Mechanism and biological significance of erythrocyte homoaggregation (rouleaux formation): temperature-dependent entropic liberation of water from cells and macromolecules

In the pre-antibiotic era, infections were usually more frequent and serious than today. Robin Fåhraeus (1888–1958) examined the erythrocyte sedimentation rate (ESR) test for infections, which was normally carried out in vitro with freshly drawn blood. His extensive studies on the mechanism and physiological significance of the enhanced sedimentation of erythrocyte aggregates (rouleaux) in disease included in vivo simulation. This led him to propose an explanation for the finding of long white strips (“fibrin coagula”) within the blood vessels of those who had died from infections. The surge of serious infections in pandemic times has likely kindled a reemergence. He further speculated that (i) the weak aggregation of red blood cells (RBCs) followed the liberation of water molecules from their surfaces, and (ii) the importance of their aggregation, which was induced by changes in serum proteins (not necessarily antibodies), extended beyond the clinic. In modern times these changes have led to immunologically significant entropic interpretations of infection-associated aggregations, whether cellular (e.g., RBC) or molecular (i.e., macromolecular polymerizations). Thus, rouleaux formation displays a process at the cellular level that can proceed in parallel at a less visible macromolecular level. It has been proposed that, when intracellular, aggregations would discriminate between self and not-self proteins in the crowded cytosol. Favoured by an associated pyrexia, this could lead, by mechanisms to be determined, to the preferential loading of peptides from proteins deemed “foreign” for presentation as major histocompatibility complexes (MHCs) to specific clones of immune cells.