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B Cell Receptor Repertoire Overlaps More Than Expected Between Individuals

NEW YORK (GenomeWeb) – Researchers from Vanderbilt University and the University of California San Diego have profiled B cell receptors in healthy adults as part of the Human Vaccines Project, uncovering a significant proportion of shared B cell "clonotypes" from one individual to the next.

"A continuing challenge in the human immunology and vaccine development fields has been that we do not have comprehensive reference data for what the normal healthy human immune system looks like," corresponding author James Crowe Jr., director of Vanderbilt University Medical Center's Vanderbilt Vaccine Center, said in a statement, noting that "overlap in antibody sequences between individuals was unexpectedly high."

Using leukapheresis-based peripheral blood mononuclear cell isolation and B cell receptor gene sequencing with samples from three healthy adult individuals, the researchers began fleshing out the receptor repertoire of circulating B cells, comparing the profiles to those in umbilical cord white blood cell samples from three infants.

The team's findings, published online today in Nature, uncovered 9 million to 17 million B cell clonotypes per person, with as many as 6 percent of the B cell heavy-chain clonotypes and up to 34 percent of light chains overlapping between at least two of the adult participants. Some of the same B cell clonotypes turned up in neonatal samples, suggesting that antigen exposure is not the only process influencing the immune cell lineage overlap identified.

"The unexpectedly high prevalence of shared clonotypes in B cell repertoires, and identification of the sequences of these shared clonotypes, should enable better understanding of the role of B cell immune repertoires in health and disease," Crowe and his co-authors noted.

For their analysis, the researchers started with 13 to 30 billion blood mononuclear cells from the three adult participants — a 47-year-old female, a 22-year-old male, and a 29-year old male — generating Illumina sequencing data from RNA and DNA in peripheral blood mononuclear cells or B cells prepared with multiplex PCR and reverse transcription or 5'-RACE amplification.

The team noted that infant samples contained 233,501 to 327,660 clonotypes with 0.1 percent overlap across all three cord blood samples. Adults carried millions of clonotypes apiece, with a 0.3 percent overlap in all three adults. Moreover, the authors pointed to 51 clonotypes shared across all six adults and infants, suggesting that "previous exposure to foreign antigens was not the only force that shaped the shared [B cell receptor] repertoires."

"Prior to the current era, people assumed it would be impossible to do such a project because the immune system is theoretically so large, but this new paper shows it is possible to define a large portion, because the size of each person's B cell receptor repertoire is unexpectedly small," Crowe said.

The authors cautioned that the current results reflect B cell receptor profiles in the bloodstream of a small handful of individuals "with limited genetic, racial, and geographic diversity" and at one point in time, and does not encompass the full suite of B immune cells across tissue types.

"Comparing these data from ultra-deep sequencing with that from emerging techniques for single-cell lymphocyte transcriptomics and linked heavy- and light-chain repertoire sequencing holds promise for developing a deeper understanding of human immune responses," they concluded.