Lower Abundance and Impaired Function of CD71+ Erythroid Cells in Inflammatory Bowel Disease Patients During Pregnancy

Abstract

Background and Aims: CD71 + erythroid cells are enriched during pregnancy with immuno suppressive properties. We investigated the frequency and functionality of CD71 + erythroid cells in peripheral blood, cord blood, and placenta of inflammatory bowel disease [IBD] patients versus healthy controls [HCs]. We aimed to determine their role in IBD pathogenesis during pregnancy. Methods: Peripheral blood was collected at preconception, the first, second and third trimesters, and postpartum. Cord blood and placental tissues were collected at the time of birth. Cells from different specimens were subjected to immunephenotyping and functional assays. CD71 + erythroid cells were purified for quantitative polymerase chain reaction [qPCR] analysis. Using an allogeneic mouse model of pregnancy, the effects of CD71 + erythroid cells depletion on intestinal homeostasis and dysbiosis was studied. Results: IBD patients had lower CD71 + erythroid cells during pregnancy compared with HCs. Placenta and cord blood CD71 + erythroid cells from IBD patients exhibited impaired functionality and expressed lower inhibitory molecules including VISTA, TGFβ, and reactive oxygen species [ROS]. Lower CD71 + erythroid cells were correlated with reduced regulatory T cells and increased immuneactivation in IBD patients. Depletion of CD71 + erythroid cells in an allogeneic pregnancy model resulted in upregulation of TLRs, IL6, and CXCL1, and enhanced production of TNFα, in intestinal tissues. In contrast, TGF β gene expression was reduced. Excessive inflammatory response in the gut [e.g. TNFα] affects intestinal integrity and CD71 + erythroid cells impact on the gut's bacterial composition. Conclusions: Reduced frequency and/or impaired functionality of CD71 + erythroid cells during pregnancy may predispose IBD patients to a more proinflammatory milieu in their gastrointestinal tract, characterised by lower Tregs, higher IL6, and TNFα, and dysbiosis.

CD71+erythroid cells exacerbate HIV-1 infection by reactive oxygen species and trans-infect HIV to CD4+T cells

“…More importantly, we observed that CECs release mitochondrial ROS, which its function can be abrogated by ROS-scavenger Apocynin but not by N-acetyl cysteine. Interestingly, we observed that CECs when obtained from the cord blood of mothers with IBD did not enhance HIV-1 infection in autologous CD4 + T cells because of their impaired ROS production ability (10).…”

“…Despite these reports, the interaction of erythroid precursors with HIV-1 has never been investigated and has remained a mystery. We have recently reported abundance of erythroid precursors (CECs) in the cord blood, placental tissues and the peripheral blood of pregnant mothers (10,15,34). We further indicated that CECs possess a wide range of immunological properties (35).…”

“…They coexpress the transferrin receptor (CD71) and the erythroid lineage marker (TER119) in mice but CD71 and CD235a in humans (15). Additionally, we found that CECs are abundant in the placenta tissue and expand in the peripheral blood of pregnant women (10,12). We and others have shown CECs have a wide range of immunomodulatory functions and suppress both the innate and adaptive immune responses (6-8, 11, 15).…”

“…In general, released reactive oxygen species (ROS) by neutrophils and macrophages are taken up by RBCs and get neutralized by the cytosolic antioxidant system (9). However, recent studies indicate that RBCs themselves also generate endogenous ROS (9) and interestingly their immature counterparts mediate immunomodulatory functions via the generation of ROS (10,11). Immature erythroid cells are typically seen in the periphery of fetuses and newborns while they are absent or in low frequency in the blood of healthy adults (3,5).…”

“…It is worth noting that under certain physiological or pathological conditions, immature red blood cells can be seen in the periphery of adults (11)(12)(13). For instance, conditions such as anemia, pregnancy, chronic infection and late stage cancer result in a process called extramedullary erythropoiesis in liver and/or spleen, which results with the presence of immature red blood cells in the periphery (6,10,11,14).…”