Complex cytokine interactions occur during blood-stage malaria which offer a unique opportunity to study their influence on the pathogenesis of malarial anaemia. Plasmodium chabaudi AS susceptible A/J mice experience severe and fatal anaemia whereas resistant C57BL/6 (B6) mice survive following moderate anaemia. In this study we analysed the role of IL-12 in erythropoiesis and tested whether the levels of IL-12 produced in these mice correlated with the extent of anaemia. In vitro, IL-12 significantly enhanced the numbers of erythroid burst (BFU-E) and colony forming units (CFU-E) in bone marrow and spleen cells from normal and day 7 infected A/J and B6 mice. Despite the presence of IL-12 in vitro, the level of splenic erythropoiesis in infected A/J mice was significantly lower than in B6 mice. Moreover, sera from infected B6 mice, but not A/J mice, significantly up-regulated erythropoiesis in vitro and this enhancement correlated with several fold higher levels of IL-12 in the sera of B6 compared to A/J mice. Furthermore, the erythropoietic potentiating effect of sera from infected B6 mice was abrogated following depletion of IL-12. Taken together, these findings suggest that defective IL-12 production in A/J mice during the early course of infection may result in fatal anaemia.

Dyserythropoiesis and severe anaemia associated with malaria correlate with deficient interleukin‐12 production

Iron deficiency anemia (IDA) and anemia of chronic disease (CDA) are often encountered in patients with inflammatory bowel disease (IBD). Inadequate intake or loss of iron is a clear cause of IDA, but mechanisms of CDA induction are multifactorial and involve erythropoiesis disturbance due to circulating inflammation mediators. The authors investigated erythropoietin (Epo) levels in children and adolescents with IBD and correlated them to disease activity, with the aim of gaining an improved understanding of the role of Epo in CDA. Thirty-three patients with IBD were examined (18 boys, 15 girls) ages 4 to 15 years (median 11 years). Two study groups related to the disease activity were formed: group A, those with active disease (n = 21), and group B, those in remission (n = 12). Epo levels were measured using a two-site chemiluminescence immunoassay. Predictive Epo values in response to the degree of anemia were calculated by the equation: logEpo = (3.48 - 0.20) x Hb. According to the results, CDA anemia was present only in patients with active disease. These patients also had a significantly higher possibility of altered Epo levels than expected compared with patients with inactive disease (16/21 vs. 4/12, P < 0.05). It was also interesting that most of the patients with anomalous Epo concentrations presented with an elevated Epo value compared with that expected from the calculation (14/20). It seems that disturbed Epo concentrations are correlated with disease activity in children and adolescents with IBD. It is possible that failure of the bone marrow to respond to increased Epo levels leads to further incremental response. These in turn lead to the high Epo concentrations detected in most of the authors' patients. Impaired Epo production is another mechanism of CDA development and is the one mainly expressed in patients with low Epo values.

Erythropoietin levels in children and adolescents with inflammatory bowel disease.

Nitric oxide (NO) has a contributory role in hemopoietic cell growth and differentiation. The effects of NO on leukemic cell growth have been predominantly studied in in vitro settings. This study was done to assess the alterations in nitrite level in myeloid leukemias. Thirty-six newly diagnosed cases of myeloid leukemia (16 AML and 20 CML) were enrolled in the study. Neutrophil precursors from the marrow aspirate and peripheral blood were separated into cell bands using the Percoll density gradient method of Borregard and Cowland. The blood plasma and marrow fluid was also collected. Nitrite (stable non-volatile end product of NO) was estimated in the cell bands, blood plasma and marrow fluid using Griess reagent. The mean nitrite level in all cell bands from peripheral blood, bone marrow, blood plasma, and marrow fluid of cases was significantly lower as compared to corresponding value in the controls. No significant difference between AML and CML was seen. On follow-up, analysis of 13 CML patients higher nitrite levels were seen (p>0.05). The significant decrease in nitrite levels in myeloid leukemia suggests a decrease in nitric oxide synthase (NOS) activity. Further work may unfold molecular targets for therapeutic role of NO modulators.

Cellular and plasma nitrite levels in myeloid leukemia: a pathogenetic decrease.

mRNA vaccines have been key to addressing the SARS-CoV-2 pandemic but have impaired immunogenicity and durability in vulnerable older populations. We evaluated the mRNA vaccine BNT162b2 in human in vitro whole blood assays with supernatants from adult (18–50 years) and elder (≥60 years) participants measured by mass spectrometry and proximity extension assay proteomics. BNT162b2 induced increased expression of soluble proteins in adult blood (e.g., C1S, PSMC6, CPN1), but demonstrated reduced proteins in elder blood (e.g., TPM4, APOF, APOC2, CPN1, and PI16), including 30–85% lower induction of TH1-polarizing cytokines and chemokines (e.g., IFNγ, and CXCL10). Elder TH1 impairment was validated in mice in vivo and associated with impaired humoral and cellular immunogenicity. Our study demonstrates the utility of a human in vitro platform to model age-specific mRNA vaccine activity, highlights impaired TH1 immunogenicity in older adults, and provides rationale for developing enhanced mRNA vaccines with greater immunogenicity in vulnerable populations.

/pdf/the-mrna-vaccine-bnt162b2-demonstrates-impaired-th1-3i0yfjwj.pdf

The mRNA vaccine BNT162b2 demonstrates impaired TH1 immunogenicity in human elders in vitro and aged mice in vivo

Iron metabolism in the anemia of chronic disease.

Nitric-oxide suppression of human hematopoiesis in vitro. Nitric oxide synthase is present in CD34+ cells and induced by interferon-gamma and tumor necrosis factor-alfa

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Nitric-oxide suppression of human hematopoiesis in vitro. Nitric oxide synthase is present in CD34+ cells and induced by interferon-gamma and tumor necrosis factor-alfa