Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71<sup>+</sup> erythroid cells

Elahi, Shokrollah; Mashhouri, Siavash

doi:10.3324/haematol.2019.243063

Cited by 28 publications

(43 citation statements)

References 41 publications

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“…Interestingly, we found that the expansion of CECs was associated with disease severity and ICU admission. CECs have a wide range of immunomodulatory properties and via cell: cell interactions or soluble mediators such as TGF-b, ROS and arginase II, and can suppress effector T cell and B cell functions 23,25,27,29,34 . Given the association of CECs with disease severity, further analyses were performed.…”

Section: Discussionmentioning

confidence: 99%

“…In light of the above, there is the possibility that SARS-CoV-2 infection directly or indirectly invades RBCs in the periphery or the bone marrow resulting in their enhanced lysis and anemia 45,46,56 . This can result in stress erythropoiesis and subsequently abundant CECs in the periphery due to passive incontinence of hematopoietic cells from the bone marrow 25,57 .…”

Section: Discussionmentioning

confidence: 99%

“…Due to their immunomodulatory properties, the pathological abundance of CECs during disease progression can have immunological consequences 22,23,25 . To better understand the biological properties of these expanded CECs in COVID-19 patients, we subjected them to immunological phenotyping.…”

Section: Cecs Express Arginase II Arginase I and Reactive Oxygen Spmentioning

confidence: 99%

“…Erythroid precursors are defined as CD71 + erythroid cells (CECs) co-expressing CD71 (the transferrin receptor) and CD235a (glycophorin A, erythroid lineage marker) in humans, and CD71 and TER119 in mice [22][23][24] . CECs are a heterogenous population of erythroid progenitors and precursors with a wide range of immunosuppressive and/or immunomodulatory properties 25 .…”

Section: Introductionmentioning

confidence: 99%

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Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Shahbaz

Sligl

et al. 2020

Preprint

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SARS-CoV-2 infection is associated with lower blood oxygen levels even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here we show significantly enriched CD71+ erythroid precursors/progenitors in the blood circulation of COVID-19 patients that have distinctive immunosuppressive properties. A subpopulation of abundant erythroid cells, CD45+CD71+cells, co-express ACE2, TMPRSS2, CD147, CD26 and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. Taken together, pathological abundance of erythroid cells might reflect stress erythropoiesis due to the invasion of erythroid progenitors by SARS-CoV-2. This may provide a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cecs Express Arginase II Arginase I and Reactive Oxygen Spmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Shahbaz

Sligl

et al. 2020

Preprint

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“…Similarly, they are enriched in the human cord blood, placenta tissues, the peripheral blood during pregnancy (17)(18)(19)(20) and in the liver of human neonates (21). CECs exhibit immunosuppressive functions regardless of their anatomical location (22). More importantly, CECs deplete Larginine by the expression of arginase-II and subsequently impair immune activation in antigen-presenting cells and T cells in vitro (13,14).…”

Section: Introductionmentioning

confidence: 99%

CD71+ Erythroid Cells in Human Neonates Exhibit Immunosuppressive Properties and Compromise Immune Response Against Systemic Infection in Neonatal Mice

et al. 2020

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Newborns are highly susceptible to infectious diseases. The underlying mechanism of neonatal infection susceptibility has generally been related to their under-developed immune system. Nevertheless, this notion has recently been challenged by the discovery of the physiological abundance of immunosuppressive erythroid precursors CD71+erythroid cells (CECs) in newborn mice and human cord blood. Here, as proof of concept, we show that these cells are also abundant in the peripheral blood of human newborns. Although their frequency appears to be more variable compared to their counterparts in mice, they rapidly decline by 4 weeks of age. However, their proportion remains significantly higher in infants up to six months of age compared to older infants. We found CD45 expressing CECs, as erythroid progenitors, were the prominent source of reactive oxygen species (ROS) production in both humans and mice. Interestingly, a higher proportion of CD45+CECs was observed in the spleen versus bone marrow of neonatal mice, which was associated with a higher ROS production by splenic CECs compared to their siblings in the bone marrow. CECs from human newborns suppressed cytokine production by CD14 monocytes and T cells, which was partially abrogated by apocynin in vitro. Moreover, the depletion of CECs in neonatal mice increased the number of activated effector immune cells in their spleen and liver, which rendered them more resistant to Listeria monocytogenes infection. This was evident by a significant reduction in the bacteria load in the spleen, liver and brain of treated-mice compared to the control group, which enhanced their survival rate. Our finding highlights the immunoregulatory processes mediated by CECs in newborns. Thus, such tightly regulated immune system in newborns/infants may explain one potential mechanism for the asymptomatic or mild COVID-19 infection in this population.

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Transcriptomic profiling of peripheral blood cells in HPV‐associated carcinoma patients receiving combined valproic acid and avelumab

Bozorgmehr,

Syed,

Mashhouri

et al. 2023

Molecular Oncology

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Human papillomavirus (HPV)‐associated cancer continues to evade the immune system by promoting a suppressive tumor‐microenvironment. Therefore, immunotherapy appears to be a promising approach for targeting HPV‐associated tumors. We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the anti‐tumor immunity in HPV‐associated solid tumors. We performed bulk RNA‐sequencing (RNA‐seq) on total peripheral blood mononuclear cells (PBMCs) of seven non‐responders (NRs) and four responders (Rs). A total of 39 samples (e.g. pre‐treatment, post‐VA, post‐avelumab, and endpoint) were analyzed. Also, we quantified plasma analytes and performed flow cytometry. We observed a differential pattern in immune response following treatment with VA and/or avelumab in NRs vs Rs. A significant upregulation of transcripts associated with NETosis [the formation of neutrophil extracellular traps (NETs)] and neutrophil degranulation pathways was linked to the presence of a myeloid‐derived suppressor cell signature in NRs. We noted the elevation of IL‐8/IL‐18 cytokines and a distinct transcriptome signature at the baseline and endpoint in NRs. By using the receiver operator characteristics, we identified a cut‐off value for the plasma IL‐8/IL‐18 to discriminate NRs form Rs. We found differential therapeutic effects for VA and avelumab in NRs vs Rs. Thus, our results imply that measuring the plasma IL‐8/IL‐18 and bulk RNA‐seq of PBMCs may serve as valuable biomarkers to predict immunotherapy outcomes.

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Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71⁺ erythroid cells

Cited by 28 publications

References 41 publications

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

CD71+ Erythroid Cells in Human Neonates Exhibit Immunosuppressive Properties and Compromise Immune Response Against Systemic Infection in Neonatal Mice

Transcriptomic profiling of peripheral blood cells in HPV‐associated carcinoma patients receiving combined valproic acid and avelumab

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Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71+ erythroid cells

Cited by 28 publications

References 41 publications

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

CD71+ Erythroid Cells in Human Neonates Exhibit Immunosuppressive Properties and Compromise Immune Response Against Systemic Infection in Neonatal Mice

Transcriptomic profiling of peripheral blood cells in HPV‐associated carcinoma patients receiving combined valproic acid and avelumab

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Immunological consequences of extramedullary erythropoiesis: immunoregulatory functions of CD71⁺ erythroid cells