Page 20 - Haematologica - Vol. 105 n. 6 - June 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1478-1483
Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71+ erythroid cells
Shokrollah Elahi1,2,3,4 and Siavash Mashhouri1
1School of Dentistry, University of Alberta, Alberta; 2Department of Medical Microbiology and Immunology, University of Alberta, Alberta; 3Department of Medical Oncology, Faculty of Medicine and Dentistry, University of Alberta, Alberta and 4Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
Introduction
Mammalian erythropoiesis occurs in three stages; the primitive, the fetal defini- tive and the adult definitive stages.1 After the primitive stage, which takes place in the yolk sac, definitive erythropoiesis moves to the fetal liver and the spleen but is finally restricted to the bone marrow, as adult definitive red blood cells, for the rest of the life.2 After birth, the location of erythropoiesis gradually switches to spongy flat bones, such as ilium, sternum, ribs, and cranium, the sites which adults rely on mostly for steady-state erythropoiesis.3 Erythrocytes are constantly produced under a highly orchestrated process regulated by multiple factors in adult bone marrow niches and local tissue microenvironments that control hematopoietic stem cell maintenance/survival.4 Nonetheless, stresses such as anemia, chronic infection, pregnancy, cancer, hematologic disorders, and stromal abnormalities disrupt this balance in the bone marrow, causing erythropoiesis to occur outside of the bone marrow (e.g. in spleen and liver).5,6 It is worth noting that stress erythropoiesis may be a better reflection of this phenomenon than extramedullary erythropoiesis (EE) in some cases. However, as will be discussed in this perspective, there is a rich body of evidence demonstrating the occurrence of EE under different physiological and pathological conditions.
EE implies the generation of erythrocytes outside of medullary spaces of the bone marrow.7 Under these circumstances, EE is considered to be the main cause of the abundance of erythroid precursors in the periphery. This may occur as a result of passive incontinence of hematopoietic cells from the sites of EE, where tissue structure/control of cell egress is less efficient than that of the bone marrow.8 However, the clinical implication of the expansion of erythroid precursors outside of the bone marrow has not been well defined. This perspective aims to provide the reader with an overview of the current understanding of the immunological consequences of EE.
Erythroid precursors are the newborn’s first-time enemies but lifelong friends
Newborns are highly susceptible to fatal infections. This susceptibility has gen- erally been ascribed to the immaturity of the neonatal immune system. Nevertheless, this old dogma has been challenged with the discovery of the phys- iological abundance of immunosuppressive erythroid precursors during this devel- opmental stage of life. It has been reported that the spleen of neonatal mice is impressively enriched with erythroid precursors co-expressing the transferrin receptor CD71 and the erythroid lineage marker TER119. The levels of these cells were maximal between days 6-9 but gradually declined to the adult level by day 21 in experiments performed in Cincinnati, USA9 and by day 28 in experiments performed in Edmonton, Canada.10 This difference might be related to geograph- ical factors, such as altitude, or differences in the animals’ microbiome. Likewise, human cord blood and placenta accommodate an equally enriched proportion of erythroid precursor cells co-expressing CD71 and the erythroid lineage marker CD235a (glycophorin A). However, these cells are sparse in the peripheral blood of healthy adults.9 Since their discovery, we have defined these cells as “CD71+ erythroid cells (CEC)”.11 CEC are mainly erythroid precursors expressing high lev- els of CD71, including reticulocytes but excluding mature red blood cells. Neonatal
Correspondence:
SHOKROLLAH ELAHI
elahi@ualberta.ca
Received: November 28, 2019. Accepted: April 6, 2020. Pre-published: April 30, 2020.
doi:10.3324/haematol.2019.243063
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1478
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