To fight pathogens, the immune system needs a large number of different antibodies. In a MDC study, a group led by BIH professor Kathrin de la Rosa has now described in the journal PNAS a “stealing” mechanism that contributes to antibody diversity.
A few years ago, Professor Kathrin de la Rosa and her colleagues in the laboratory of the Swiss immunologist Antonio Lanzavecchia made an unusual discovery. The team found antibodies in the blood of malaria patients that had been made according to the blueprint of a gene that actually had a completely different function. “This gene usually codes for a receptor that inhibits the immune system, which the malaria pathogen can target to reproduce more easily,” explains de la Rosa, who directs the laboratory of immune mechanisms and human antibodies at the Center Max Delbrück of Molecular Medicine in Berlin. Helmholtz Association (MDC) and the Berlin Institute of Health in Charité (BIH).
However, the immune system of people infected with malaria had obviously been defeated. “The antibodies we found had integrated a piece of this receptor, called LAIR1, and thus achieved the ability to recognize parasites more effectively,” says de la Rosa, who also holds the Johanna Quandt Chair of Mechanisms at the BIH Immunitaris Translationals, which is financed by Stiftung Charité.
The strategy is widespread
The initial discovery raised many questions for de la Rosa. Could this trick only be performed by the immune system of malaria patients? Or by people of African origin? Is the LAIR1 receptor unique in its ability to integrate into antibodies? Or perhaps they discovered a completely unknown mechanism generally used by the human immune system to create antibodies in its B cells?
In a study just published in the journal Proceedings of the National Academy of Sciences (PNAS), de la Rosa and his team have provided initial answers to these questions.
In more than 80 percent of European and African donors, we detected antibodies whose creation required the use of foreign genes or other distant DNA fragments. And it didn’t matter whether these people had been infected with malaria before or what ethnic group they belonged to.”
Mikhail Lebedin, first author of the study and researcher in de la Rosa’s laboratory at the MDC
The robbery follows a plan
Furthermore, according to Lebedin, the foreign material was found only in a specific region of the antibodies, the heavy chain segments of the Y-shaped proteins. To him and his colleagues, this was an important indication that the “theft” of foreign genetic material followed a plan. The researchers found evidence to support this when they mapped the stolen fragments to the human genome and discovered conspicuous patterns of their origin. “For example, they very often came from the mitochondria of the cells or from the ends of the chromosomes in the cell nucleus,” explains Lebedin.
For their work, the research team developed their own technique to study antibody transcripts, ie the RNA arrays that are read during protein production, using high-throughput analysis. “We needed a highly sensitive procedure, since antibodies with foreign components would otherwise be easily missed in antibody masses,” says de la Rosa. “Because only about one in ten thousand to one hundred thousand antibodies in the blood have these special properties.” But this seems to be enough to make the immune system particularly robust in certain conditions, such as malaria.
The goal is a cellular vaccine
“Until now, it has been assumed that antibody diversity resulted only from mutations in antibody genes,” explains de la Rosa. But this hypothesis was incomplete. “However, our study ultimately raises more questions than it answers,” he says. For de la Rosa, the two most important questions are: How does the DNA theft process really work? And can it be used to artificially create new specific antibodies and the B cells that produce them?
“During the COVID pandemic, millions of people around the world learned and experienced firsthand the importance of antibodies as they protect us from pathogens like SARS-CoV-2. They are created when we are infected or vaccinated,” he says the immunologist “For me, it’s very important to understand how antibody diversity occurs, because only then can we develop new approaches that can help us make even better vaccines in the future.” One possibility in de la Rosa’s mind is a cell vaccine. His goal is to modify endogenous B cells in his laboratory so that they produce even more powerful antibodies than their natural models.
Source:
Max Delbrück Center for Molecular Medicine of the Helmholtz Association
Journal reference:
Lebedin, M., et al. (2022) Different classes of genomic insertions contribute to human antibody diversity. PNAS. doi.org/10.1073/pnas.2205470119.