B cells
The second line of defence
Credit: Art by Nelly Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Semeli Platsaki, PhD. Project Coordinator: Dr. Masia Maksymowicz. Series Director: Dr. Radhika Patnala
#Extraordinarycelltypes #sciart #lifescience
We are under invasion!
What happens when the body is attacked by a pathogen? It could be a bacterium, a virus or a parasite. The first line of defense (aka the innate immune response) is activated, conducted by phagocytic cells, whose role is to capture the invaders and destroy them. And what if this first line starts to crack? Here comes the second, more sophisticated line of defense, made up, among others, of B cells. B cells are a remarkably diverse immune cell type, a feature that enables them to adapt to the invading environmental factors and produce an appropriate response (1), referred to as adaptive immunity.
A day in the life
B cells start their life in primary lymphoid organs such as the human bone marrow, where hematopoietic stem cells develop into immature B cells (2, 3). Each immature B cell is equipped with a B cell receptor (BCR), the membrane-anchored form of IgM and IgD antibodies, that is able to recognise a unique antigen and alert the cell about the presence of an invader (4). The superpower of B cells to recognize many different antigens is due to a process called V(D)J recombination, through which different genes coding for the Variable, Diversity and Joining immunoglobulin chains of the BCR are shuffled and assembled together in nearly infinite combinations. Each cell has one BCR combination, giving it a unique antigen specificity. Each cell is somewhat special.
Now, how do B cells make sure they react only to ‘foreign’ and not ‘self’ antigens? Central tolerance mechanisms ensure the correct assembly and function of BCRs; autoreactive B cells die by programmed cell death, apoptosis, or become unresponsive to antigens and eventually die through a process called anergy. Finally, autoreactive BCRs can undergo receptor editing, by which antibody light chain genes are rearranged. These checkpoints are part of the necessary quality control that B cells have to pass to be considered apt for further development (3).
On patrol
The immature B cells transition from the bone marrow and enter the peripheral blood circulation to patrol the lymphatic organs looking for antigens, through which they will become activated. Antigens engage mainly with BCRs, but can also be bound by B cells’ complementary surface receptors (4). After internalization via endosomes, the BCR-antigen complex is carried to lysosomes, for enzymatic degradation. The resulting antigen-derived peptides are displayed at the surface of the B cells by major histocompatibility complex II for recognition by T cells, resulting in the activation of the latter (4). The journey doesn’t end here, as activated B cells have more differentiation steps to go through, depending on the antigens encountered, as well as cytokines and other co-activating signals. In the spleen, B cells will further differentiate into short-lived plasma B cells. As part of the primary immune response, short-lived plasma B cells recognize antigens based on the basic BCR diversity defined in the bone marrow and secrete the respective generic antibodies.
The ones that remember
A small population of B cells may enter the germinal center of secondary lymphatic organs (for example the lymph nodes) (5), where they will further evolve to acquire ‘memory’ (5). In the germinal center, B cells diversify their BCRs by two complementary processes: (i) class switch rearrangement, through which the genes expressing the light chains of antibodies undergo rearrangements, and (ii) somatic hypermutation, through which specific mutations are introduced on the antibodies’ variable regions. Both these processes refine BCR affinity and selectivity for antigens (5). As a consequence, the produced antibodies are more specific. Notably, germinal center B cells have an elongated probing protrusion for optimizing the search for surface-displayed antigens. This morphology is distinct to the one of naïve (inactivated) B cells.
Finally, germinal center B cells can differentiate into long-lived plasma B cells or memory B cells, based on BCR affinity as the main criterion (6–8). Plasma B cells are responsible for producing and releasing specific antibodies against the invading pathogens, while memory B cells, like elephants, have an excellent memory! They are capable of rapid response of high magnitude to subsequent exposures to a known antigen, a process also known as secondary immune response. This kind of ‘memory’ is the principle behind classical vaccination; by releasing a small amount of antigen in the ‘naive’, non-exposed individual, the vaccine allows the body to create a memory of this antigen and be able to efficiently respond to it in future encounters.
Double-edged sword
As you may have guessed by now, the central role of B cells in the immune response comes with the heavy weight of responsibility. As much as B cells can be beneficial by providing memory to our immune system, they can also be misled and use their ‘weapons’ against the body itself, resulting in autoimmune disease development (9). The B cell maturation processes described earlier are far from perfect. Take VDJ recombination as an example: this process can generate up to 75% of autoreactive BCR species (BCRs that react to self-antigens of the body), which can, subsequently, generate autoimmunity. In such cases, B cells produce auto-antibodies that recognize peptides of the body as antigens and present them to self-reactive T cells that then produce proinflammatory cytokines (9, 10). Examples of autoimmune diseases caused by such reactions include rheumatoid arthritis and lupus erythematosus.
B cells in the fight against cancer
The role of B cells in cancer development is still a matter of controversy, as B cells can contribute both to tumor suppression and development, depending on the cancer type. Still, B cells are a very interesting target for immunotherapy. Antigen presentation by B cells, together with the subsequent activation of T cells, works as a defense mechanism against virus-induced cancers, as in the case of virus-induced leukemia (11, 12). Antibody production by B cells is another element that can work in both directions: certain antibodies may target antigens expressed by tumor cells and therefore activate tumor suppression mechanisms such as antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity (13). In other cases, the tight binding of antibodies to tumor antigens generates immune complexes that circulate in the body and are thought to be responsible for further tumor development (14).
Altogether, the multifaceted profile of B cells renders them intriguing for further studies that will provide more leads on how they can be exploited in the therapeutics field.
Recognizing and appreciating the labs working in this space:
- K. Rajewsky Lab, Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, https://www.mdc-berlin.de/k-rajewsky
- Cyster Lab, UCSF School of Medicine, San Fransisco, California USA, https://cysterlab.ucsf.edu/
- Prof Tru GiangPhan, UNSW Sydney, Garvan Institute, Australia https://research.unsw.edu.au/people/professor-tri-giang-phan
- Lucy Walker Lab, University College London (UCL) Institute of Immunity and Transplantation, London, UK, https://www.lucywalkerlab.com/, @LucyWalkerlab
- Clarke Group- Metabolism and Immunity, University of Oxford, Medical Sciences Division, UK, https://www.ndorms.ox.ac.uk/research/research-groups/translational-immunometabolism, @a_j_clarke
- Greenberg Lab, Department of Pediatrics, University of Washington, Seattle, USA, https://research.fredhutch.org/greenberg/en/research.html
- Pierre Bruhns Lab, Institut Pasteur, Paris, France, https://research.pasteur.fr/en/member/pierre-bruhns/
- B cell immunobiology Lab, NYU Grossman School of Medicine, New York, USA, https://med.nyu.edu/research/silverman-lab/
- Wesemann Lab, Harvard, Division of Medical Sciences, Boston, Massachusetts, USA, https://wesemann.bwh.harvard.edu/, @duane_wesemann
- Mauro Gaya, B cell Immunity to Infection Team, Center for Immunolofy Marseille Luminy, Marseille, France, http://www.ciml.univ-mrs.fr/science/lab-mauro-gaya/b-cell-immunity-infection
References
1. Graf, Robin et al. “BCR-dependent lineage plasticity in mature B cells.” Science (New York, N.Y.) vol. 363,6428 (2019): 748–753. doi:10.1126/science.aau8475
2. JEM Editorial Team. “Over a century of novel conceptual insights: The beginning of JEM’s 125th anniversary year.” The Journal of experimental medicine vol. 218,1 (2021): e20202668. doi:10.1084/jem.20202668
3. Bonasia, Carlo G et al. “B Cell Activation and Escape of Tolerance Checkpoints: Recent Insights from Studying Autoreactive B Cells.” Cells vol. 10,5 1190. 13 May. 2021, doi:10.3390/cells10051190
4. Cyster, Jason G, and Christopher D C Allen. “B Cell Responses: Cell Interaction Dynamics and Decisions.” Cell vol. 177,3 (2019): 524–540. doi:10.1016/j.cell.2019.03.016
5. Schultheiß, Christoph et al. “B cells in autoimmune hepatitis: bystanders or central players?.” Seminars in immunopathology vol. 44,4 (2022): 411–427. doi:10.1007/s00281–022–00937–5
6. Loder, F et al. “B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals.” The Journal of experimental medicine vol. 190,1 (1999): 75–89. doi:10.1084/jem.190.1.75
7. Phan, T.G., et al. 2006. J. Exp. Med. https://doi.org/ 10.1084/jem.20061254
8. Foy, T M et al. “gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.” The Journal of experimental medicine vol. 180,1 (1994): 157–63. doi:10.1084/jem.180.1.157
9. Raza, Iwan G A, and Alexander J Clarke. “B Cell Metabolism and Autophagy in Autoimmunity.” Frontiers in immunology vol. 12 681105. 7 Jun. 2021, doi:10.3389/fimmu.2021.681105
10. Molnarfi, Nicolas et al. “MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies.” The Journal of experimental medicine vol. 210,13 (2013): 2921–37. doi:10.1084/jem.20130699
11. Tan, Rongying et al. “The role of B cells in cancer development.” Frontiers in oncology vol. 12 958756. 11 Aug. 2022, doi:10.3389/fonc.2022.958756
12. Schultz, K R et al. “The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia.” Science (New York, N.Y.) vol. 249,4971 (1990): 921–3. doi:10.1126/science.2118273
13. Bruhns, Pierre. “Properties of mouse and human IgG receptors and their contribution to disease models.” Blood vol. 119,24 (2012): 5640–9. doi:10.1182/blood-2012–01–380121
14. Gunderson, Andrew J, and Lisa M Coussens. “B cells and their mediators as targets for therapy in solid tumors.” Experimental cell research vol. 319,11 (2013): 1644–9. doi:10.1016/j.yexcr.2013.03.005
About the author:
DR. SEMELI PLATSAKI
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Semeli is a biochemist at heart, holding a degree in Chemistry and a PhD in protein biochemistry. After working as a researcher studying the structure-function relationship of protein in a range of biological contexts, from bacterial metalloproteins to synaptic signaling, Semeli moved on to a role in Scientific communication and project management in the European Virus Archive, a collection of virus and virus-derived resources available to researchers worldwide. Semeli is passionate about the creative mix of art, words and science, one of the best ways to make Science impactful.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
