“Missense mutations in PIEZO1, encoding the Piezo1 mechanosensor protein, define the Er red blood cell antigens” prepublished by Thornton’s team in Blood, in September 20221, is an excellent study showing that Piezo1, a protein of wide biological interest, is the carrier of three known antigens that did not fit into any known blood group system. Using a combination of cutting-edge DNA sequencing, gene-editing techniques and more traditional approaches, researchers were able to answer questions that would have been impossible to answer not many years ago by identifying the molecular basis of five Er blood group antigens, the recognized Era, Erb and Er32–4 and two novel high-incidence Er antigens, Er4 and Er5. Thus, Er is the 44th blood group system to be discovered, 40 years after the high incidence red blood cell Era antigen was first described. The study is the first to describe different mutations of the antigen; due to a high level of polymorphism of PIEZO1 it is likely that further antigens may be added to the Er system in the future. Massive parallel sequencing will facilitate the recognition of new antigens and the determination of the frequency of different alleles in the population5.
The results of the study, also possible thanks to the fact that the team started their investigation having historical blood samples from just 13 people gathered over 40 years, will be officially ratified as defining a new blood group system at a next meeting of the International Society of Blood Transfusion. Piezo1 is known to have important roles in normal conditions and in multiple diseases (e.g., dehydrated hereditary stomatocytosis, hereditary xerocytosis) and this research represents another new milestone in hematology and in immunohematology6,7. The new discovery adds important knowledge for the characterization of red blood cell immunization and it has been well received by the scientific community; on the other hand we do not agree with reports in the newspapers that compared the new system Er to the well-known, and most relevant for transfusion medicine, ABO system. Lay press also gave too much emphasis to the Er system as the most important one in the genesis of hemolytic disease of the fetus and newborn (HDFN). Reported cases of Er alloimmunization are rare; however, the majority of Er antibodies considered in Thornton’s study were identified during pregnancy, and anti-Er4 and anti-Er5 were implicated in severe HDFN. HDFN, occurring when pregnant women produce antibodies against fetal red cell antigens, affects 3/100,000 to 80/100,000 patients per year; it is a complex pathology, and several blood group systems must be considered in relation to the immunogenicity of each of them8. Antibodies to the RhD antigen are the most frequent causes of moderate to severe HDFN. IgG antibodies against other Rh antigens (including c, e, C, E) and blood group antigens (including Fya and K) occur in about 0.5% of pregnancies9,10. The diagnosis and management of HDFN today is based on serological tests and imaging of the fetus. A new tool to diagnose maternal immunization correctly can be useful for monitoring pregnancies and hopefully for developing therapeutic or prophylactic strategies. Discovering the genetic basis of blood groups will allow scientists to develop new tests and provide the best possible care even for patients with the rarest of blood types, considering the prevalence, not yet known, of antigen-negative individuals in populations of different ethnicity. For example, in the future it could become possible to select red blood cells for these antigens to be used for diagnostic and transfusion purposes.
At present, the value of this discovery clashes with the daily routine of the clinical tests to which pregnant women are subjected: not all immunohematology laboratories will be able to investigate this new system. Due to the small number of patients with these variants, it will be labor intensive to find commercial antisera or Er-negative red blood cells able to investigate this group of antigens. This type of investigation will be possible in accredited immunohematology reference laboratories, in which this will be another antibody specificity to be considered in the diagnosis of cases of HDFN in women with panreactive antibodies or in alloimmunized transfused recipients.
Footnotes
The Authors declare no conflicts of interest.
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