‘Stolen DNA’ is a Third Route to Antibody Formation

An illustration of antibody diversification by exchange of DNA between chromosomes. DNA encoded on distant loci of different chromosomes can integrate into the antibody heavy chain locus. In this way, other parts of our genome contribute to the formation of antibodies containing additional fragments (highlighted in distinct colors). Credit: Kathrin de la Rosa, MD

While antibodies don’t normally get a lot of attention, millions of people around the world became overly aware of their importance during the COVID-19 pandemic. The route to establishing SARS-CoV-2 antibodies became common knowledge: become infected with the virus, or get vaccinated.

But now, in a very unusual discovery, German researchers have demonstrated a third route to antibody production. In a new study, Kathrin de la Rosa and her colleagues describe a “stealing” mechanism that uses foreign genes or other distant DNA fragments to create disease antibodies—even if a patient has never been infected with said disease.

The discovery began a few years ago when Kathrin de la Rosa and her colleagues 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. Normally, the gene coded for a receptor that inhibits the immune system, which the malaria pathogen could target to reproduce more easily. But, de la Rosa and her team saw that the immune systems of those infected actually fought back.

“The antibodies we found had integrated a piece of this receptor, called LAIR1, thereby gaining the ability to recognize the parasites more effectively,” said de la Rosa.

In a paper recently published in PNAS, de la Rosa and her team shed more light on LAIR1 since their initial discovery. The team used high-throughput analysis to study the antibodies, but they had to modify the technique for extra sensitivity since it was like searching for a needle in a haystack.

“We needed a highly sensitive procedure as antibodies with foreign components would otherwise be easily overlooked in the masses of antibodies,” explained de la Rosa. “Only about 1 in every 10,000 to 100,000 antibodies in the blood has these special properties.”

According to the study results, the team detected antibodies whose creation required the use of foreign genes or other distant DNA fragments in 80% of donors. Further, they found the foreign material in only one region of the antibodies—the heavy-chain segments of the Y-shaped proteins. The researchers said this discovery was critical as it indicated that the “theft” of foreign genetic material followed a standard blueprint. They found further evidence of this blueprint when they mapped the stolen fragments onto the human genome and discovered obvious patterns of their origins.

“For example, they very often came from the mitochondria of the cells or from the ends of chromosomes in the cell nucleus,” explained first author Mikhail Lebedin, a researcher in de la Rosa’s lab at the Max Delbrück Center for Molecular Medicine (MDC).

Even though the “special” antibodies were severely outnumbered, the researchers confirmed the small amount they found was indeed enough to make the immune system robust under certain conditions, including malaria. Incredibly, they discovered that the special antibodies appeared regardless of infection status, meaning a person never infected with or vaccinated against malaria could still have a certain amount of immunity to the parasite.

“The assumption was that the diversity of antibodies only resulted from mutations in the antibody genes,” de la Rosa explains. “But this assumption was incomplete.”

Still, the immunologist says the new study ultimately raises more questions, including: how does the process of stealing DNA work?, and can it be used to artificially create specific new antibodies and the B cells that produce them?

A future goal for de la Rosa is the development of a cellular vaccine. She is looking into modifying endogenous B cells in her lab so they produce antibodies that are even more powerful than their natural models.

“It’s very important to understand how antibody diversity comes about, for only then can we develop new approaches that can help us make even better vaccines in the future,” concluded de la Rosa.