Red blood cells in focus On functional heterogeneity and mechanisms of clearance

Red blood cells (RBCs) are the most abundant cells in human blood and are essential for oxygen transport and tissue homeostasis. Although RBCs have traditionally been viewed as a functionally homogeneous population devoted to their primary role, emerging evidence reveals they are active participants in vascular and immune homeostasis.
This research reveals previously unrecognized functional heterogeneity within the RBC population by identifying two functionally distinct subpopulations that can be defined by Lutheran/Basal Cell Adhesion Molecule (Lu/BCAM) expression. We demonstrate that Lu/BCAM-negative erythroid progenitors possess a distinct molecular signature, including expression of the F2R (PAR1) gene and genes involved in PAR1 signaling. Lu/BCAM-negative mature RBCs respond to thrombin with increasing intracellular calcium, enhanced fibrin binding, and preferential localization to fibrin-rich regions of blood clots, suggesting a specialized role in coagulation.
Shifting to pathological RBC clearance, we developed an artificial intelligence-based imaging flow cytometry (IFC) platform to quantify erythrophagocytosis with high precision. In rare IgA-mediated autoimmune hemolytic anemia (AIHA), our findings demonstrate that phagocytosis is not the predominant mechanism of RBC destruction, identifying antibody-induced membrane instability and complement-independent vesiculation as potential contributors to fulminant hemolysis. Furthermore, we provide clinical evidence that targeting long-lived plasma cells with the proteasome inhibitor bortezomib offers a successful therapeutic strategy for refractory cases.
Together, this work expands the current understanding of RBC functional heterogeneity and provides new mechanistic insights into immune-mediated RBC destruction, supporting the development of precision diagnostics and targeted therapies for rare IgA-mediated AIHA.