Cells play “molecular roulette” to determine how the body fights disease

A new discovery about how cells make antibodies has revealed a surprisingly random way the body’s immune system defends itself against infection and disease.

The WEHI-led study found that the cells responsible for making antibody proteins use a process of randomization to determine which type of antibody to make, a behavior scientists have dubbed “molecular roulette.”

The researchers used important insights to create a formula to predict this distribution process, an important step toward understanding why some people are biologically predisposed to developing diseases such as asthma, autoimmune diseases, and infections.

Antibodies are produced immune cells to protect our bodies from disease by alerting the immune system to foreign invaders such as pathogens and viruses.

B cells are a type of immune cell (also known as B lymphocytes) that produce five different classes antibodieseach of which is designed to protect the body from a specific bug, including bacteria and parasites.

Principal investigator Professor Phil Hodgkin said understanding how cells use randomization processes to make decisions was a cornerstone of his work, but to find that B cells use a similar system to select antibodies was surprising.

“Rather than instructing each cell what to do, as previously thought, our B cells actually run a little casino behind the scenes,” said Professor Hodgkin, head of immunology at WEHI.

“These immune cells ultimately play molecular roulette to allocate a certain number of cells to each class of antibody, thus causing different outcomes through a game of chance.

“We have long known that B cells use a process of random gene shuffling to create individual antibodies, but finding that these cells deploy a common system to select an entire class of antibodies is an important discovery for the field.

“This discovery is a significant step forward in understanding how these different probabilities can affect people when it comes to their likelihood of developing certain diseases, and also expands our understanding of how cells behave at the molecular level.’

Decisive forecasts

Using the mathematical expertise of their international colleagues and WEHI’s single-cell technology, the team created a formula to better understand the distribution process of B cells. The formula is based on a subset of well-defined molecules from the researchers’ infection models.

First author Dr. Miles Horton said the simulations bring the field as close as possible to accurately predicting, for the first time, which class of antibodies a B cell will produce, when the antibodies will be produced, and whether a cell will choose to produce a specific class of antibody over another.

“This is very important because we know that certain autoimmune diseases and infections can be triggered if this distribution process goes wrong and if the wrong type of antibody is produced,” he said.

“Our precise formula is a major starting point in understanding how a person’s molecular roulette (or genetic variation) can affect the predetermined probability of developing certain diseases, such as asthma, a disease caused by a certain class of antibodies.”

With this research, the team hopes to begin studying how the immune system can be manipulated for therapeutic benefit in the future to prevent this process from mis-distributing.

“Our ultimate goal is to move from a qualitative description of how immune system behaves quantitatively, and this discovery brings us a significant step closer to achieving this,” said Dr. Horton.

The study, Lineage tracing reveals that B-cell antibody class switching is stochastic, autonomous, and tunable, is published in Immunity.