by The devastating loss of a pair of newborns has yielded critical insights into a rare set of blood types first identified in humans 40 years ago.
By revealing the molecular identity of the relatively new blood type known as the Er system, a new study could prevent such tragedies in the future.
“This work shows that even after all the research that has been done to date, the simple red blood cell can surprise us,” says cell biologist Ash Toye of the University of Bristol.
Blood type describes the presence and absence of combinations of proteins and sugars that coat the surfaces of our red blood cells. Although they can serve different purposes, our body generally uses these cell surface antigens as recognition markers to distinguish itself from potentially harmful invaders.
We are most familiar with the ABO and rhesus factor (that’s plus or minus) blood group systems, thanks in large part to their primary importance in matching blood transfusions. But there are actually many different blood group systems based on a wide variety of cell surface antigens and their variants.
Most of the most important ones were identified in the early 20th century, although a latecomer to the collection, named Well, it only appeared on our radar in 1982, forming the foundation for a 44th blood type. Six years later, a version named Ersi identified. The code Er3 was used to describe the absence of Erone and Ersi.
While it has been clear for decades that these blood cell antigens exist, very little is known about their clinical impact.
When a blood cell shows up with an antigen that our body has not classified as our own, our immune system is activated, sending antibodies to tag the suspect antigen-bearing cells for destruction. In some cases, a mismatch between an unborn baby and its mother’s blood type can cause problems if the mother’s immune system becomes sensitized to foreign antigens. Antibodies produced in response can then cross the placenta, leading to hemolytic disease in the unborn baby.
Fortunately, there are many methods of preventing or even treating hemolytic disease in newborns these days, including shots for pregnant mothers and blood transfusions for babies.
Unfortunately, for one of the cases reported in the study, a blood transfusion after a C-section delivery failed to save the child’s life, suggesting that the doctors—and the researchers—were missing something.
“We work in rare cases,” said serologist Nicole Thornton from the UK’s National Health Service for Blood and Transplantation (NHSBT). Wired. “It starts with a patient with a problem we’re trying to solve.”
Hints of these rare antibodies have emerged over the years, but their rarity has eluded our understanding until now.
So Thornton and his colleagues, led by NHSBT serologist Vanja Karamatic Crew, analyzed the blood of 13 patients with the suspected antigens. They identified five variants in the Er antigens: the known Er variantsoneQsiEr3, and two new ones Er4 and Er5.
By sequencing the patients’ genetic codes, Crews and the team were able to locate the gene that codes for the cell surface proteins. Surprisingly it was a gene already known to medical science: PIEZO1.
“Piezoproteins are mechanosensory proteins used by red blood cells to sense when they are being squeezed,” Toye explains.
The gene is already linked to several known diseases. Mice without this gene die before birth, and those with the gene deleted only in their red blood cells end up with over-hydrated and fragile blood cells.
Crews and the team confirmed their findings by deleting PIEZO1 in a cell line of erythroblasts, a precursor to red blood cells, and testing the antigens. Certainly, PIEZO1 is required to add the Er antigen to the cell surface.
As they found a high prevalence of an Er5 variant in African populations, the researchers suspect that this variant may offer some kind of advantage against malaria, like some other rare blood types found there.
“The protein exists in only a few hundred copies in the membrane of each cell,” explains Toye. “This study really highlights the potential antigenicity of even very low-expressed proteins and their importance for transfusion medicine.”
Their research was published in Blood.
