Thursday, September 19, 2013

The Road to Unconventional Immune System Memory

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

Memory Cell Diagram

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