NEW STUDY. A study by researchers in the Department of Rheumatology and Inflammation identifies a mechanism in the signal system that activates B cells. The findings could enable new ways of treating cancer diseases caused by B cells becoming malignant, such as certain forms of lymphoma.
This research is fundamental and increases the understanding of the cascade of signals that lead to activation of a B cell when it encounters viruses, bacteria, or other pathogens in the body. This first leads to the cell dividing (proliferating) and then starting to secrete just the antibody needed to deal with that particular invader. The study concerns mechanisms that are activated when the membrane-bound antibody on the surface of the B cell (the B cell receptor IgM-BCR) binds its specific pathogen. This leads to the cell dividing and then differentiating into a plasma cell, which is a type of cell that secretes large amounts of antibodies, initially IgM.
The findings are highly relevant for cancer research, as the critical molecule (the protein CD38) is highly overexpressed in almost all forms of cancer involving B cells.
The findings have been published by the Journal of Experimental Medicine.
Chance led to a new direction
It was a pure chance that Alessandro Camponeschi started investigating CD38. As a newly minted postdoctoral fellow in Lill Mårtensson-Bopp’s team, he worked on labeling cells with antibodies and sorting them into different cell populations.
“We investigated phenotypes for different types of cells, i.e., differences in the cells’ expression of surface proteins, and I had the idea to add antibodies that recognize CD38. Suddenly, to my surprise, the B cells stopped dividing and secreting IgM antibodies. Now, five years later, it is my main focus and has resulted in a publication in a reputable journal,” says Alessandro Camponeschi, who is the first author of the article.
The current study shows that the cell surface protein CD38 is needed to activate the receptor, IgM-BCR, which leads to the production of the antibody IgM. Previously it has been suggested by other researchers that CD38 plays an important role in the activation of the receptor, which this study now demonstrates.
“When we blocked CD38 with an antibody or removed this molecule using the gene scissors CRISPR/Cas9, the connection between the receptor IgM-BCR and its co-receptor CD19 was inhibited. This impaired the signaling system that activates the IgM-BCR in both normal and malignant B cells,” says Alessandro, who is a researcher at the Department of Rheumatology and Inflammation at the Institute of Medicine.
In the study, the researchers also found that CD19, another protein that interacts with IgM-BCR, is located in the same small compartment on the B cell’s surface with CD38 and together they move close to the IgM-BCR upon pathogen recognition.
“We were able to show that the two molecules CD38 and CD19 sit very close to each other and move together when the IgM-BCR receptor is activated. Without either of these two proteins, the B cell is not activated.”
Relevant to cancer research
A large amount of CD38 is expressed in almost all forms of cancer involving B cells (multiple myeloma, lymphoma, and leukemia). Antibodies for the CD38 protein are already used in immunotherapy when treating multiple myeloma. The findings of this study indicate that antibodies against CD38 could be used as a treatment for other B cell malignancies, where these are driven by signaling via the IgM-BCR receptor.
One of the cancers where the findings are relevant is Burkitt’s lymphoma. It is a rare but very aggressive form of lymphoma that starts from mature B cells. When it comes to children, however, Burkitt’s lymphoma is one of the more common forms of cancer. In Sweden, around 15 children are struck by the disease each year. Variants of the disease are also significantly more common in countries around the equator.
“Research has made progress and treatments have improved. Many patients can become completely cancer-free from a combination of high-intensity cytostatics. But between ten and twenty percent of cases develop treatment resistance, so more drug options are needed.”
A pizza in Rome
Alessandro Camponeschi describes himself as a B cell geek; he is fascinated by B cells and the signaling pathways that control the cell’s behavior. He clearly remembers the event that steered him towards studying cell biology:
“I was working with pizza delivery at home in Rome that included delivering to a children’s hospital. Meeting the children with cancer stirred my desire to make a contribution to fight malignancies that affect children. I felt that I wanted to help.”
A few years later, he did his dissertation, also in Rome, and then applied to Gothenburg for the postdoctoral position in Lill Mårtensson-Bopp’s team.
“Lill is internationally renowned in the field of B cells, and the work in her team led to my own focus on B cells. She is also the last author of the work we have now published, says Alessandro, who now wants to establish his own research group.
Title: Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells, Journal of Experimental Medicine; https://doi.org/10.1084/jem.20220201
AV: ELIN LINDSTRÖM