Memory B cell

Memory B cells are a B cell sub-type that are formed within germinal centers following primary infection. Memory B cells can survive for decades and repeatedly generate an accelerated and robust antibody-mediated immune response in the case of re-infection (also known as a secondary immune response).[1][2]

B lymphocytes are the cells of the immune system that make antibodies to invading pathogens like viruses. They form memory cells that remember the same pathogen for faster antibody production in future infections.

Primary response

           In a T-cell dependent development pathway, naïve follicular B cells are activated by antigen presenting TFH cells during the initial infection, or primary immune response.[2] After activation, the B cells move into the secondary lymphoid organs (i.e. spleen and lymph nodes).[2] Within the secondary lymphoid organs, most of the B cells will enter B-cell follicles where a germinal center will form. Most B cells will eventually differentiate into plasma cells or memory B cells within the germinal center.[2][3]

           Once inside the germinal center, the B cells undergo proliferation, followed by mutation of the genetic coding region of their surface receptors, a process known as somatic hypermutation.[2]  The mutations will either increase or decrease the affinity of the surface receptor for a particular antigen, a progression called affinity maturation. After acquiring these mutations, the receptors on the surface of the B cells (B cell receptors) are tested within the germinal center for their affinity to the current antigen.[4] B cell clones with mutations that have increased the affinity of their surface receptors receive survival signals via interactions with their cognate TFH cells. [1][2][5] The B cells that do not have high enough affinity to receive these survival signals, as well as B cells that are potentially auto-reactive, will be selected against and die through apoptosis.[3] In addition to somatic hypermutation, many B cells will also undergo class switching before differentiation, which allows them to secrete different types of antibodies in future immune responses.[2]

           Many B cells will differentiate into the plasma cells, also called effector B cells, which produce a first wave of protective antibodies and help clear infection.[3][1] A fraction of the B cells differentiate into memory B cells that survive long-term in the body.[6]  The process of differentiation into memory B cells within the germinal center is not yet fully understood.[2] Some researchers hypothesize that differentiation into memory B cells occurs randomly.[3][7] Other hypotheses propose that the transcription factor NF-κB and the cytokine IL-24 are involved in the process of differentiation into memory B cells.[8][2] An additional hypothesis states that the B cells with relatively lower affinity for antigen will become memory B cells, in contrast to B cells with relatively higher affinity that will become plasma cells.[3][8]

           After differentiation, memory B cells relocate to the periphery of the body where they will be more likely to encounter antigen in the event of a future exposure.[3][1][2] Many of the circulating B cells become concentrated in areas of the body that have a high likelihood of coming into contact with antigen, such as the Peyer’s patch.[2]

Secondary Response and Memory

The memory B cells produced during the primary immune response are specific to the antigen involved during the first exposure. In a secondary response, the memory B cells specific to the antigen or similar antigens will respond.[2] When memory B cells reencounter their specific antigen, they proliferate and differentiate into plasma cells, which then respond to and clear the antigen.[2] The memory B cells that do not differentiate into plasma cells at this point can reenter the germinal centers to undergo further class switching or somatic hypermutation for further affinity maturation.[2]  Differentiation of memory B cells into plasma cells is far faster than differentiation by naïve B cells, which allows memory B cells to produce a more efficient secondary immune response.[7]  The efficiency and accumulation of the memory B cell response is the foundation for vaccines and booster shots.[7][2]

Lifespan

Memory B cells can survive for decades, which gives them the capacity to respond to multiple exposures to the same antigen.[2]  The long-lasting survival is hypothesized to be a result of certain anti-apoptosis genes that are more highly expressed in memory B cells than other subsets of B cells.[3] Additionally, the memory B cell does not need to have continual interaction with the antigen nor with T cells in order to survive long-term.[7]

Markers of memory B cells

Memory B cells are typically distinguished by the cell surface marker CD27, although some subsets do not express CD27. Memory B cells that lack CD27 are generally associated with exhausted B cells or certain autoimmune conditions such as HIV, lupus, or rheumatoid arthritis.[1][2]

Because B cells have typically undergone class switching, they can express a range of immunoglobulin molecules. Some specific attributes of particular immunoglobulin molecules are described below:  

           IgM: Memory B cells that express IgM can be found concentrated in the tonsils, Peyer’s patch, and lymph nodes.[2] This subset of memory B cells is more likely to proliferate and reenter the germinal center during a secondary immune response.[7]

           IgG: Memory B cells that express IgG typically differentiate into plasma cells.[7]

           IgE: Memory B cells that express IgE are very rare in healthy individuals. This may occur because B cells that express IgE more frequently differentiate into plasma cells rather than memory B cells [7]

           IgD only: Memory B cells that express IgD are very rare. B cells with only IgD are found concentrated in the tonsils.[2]

The receptor CCR6 is generally a marker of B cells that will eventually differentiate into MBCs. This receptor detects chemokines, which are chemical messengers that allow the B cell to move within the body. Memory B cells may have this receptor to allow them to move out of the germinal center and into the tissues where they have a higher probability of encountering antigen.[3]

Subsets of Memory B Cells

Germinal center independent memory B cells

This subset of cells differentiates from activated B cells into memory B cells before entering the germinal center. B cells that have a high level of interaction with TFH within the B cell follicle have a higher propensity of entering the germinal center. The B cells that develop into memory B cells independently from germinal centers likely experience CD40 and cytokine signaling from T cells.[7] Class switching can still occur prior to interaction with the germinal center, while somatic hypermutation only occurs after interaction with the germinal center.[7] The lack of somatic hypermutation is hypothesized to be beneficial; a lower level of affinity maturation means that these memory B cells are less specialized to a specific antigen and may be able to recognize a wider range of antigens.[8][9][7]

T-independent memory B cells

T-independent memory B cells are a subset called B1 cells. These cells generally reside in the peritoneal cavity. When reintroduced to antigen, some of these B1 cells can differentiate into memory B cells without interacting with a T cell.[7] These B cells produce IgM antibodies to help clear infection.[10]

T-bet memory B cells

T-bet B cells are a subset that have been found to express the transcription factor T-bet. T-bet is associated with class switching. T-bet B cells are also thought to be important in immune responses against intracellular bacterial and viral infections[11]

See also

References
  1. Weisel, Florian; Shlomchik, Mark (2017-04-26). "Memory B Cells of Mice and Humans". Annual Review of Immunology. 35 (1): 255–284. doi:10.1146/annurev-immunol-041015-055531. ISSN 0732-0582. PMID 28142324.
  2. Seifert, M; Küppers, R (2016-08-08). "Human memory B cells". Leukemia. 30 (12): 2283–2292. doi:10.1038/leu.2016.226. ISSN 0887-6924. PMID 27499139.
  3. Suan, Dan; Sundling, Christopher; Brink, Robert (2017-04-01). "Plasma cell and memory B cell differentiation from the germinal center". Current Opinion in Immunology. Lymphocyte development and activation * Tumour immunology. 45: 97–102. doi:10.1016/j.coi.2017.03.006. ISSN 0952-7915. PMID 28319733.
  4. Allman, David; Wilmore, Joel R.; Gaudette, Brian T. (March 2019). "The continuing story of T‐cell independent antibodies". Immunological Reviews. 288 (1): 128–135. doi:10.1111/imr.12754. ISSN 0105-2896. PMC 6653682. PMID 30874357.
  5. Victora, Gabriel D.; Nussenzweig, Michel C. (2012-03-26). "Germinal Centers". Annual Review of Immunology. 30 (1): 429–457. doi:10.1146/annurev-immunol-020711-075032. ISSN 0732-0582. PMID 22224772.
  6. Gatto, Dominique; Brink, Robert (2010-11-01). "The germinal center reaction". Journal of Allergy and Clinical Immunology. 126 (5): 898–907. doi:10.1016/j.jaci.2010.09.007. ISSN 0091-6749. PMID 21050940.
  7. Kurosaki, Tomohiro; Kometani, Kohei; Ise, Wataru (March 2015). "Memory B cells". Nature Reviews Immunology. 15 (3): 149–159. doi:10.1038/nri3802. ISSN 1474-1733. PMID 25677494.
  8. Shinnakasu, Ryo; Kurosaki, Tomohiro (2017-04-01). "Regulation of memory B and plasma cell differentiation". Current Opinion in Immunology. Lymphocyte development and activation * Tumour immunology. 45: 126–131. doi:10.1016/j.coi.2017.03.003. ISSN 0952-7915. PMID 28359033.
  9. Pupovac, Aleta; Good-Jacobson, Kim L (2017-04-01). "An antigen to remember: regulation of B cell memory in health and disease". Current Opinion in Immunology. Lymphocyte development and activation * Tumour immunology. 45: 89–96. doi:10.1016/j.coi.2017.03.004. ISSN 0952-7915. PMC 7126224. PMID 28319732.
  10. Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2012-01-27). "B-1 B Cell Development in the Fetus and Adult". Immunity. 36 (1): 13–21. doi:10.1016/j.immuni.2011.11.017. ISSN 1074-7613. PMC 3269035. PMID 22284417.
  11. Knox, James J.; Myles, Arpita; Cancro, Michael P. (March 2019). "T‐bet + memory B cells: Generation, function, and fate". Immunological Reviews. 288 (1): 149–160. doi:10.1111/imr.12736. ISSN 0105-2896. PMC 6626622. PMID 30874358.
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