Page 24 - Haematologica - Vol. 105 n. 6 - June 2020

E. Elahi and S. Mashhouri
conditions such as cancer can also promote the develop- ment of Treg and indirectly suppress T-cell effector func- tions.
Human immunodeficiency virus binds to erythroid precursors via CD235a
Although an interaction of human immunodeficiency virus (HIV) with red blood cells via the Duffy antigen receptor for chemokines and complement receptor-1 has been documented,38,39 the role of CEC in HIV pathogenici- ty has not been investigated until now. Expansion of CEC in the blood of HIV-infected and anemic individuals was recently reported.40 It was demonstrated that these cells, via ROS, exacerbate HIV replication/infection in CD4+ T cells and even make CD4+ T cells more permissive to HIV infection. Besides, by binding to CD235a on the surface of CEC, HIV can travel to different parts of the body.40 In support of this, a positive correlation between plasma viral load and the frequency of these cells was found in HIV patients. More importantly, it was observed that infective HIV particles reside inside CEC but not inside mature red blood cells. Therefore, by harboring HIV, CEC can play an important role in the pathogenesis of HIV- related disease.
Conclusion
In general, EE is not considered a physiological event in adults but a compensatory mechanism occurring second- ary to inadequate medullary function in adults.41 EE is, therefore, identified as secondary or accessory to another factor that directly affects the bone marrow or to a sys- temic event that subsequently impacts the bone marrow. For instance, EE can be related to stromal abnormalities in the bone marrow such as osteopetrosis, and marrow fibrosis in which narrow storage becomes limited. Moreover, EE can be prompted by hematologic disorders, chronic infections and cancer.41,42 Overall, in terms of clin-
ical relevance, EE should be considered a risk factor for an underlying condition in adults. However, EE may be con- sidered a normal physiological process during pregnancy and in developing newborns.
Regardless of the underlying mechanism, EE results in the development of erythroblastic islands in other organs/tissues, in particular the spleen and liver. EE results in an abundance of erythroid precursors or CEC in the periphery, which can be costly for the host. As we dis- cussed above, erythroid precursors have immunosuppres- sive or immunomodulatory properties and their expansion can, therefore, have an impact on the effector functions of various different immune cells. CEC compromise neonatal innate immune responses against prenatal pathogens9,10 and also impair adaptive immunity in newborns.12 We and others have demonstrated that CEC, via soluble mediators such as arginase-2, TGF-β, and ROS or through cell-cell interactions (e.g. PD-1:PDL-1, VISTA:?), suppress/modu- late different immune cells in vitro and in vivo.11,14,36,43 These observations highlight the diverse immunosuppressive and/or immunomodulatory properties of CEC in different scenarios. The immunological consequences of EE in dif- ferent pathological conditions such as autoimmune dis- eases, hematologic disorders, chronic infections, malnutri- tion, anemia, parasitic infections, and cancer should, there- fore, be taken into consideration. Moreover, understanding the mechanisms controlling the extramedullary microenvi- ronment might lead to a better comprehension of the rules balancing immunity and tolerance induction contributed by CEC, particularly during pregnancy and in newborns. In conclusion, more in-depth investigations are required to better appreciate the diverse immunological properties of these forgotten cells in different circumstances such as tha- lassemia, malaria and other hematologic disorders.
Acknowledgments
This work was supported by the Canadian Institutes of Health Research (CIHR), a CIHR New Investigator Salary Award (360929) and a CIHR Foundation Scheme Grant (353953) (all to SE).
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