Why Can Blood Be Incompatible? Molecules on the Surface of a Cell

The surface of a red blood cell carries a great many molecules, and some of them vary between people. Whether a person has a particular one is determined genetically, and the immune system learns during development to tolerate whatever is present on that person's own cells while treating unfamiliar variants as foreign. If cells carrying an unfamiliar variant are introduced, antibodies bind to them and cause them to clump together and break apart, which blocks small vessels and releases their contents, producing a reaction that can be rapidly fatal. A blood group system is a set of related variants controlled by the same genetic locus, and several dozen such systems are recognised, of which two matter most in practice.

Routine practice is dominated by two systems:

• •The ABO system, with four groups determined by which of two molecules are present
• •Antibodies against the absent variants are present from infancy without prior exposure, which is why ABO mismatch is so dangerous
• •Group O cells lack both and can be given to anyone, which is why O negative is the emergency default
• •Group AB individuals have neither antibody and can receive any type
• •The Rh system, of which one component matters most and is what positive and negative refer to
• •Rh antibodies form only after exposure, which is why the first mismatched transfusion may pass without incident

Transfusion was attempted repeatedly from the seventeenth century with results that were unpredictable and frequently fatal, and the reason was unknown. Karl Landsteiner established it in 1901 by the direct method of mixing serum from each of his colleagues with cells from the others and recording which combinations clumped, which revealed three groups, with the fourth identified shortly afterwards. He received a Nobel Prize in 1930. The Rh system was identified in the 1930s and 1940s and explained a devastating condition in newborns, in which an Rh negative mother sensitised by a previous pregnancy produces antibodies that attack the cells of a subsequent Rh positive baby, which is now prevented routinely by giving the mother an injection that clears the foreign cells before she responds to them.

A popular framework holds that people should eat according to their blood group, on the reasoning that the groups arose at different points in human history alongside different diets. The historical claim is wrong, since all the main groups are far older than agriculture and are shared with other primates, and the dietary claim has been tested directly. A large study published in 2014 examined whether adherence to each prescribed diet produced the benefits claimed for people of the corresponding group, and found that the diets had measurable effects on health markers that were entirely unrelated to the participants' actual blood groups, meaning the diets work or not for ordinary reasons and the group is irrelevant. Subsequent work has reached the same conclusion.

The existence of the variation raises the question of why it is there, since the immune consequences are purely harmful and there is no transfusion in nature. The leading explanation concerns infection, since the same molecules are present on other cell types and on the surfaces lining the gut, and several pathogens bind to them specifically, so a variant conferring resistance to one disease may confer susceptibility to another, which maintains variation in the population. Associations between blood group and susceptibility have been reported for cholera, malaria, some bacterial infections and some cancers, with effects that are real and generally modest. The frequencies of the groups vary substantially between populations in patterns that have been used, cautiously, to trace population history.

Variable molecules on the red cell surface are tolerated by the person carrying them and attacked as foreign by somebody who lacks them, which destroys the transfused cells. ABO antibodies exist without prior exposure, which makes mismatch immediately dangerous, while Rh antibodies form only after exposure. Landsteiner established the system in 1901 by mixing colleagues' blood and recording what clumped.