Not sure there is such a thing as a central memory B cell.
Historically, the attributes of Somatic hypermutation – Wikipedia or SHM and Immunoglobulin class switching – Wikipedia or CSR were thought to separate a memory B cell from its naive counterpart.
Experiments have now confirmed that a B cell can be memory even without CSR. Specifically, memory B cells have been found to include incompletely spliced IgM-expressing B cells which by definition haven’t yet undergone CSR. However, such IgM+ B cells were found to have undergone SHM.
A brief primer on naive versus memory B cells may be useful at this point.
- Naive B cells secrete IgM – naive here means a mature B cell that hasn’t yet interacted with its antigen.
- This IgM is a low affinity germline antibody – affinity here refers to strength of interaction with antigen while germline means the product of a B cell that hasn’t yet undergone SHM, the process that typically exponentially increases an antibody’s affinity for its antigen.
- Being low affinity and germline, IgM was historically considered not part of a memory immune response. Implicit in this assumption was the idea that SHM goes hand in hand with CSR, which meant that a memory B cell response couldn’t be IgM since it is pre-CSR.
- SHM consists of mutations in the variable region of the immunoglobulin (antibody) molecule, a process that improves an antibody’s antigen binding specificity and therefore its affinity for that antigen while CSR entails replacement of the Fc portion of the IgM immunoglobulin (antibody) molecule with the Fc portion of other antibody isotypes such as the various IgGs (IgG1, 2, 3 or 4 in humans) or IgA or IgE.
The first time around a naive B cell’s antibody response to its antigen is slow, consisting of low affinity germline IgM and a full-blown high affinity class-switched antibody response takes 2 to 3 weeks on average to mature to full bloom.
- In this maturation process that usually takes place within specialized compartments called germinal centers within lymph nodes and the spleen, the number of B cells responding to a particular antigen typically increase to several hundreds to thousands and sometimes even tens of thousands-fold.
- Most of these activated cells eventually die, a few survive to become memory B cells while others differentiate to become plasmablasts that eventually become plasma cells – cells that lose their B cell receptors and live mostly in the bone marrow as antibody secreting factories, often for decades on end.
By comparison, when memory B cells reencounter their antigens, they get up to speed in spewing out highly specific and high affinity antibodies in a matter of days.
Germline IgM is a blunt instrument in other words – good enough in the beginning of an immune response to keep harm in abeyance while a more specific, sensitive, finely honed and targeted antibody response in the form of higher affinity, class-switched IgGs, IgA and/or IgE get going as more information percolates through the tiers of cells that make up the immune system and shapes the developing immune response. Such information takes the form of more antigens as well as secretory molecules such as cytokines and chemokines and cell-surface molecules such as receptors and ligands.
Both SHM and CSR were considered necessary hallmarks of differentiation into memory until research starting in the late 1990s began to show subsets of memory B cells that expressed IgM on their cell surface as well as secreted it. That wasn’t all. This IgM wasn’t germline but instead somatically hypermutated (1, 2, 3, 4). Some of this IgM is T cell-dependent (1, 2), other not (3, 4).
Thus SHM but not CSR is now considered a necessary feature of memory B cell response.
That said, much about memory B cells still remains unknown.
- For example, though the cell surface molecule CD27 was considered a reliable marker of human memory B cells at one point, now it is better understood as one that marks post-activation B cells.
- Lack of unique markers that reliably single out memory B cells means that studies are ever tussling with the issue of whether they dealt with bonafide memory B cells or with memory-like B cells.
- What are the rules that determine memory B cell formation – what separates the activated B cells destined to die from those destined for memory fate? Why do some activated B cells stay IgM+ while others switch to other isotypes (IgGs, IgA or IgE)?
- Upon reencounter with their antigen, do IgM+ memory B cells proliferate to give rise to only clonal progeny or can they give rise to B cells that secrete other antibodies? What rules determine which outcome prevails?
- Do IgM+ memory B cells differentiate into plasmablasts (and eventually plasma cells)?
- What determines the share of IgM+ memory B cells in any given immune response?
A table and figures from 5 and 6 summarize recent classifications of memory B cells, how they appear to develop and the basics of competing models that attempt to explain how they arise and how they’re maintained.
Bibliography
1. Klein, Ulf, Ralf Küppers, and Klaus Rajewsky. “Evidence for a large compartment of IgM-expressing memory B cells in humans.” Blood 89.4 (1997): 1288-1298.
2. Klein, Ulf, Klaus Rajewsky, and Ralf Küppers. “Human immunoglobulin (Ig) M+ IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells.” Journal of Experimental Medicine 188.9 (1998): 1679-1689.
3. Kruetzmann, Stephanie, et al. “Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen.” Journal of Experimental Medicine 197.7 (2003): 939-945.
4. Weller, Sandra, et al. “Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire.” Blood 104.12 (2004): 3647-3654.
5. Seifert, M., and R. Küppers. “Human memory B cells.” Leukemia 30.12 (2016): 2283.
6. Shlomchik, Mark J., and Florian Weisel. “Germinal center selection and the development of memory B and plasma cells.” Immunological reviews 247.1 (2012): 52-63.