One
of the coolest parts of the human immune system is its ability to remember
previous exposure to viruses, bacteria, or other foreign invaders. This is crucial in creating effective
vaccines that prevent humans from contracting potentially fatal diseases. If an invader is remembered, the immune
system can launch a highly specific attack and prevent the person from ever
getting sick. However, this memory
is not well understood by scientists.
As more and more studies are completed, new information about new
subsets of cell types involved in or capable of memory is being released. For example, you may know how long it
takes to drive from Philadelphia to Denver, but what good is that if you
don’t know what roads to take? This
same idea can be applied to the memory function of the immune system. It’s great that scientists know that
once a person is infected, certain cell types can remember the invader, but
it’s difficult to promote a memory response if it’s unknown how the response
even occurs. |
| General Memory B Cell Development |
A
recent paper published in The Journal of
Immunology explores the road to a memory response. The two big cell types involved in the
pathway they explore are T and B cells.
The T cells involved help to activate B cells, which then produce
antibodies. These are small
proteins that circulate through the body are responsible for “tagging” foreign
bodies, or antigens, for destruction by other immune cells or neutralizing the
effect of the foreign body. Antibodies
come in different structures with different functions, and can switch
structures during the development and maturation of the B cell from a naïve
cell to memory cell. The two
structures the researchers look at are IgM, which are usually produced by naïve
cells that haven’t switched antibody type yet, and IgG, which are usually
produced by B cells that have fully matured into memory B cells. However, recent studies have shown that
there are also memory IgM B cells, but their characteristics, purpose, and
development are unclear. Immune
cells are often identified and characterized by the molecules expressed on
their cell surface. Called CD
markers, or cluster of differentiation, they allow scientists to give a unique
expression pattern to help identify and isolate new types of immune cells. In the quest to understand the memory
IgM B cells, one of the things the authors tried to undercover was a unique CD
expression pattern on these cells.
They also looked at a mouse model of human ehrlichiosis, a bacterial infection
from ticks, to explore the necessity of a T cell-B cell interaction for the
activation of these IgM memory cells.
The also used this model to look at a secondary exposure to an antigen
and determine the connection between these new memory cells and typical IgG
memory
The
authors first found a population of B cells that expressed CD11c in the spleen
of the infected mice using flow cytometry. This technique uses antibodies specific for certain cell
surface markers attached to flourochromes to detect what antibodies attached to
what cells. These CD11c+ B cells
expressed IgM as well as CD21 and CD23, which are also expressed on IgG memory
B cells from a particular origin. The CD11c+ population was used as the main characteristic to identify the memory IgM population throughout the rest of the study. However
the IgM cells were missing GL7 and expressed CD38, an expression pattern that
is inconsistent with the IgG B cell origin suggesting that these cells aren’t
identical to IgG B cells. These
IgM B cells were even found to persist in the mice post-infection after they
had been treated for antibiotics.
The fact that they lasted so long after infection made the authors think
that these B cells could be memory IgM cells. In order to support this idea, they looked at other cell
surface markers that are present on typical memory B cells. CD11+ B cells expressed CD38, CD73,
CD80, CD95, and PD-L2, which are all expressed on other memory B cells. Another characteristic of memory cells
is that they only divide a limited number of times. To test this, they challenged the mice with BrdU, a chemical
that is incorporated into proliferating (dividing) cells. After being incubated with the chemical, the IgM cells
didn’t show any signs of having incorporated the BrdU, supporting that they
again share another characteristic of memory B cells
Next,
they looked at the mutations in the genes coding for antibodies in B
cells. In memory cells, these
genes contain a high number of mutations to show that they code for a very
specific antibody. When isolated,
the majority of the gene segments in the CD11c+ cells contained mutations,
whereas CD11- cells didn’t contain mutations. The mutations were consistent with previous studies that
explored IgM memory B cells.
Memory IgG B cells created in certain locations within the body are
unique because they require T cells to become activated. If the IgM memory B cells also require
T cells to develop, then they may be coming from the same location as typical
IgG B cells. These CD11+ cells
were unable to form when mice were deficient of the CD4+ T cells that perform
the activation, but were able to form when the T cells were present. The CD11+ cells were also found in the
same location as other memory B cells when mice were presented with antigen and
then their spleens were stained for certain cell types. To then test if the CD11+ cells were
necessary to fight the antigen in memory recall, mice were exposed to the
antigen, allowed to create CD11+ cells, and then some of the mice were depleted
of those B cells. Mice without
those cells had a much lower level of IgG and IgM antibodies specific to that
disease than the mice with those cells, supporting that the IgM response was
important to help elicit an IgG memory response as well as an IgM memory
response.
Going
back to the driving metaphor, the authors of this paper were able to figure out
how to “drive” from an infection to a memory IgM response. The roads they took included finding
characteristics shared by IgM and IgG memory B cells as well as unique
characteristics only found in the IgM variety. They also took a scenic route to show that the memory IgM
response was necessary for the memory IgG response in mice. The main challenge then becomes
translating this to humans, since mouse and human immune systems do differ to a certain extent. They also don’t address other types of
antibodies/B cell type other than IgG.
These memory IgM cells may have some other important connections to
other types of B cell types. It
would also be useful to test out this type of memory with other bacterial or
even viral infections to look at the breath of protection these IgM B cells can
provide. As previously mentioned,
this memory is crucial for vaccinations.
If scientists can understand how this memory response occurs, they can
create specific vaccines that take advantage of activation and production of
antibodies that are better suited to destroy the antigen the vaccine protects
against. This study also
demonstrates the incredible capacity that the immune system has to be able to
adapt to different invaders and destroy them in the most efficient and most
effective way. This could also
have repercussions in the field of autoimmunity. If certain B cell types are produced against your own body,
but it’s unknown how that occurs, it’s difficult to try and create
treatments. Sometimes scientists
just need to work to fill in the gaps in the information already known to the
scientific community, and this study does a great job at filling in the “road”
to memory and giving other scientists a basis to work off of.
Main Article
Yates JL, Racine R, McBride KM, Winslow GM. 2013. T cell-dependent IgM
memory B cells generated during bacterial infection are required for IgG
responses to antigen challenge. Journal of Immunology (Baltimore, Md.: 1950)
191(3):1240-9.
Background on
ehrilichiosis
http://www.cdc.gov/ehrlichiosis/
Memory Cell Diagram
http://www.nature.com/nri/journal/v2/n1/fig_tab/nri706_F1.html
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