that like other memory cells, they undergo limited cell division,
and contain mutations that are evidence for affinity maturation.
Once the researchers established
that the CD11c-positive cells were IgM memory B cells, they wanted to determine
where they are located in the immune system. They stained the spleen with a
fluorescing antibody tag that binds CD11c-positive cells, and observed that
they were located in the marginal zone of the spleen; this is consistent with
previous studies that have shown that other types of memory B cells localize in
the marginal zone of the spleen, where the cells contact flowing blood that may
carry antigen.
The researchers then showed that
when mice were infected for a second time with E. muris, there was a robust
immune response from the memory cells specific for E. muris. So they wanted to
determine if the CD11c-positive memory B cell population was directly
responsible for the robust and rapid immunological response upon secondary
infection, or if another memory B cell population was responsible. They
investigated the role of the CD11c-positive memory B cells by re-infecting mice
with E. muris 30 days after initial infection. In the experimental group of
re-infected mice, the researchers depleted the CD11c-positive cell population
by giving the mice a toxin that resulted in the depletion of the IgM memory B
cells. They then analyzed the effect of IgM depletion by looking at IgG
production in the control versus depleted mice. They found that mice that were
depleted in IgM memory B cells had significantly lowered levels of IgG
antibody. This suggests that that IgM memory cells undergo class switching upon
secondary Ag challenge, and are responsible for the IgG response (generated by
class switching).
Taking the data together, the
researchers showed that IgM memory B cells are established in response to
bacterial infection and that these IgM memory cells are responsible for IgG
production during secondary challenge. But why is this important? Why does it
matter that IgM memory B cells are now thought to play an important role in
memory cell response to secondary infection? Yates and collegues’ finding help
us to better understand memory cell generation. The findings suggest that
different types of memory cells are best suited for different types of pathogens.
While IgG memory B cells may be important for viral pathogens, this study shows
that IgM memory cells may be the superior memory cell type for a bacterial
infection.
While these findings are important,
further research can be done to elucidate the functions of IgM memory cells.
All of the experiments presented by Yates et al. were done in a mouse model.
Research should be conducted to determine if IgM memory B cells are present in
humans. If they exist, what characteristics do they share with the isolated IgM
memory cells in mice, and what characteristics are different? In addition, the
researchers only looked at one type of bacteria, E. muris. Future experiments can look for IgM memory
cell production in response to different types of infections, in both humans
and mice. Lastly, in future experiments researchers can look to see if IgM
memory cells undergo class switching to generate other antibody isotypes upon
secondary infection. Further investigation will help the scientific community
to better understand immunological memory in response to different types of
pathogens, and may help us to create better vaccines for specific types of
pathogens.
Link to the article:
Primary Source:
Yates, J.L.,
Racine, R., McBride, K.M., & Winslow, G.M. (2013). T Cell-Dependent IgM
Memory B Cells Generated during Bacterial Infection Are Required for IgG
Responses to Antigen Challenge. J.
Immunol., 191, 1240-1249.
Secondary Sources
1. McHeyzer-Williams,
M., Okitsu, S., Wang, N., & McHeyzer-Williams, L. (2012). Molecular
programming of B cell memory. Nat. Rev.
Immunol., 12, 24-34.
2. Good-Jacobson,
K.L., & Tarlinton, D.M. (2012). Multiple routes to B-cell memory. Int. Immuunol., 24, 403-408.
Image Sources
http://leslielivingenvironment.blogspot.com/2010/01/antibody-animation.html
http://www.mcqbiology.com/2013/02/multiple-choice-questions-on-immunology.html
Pillai, S., & Cariappa, A. (2009). The follicular versus
marginal zone B lymphocyte cell fate decision. Nat. Rev. Immunol., 9, 767-777.
I wonder if the switch from IgM to IgG is beneficial maybe not for the type of infection (considering the secondary Ag response is to the same type of infection) but maybe there is some inherent advantage in the structure of the IgG domain. Perhaps the IgG domain is better at evoking an immune response (because its better recognized by certain lymphocytes?) and thus switching to IgG helps clear the pathogen faster? Another way IgG domains might be more inherently beneficial is that they could be more stable in some way so that they would have a longer half life compared to IgM? It would make sense if this were the case because if an antigen is encountered a second time it might be more likely to encounter it again in the future and needs to be prepared with longer lived, more stable antibodies. If I were the researchers I would look into the half life of the original IgM antibodies compared to that of the secondary IgG antibodies.
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