Stanford researchers map human body's antibody production

Stanford University researchers have mapped out how the human body creates antibodies of every class in the immune system, revealing that a diverse set of antibody-producing cells springs from the same kind of ancestor.

When the immune system fights back against viruses and bacteria, defenders called B-cells swarm into affected areas, unleashing antibody molecules of different specialist classes to seek and destroy the invaders: some antibodies envelop invading pathogens or block them from entering healthy cells, while other antibodies create inflammation that can speed the healing process.

"How do we make all the players that protect us?" Felix Horns, a biophysics graduate student and first author of a paper published in the journal eLife, was quoted as asking by a news release from Stanford. "What we' ve done is measure that."

The team of eight researchers was led by Horns' adviser, Stanford bioengineering professor Stephen Quake, who believes that creating an overview of the body' s natural defense system will enable researchers to develop novel treatments for a variety of immune disorders.

"This map will help us understand what goes awry in immune disease," said Quake. "As a result, we may be able to crack problems like allergies."

To assemble their map, the researchers extracted the B-cells from blood samples from 22 young, healthy adults. Using a high-throughput genetic sequencing machine, which reads out the individual nucleotides that make up a cell' s genetic code, they created a large library of antibody-producing genes from all the B-cells in the sample, and traced the lineage of B-cells by counting the number of acquired mutations in the cells' genes, finding that cells in later generations had more genetic mutations.

They also looked for evidence that the B-cells had switched the types of antibody they produced, which allows the immune system to customize its response to incoming threats.

"Each B-cell starts out as a single cell that makes a certain type of antibody," Horns said. "If it protects you, it expands and creates descendants." About three-quarters of the cells the team analyzed were programmed to create the IgM antibody class. IgM is "the default class in which all antibodies are born," Horns said. "When activated by immune challenge, they undergo class switching."

The insights into the class-switching process could lead to a range of new treatment approaches for immune disorders.

A few doctors have tried methods like "helminthic therapy," which involves infecting patients with parasitic worms that tweak the body's antibody production. Horns envisions a more precise solution: designing drugs to mimic the signaling molecules that control the antibody class-switching process. "You can think about the worm as a very blunt instrument," he said, "whereas you can imagine using a designer drug as a scalpel."

As a next step, Horns plans to sequence the genes of people who suffer from immune disorders. Finding out how their antibody production differs from his baseline map would be a key step toward creating drug therapies that would restore an optimal antibody balance. Enditem