**13. Medical and societal impact of erythrocyte science**

Treatments and diagnosis based on erythrocytes have been much sought for, and many have been developed. For instance, several modulators of S1P-receptors have been developed, the first and most well-known being fingolimod. These are now being used as therapy for multiple sclerosis. Fingolimod is first phosphorylated to fingolimod-phosphate by sphingosine-kinase-2, which resides in the nucleus of nucleated cells. The S1P-receptor-1 is then internalized, thus preventing lymphocyte egress along the S1P gradient. The result is reduced damage from the immune system on the central nervous system or other organs. It is likely that new treatments or modulators based on S1P will be developed.

Erythrocyte microvesicles present diagnostic and possibly also therapeutic opportunities. Erythrocyte microvesicles may be used as carriers in pharmaceutical applications, or as alternatives to whole cells in cell therapy applications. Microvesicles are less complex to handle in biological product formulation and production and confer less safety issues than cells [174]. Erythrocyte microvesicles could be used to deliver the miRNAs they harbor naturally or engineered for more specific delivery. Potential challenges include multiple effects of the same miRNA and the existence of many different miRNAs, with different and opposing effects, in the same microvesicle. It is also important to consider the conditions that favor microvesicle formation. Lysophosphatidic acid (LPA) has been shown to induce phosphatidylserine exposure and microvesicle formation [175].

Malaria is the disease caused by the erythrocyte parasite Plasmodium. Malaria is still of considerable importance as a devastating disease in many parts of the world. It is to be expected that new knowledge on erythrocytes and the interaction with Plasmodium could lead to new treatments against malaria. For instance, it may be possible to interfere with the attachment of infected erythrocytes to the endothelium [176]. That strategy may circumvent undesirable side effects of many other approved antimalarial drugs.

Population levels of selenium can be increased by fortification of foodstuff [177] or by fertilization of crops. Foliar selenium fertilization has been shown to increase selenium levels in serum and erythrocyte glutathione peroxidase activity in subjects consuming the crop [178]. That selenium in foodstuff finds it way to the erythrocyte was elegantly shown in the case of selenoneine from the beluga whale that was found in erythrocytes of inuits [179]. Magnesium can be easily replenished by mineral supplements, or by a diet rich in vegetables and some other known sources of magnesium. More reliable diagnostics for assessment of whole-body magnesium status may be desirable to detect subclinical cases of magnesium deficiency. Several
