IRCM team Uncovers New Important Mechanisms Supporting Immunity

IRCM team Uncovers New Important Mechanisms Supporting Immunity
An advance that could pave the way toward improved therapies in infectious diseases and lymphoma.

A Montreal Clinical Research Institute (IRCM) team, led by scientist Dr. Javier Di Noia, Director of the Molecular biology of the B cell Research Unit and Full Research Professor at Université de Montréal, has recently uncovered a mechanism underlying the generation of efficient antibody responses, with an exciting potential for applications in therapies against lymphoma.

Their findings, published in the Journal of Experimental Medicine, show that an enzyme called PRMT1 plays a key role for developing high-quality antibody responses, a crucial aspect in preventing infectious diseases.

B-lymphocytes or B cells, the guardians of the body
B Cells, also called B-lymphocytes, are an essential part of the immune system. As protective agents, their role is to generate antibodies responsible for fighting pathogens or any other form of threats that enter the body. 

In order to develop the ability to recognize and destroy threats effectively, B-lymphocytes responding to an infection must improve the quality of their antibodies. This is akin to an education period, during which the B cell prepares to produce better antibodies, before being able to effectively fight the infection. To do so, B cells must differentiate into specialized cell types named plasma cells, the body’s defence squad that produce large amounts of antibodies to fight the threat, or memory cells, a reserve army ready to act in the future. 

The Example of Vaccination
The basic process of antibody immune responses has been known for years in the medical field. In fact, it is the foundation of vaccination, which has been instrumental in defeating many deadly infectious diseases such as measles, rubeola, smallpox, among others. Vaccination allows the body to get in contact with a germ that was made harmless. B cells are thus introduced to the germ and given a chance to create the proper high-quality antibodies. They then become either plasma cells that secrete protective antibodies, or memory B cells. In vaccinated individuals, memory B-cells become a quiet yet highly effective sentinel army, circulating through the body for early detection in case of future exposures to the same pathogen, and preventing the infection to develop. 

However, questions remain with regards to the underlying mechanisms that regulate the creation of effective plasma and memory cells. In particular, the fate decision between continuing to improve the antibody quality, or differentiating into plasma or memory cells, is critical. Early differentiation would result in low quality antibodies, while too late may allow a lethal infection. This fate decision is also relevant for B cells cancers, called lymphoma, which grow uncontrollably by avoiding differentiation.

“We were interested in these questions because deeper knowledge of these molecular mechanisms is the key to steering investigations toward more precise and effective therapeutic options,” explained Dr. Di Noia, who is a Full Research Professor, at Université de Montréal, and Adjunct pro-fessor at McGill University.

A Study That Provides New Light
Di Noia’s study showed that an enzyme called PRMT1 might answer some of these interrogations. 

1. The PRMT1 plays an important role in the quality of the immune response. When PRMT1 is inexistent or low, the differentiation will occur too quickly, not allowing enough time for the process to be optimal. In fact, B cells that differentiate too early produce low-quality plasma and memory cells, which in turn will provide less effective antibodies and inefficient memory, hence compromising the success of the immune response.

Therefore, PRMT1 acts as a gate keeper of the decision-making process. It enables the proper pace to define the optimal moment for B-lymphocytes’ differentiation, allowing time for their antibodies to be improved. This increases the efficacy of the antibodies in the bloodstream, allows for the generation of high-quality memory responses, and results in a stronger and more efficient immune response.

“This knowledge helps us understand much better the conditions for effective vaccination, and what happens when it does not work well.”  

2. PRMT1 is also involved in the growth of the cancerous B cells that cause Lymphoma. Lymphoma develops when the system malfunctions, causing B cells to proliferate indefinitely, preventing them from differentiating or dying. The IRCM team found that PRMT1 is highly expressed in certain lymphomas’ human samples and that high expression of PRMT1 in B cell lymphoma was associated with bad prognosis.

More precisely, the team demonstrated that too much PRMT1 actually boosts the proliferation of cancerous B cells, whereby it would contribute to the disease progression. The excess of PMTR1 also prevents the differentiation, which is known to have tumour suppressing effect.

Future Perspectives
This important work suggests that manipulating PRMT1 could be promising to optimize the immune response and support future work toward new solutions for lymphoma. The identification of the critical role of PRMT1 for antibody responses also raises other possibilities, including the notion that mutations in PRMT1 could underlie certain immunodeficiencies.

“This central role of PRMT1 in immune cells open a promising new research avenue, as they provide the rationale to push investigations forward on PRMT1 and other proteins of the same family, explained Dr. Di Noia. Our study also helps to provide rationale for the development of PRMT1 inhibitors to be used against cancer.”

This study was conducted by co-leading authors, former PhD student Ludivine Litzler and research associate Dr. Astrid Zahn, with the contributions of students Kiersten Dionne, Adrien Sprumont and Michael Slattery, and postdoctoral fellow Silvana Ferreira. It was also made possible thanks to the collaboration of Dr. Claudia Kleinman and Dr. Stephan Richard from the Lady Davis Institute at the Montreal Jewish Hospital. The study was funded by the Cancer Research Society, Bergeron-Jetté Foundation and the Canadian Institutes for Health Research (CIHR). Dr. Di Noia was a chercheur boursier de mérite FRQ-S during the study.

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