The senescent antigen hypothesis of RBC evanescence: 50 years of correlation without causation

Warm autoimmune hemolytic anemia: new insights and hypotheses

“…These senescent RBCs are removed from circulation in the spleen or liver by macrophages; however, the exact mechanism of how these aged RBCs are removed by macrophages remains controversial [ 33 ▪▪ ]. Again, how RBCs die has been a subject of interest for many years and the mechanism remains a contentious topic [ 32 , 33 ▪▪ , 34 ▪▪ , 35 ▪▪ ]. In the 1980s, Marguerite Kay proposed that RBC senescence occurs due to band 3 changes in its external conformation during aging to create a neoantigen that is recognized by a naturally present autoantibody to this neoantigen [ 26 , 27 , 36 , 37 ].…”

“…The results of Hudson et al [ 43 ] compared to Singer et al [ 41 ] may simply indicate redundant pathways in mice for RBC senescence and/or differences in mouse strains. Mice have many differences in hematology and biochemistry compared to humans, indicating a high rate of age-dependent RBC clearance [ 44 , 45 ], and may not be a good model to study human RBC senescence [ 34 ▪▪ , 46 ]. Mouse RBC half-life is much shorter than in humans, mice have high retic counts compared to human, and have some nucleated RBCs in their peripheral blood, not found in humans [ 44 – 46 ].…”

“…In vitro aging of human RBCs in autologous plasma also results in accumulation of autologous IgG on the RBCs as they are stored, up to 60 days, allowing the IgG autoantibody to be eluted from the stored RBCs [ 35 ▪▪ ]. What is a problem with all of these studies is that there is no direct evidence that these autoantibodies are causative for the removal of the aged RBCs [ 34 ▪▪ ]. It is of note that the studies by Christian et al [ 42 ] and Franco et al [ 49 ], did not show increased PS exposure as the RBCs aged.…”