Anti-erythropoietin antibody levels and its association with anaemia in different strains of semi-immune mice infected with Plasmodium berghei ANKA

Abstract

BackgroundMalaria anaemia is still a major public health problem and its pathogenesis still unclear. Interestingly, the progression of anaemia is at relatively low parasitaemia with some mortality in the semi-immune individuals in the endemic areas despite adequate erythropoietin (EPO) synthesis. A recent study has shown that treatment with exogenous anti-erythropoietin (anti-EPO) antibodies (Ab) of infected mice gives protection against malaria infection, suggesting an important role for anti-EPO Ab in malaria. The objective of the study was to evaluate anti-EPO antibody levels in anaemic condition of different strains of semi-immune mice with malaria.MethodologySemi-immune status was attained in four mice strains (Balb/c, B6, CBA and NZW) by repeated infections with 104Plasmodium berghei ANKA, and treatment with chloroquine/pyrimethamine. ELISA was used to measure anti-EPO Ab, transferrin and EPO while inflammatory cytokines measurement was done using bead-based multiplex assay kit.ResultsThe mean anti-EPO Ab levels in the mice strains [Optical Density (OD) values at 450 nm: Balb/c (2.1); B6 (1.3); CBA (1.4) and NZW (1.7)] differed (p = 0.045), and were significantly higher when compared with uninfected controls, p < 0.0001, and mean anti-EPO Ab levels in the mice strains at recovery [OD values at 450 nm: Balb/c (1.8); B6 (1.1); CBA (1.5) and NZW (1.0) also differed (p = 0.0004). Interestingly, EPO levels were significantly high in NZW and low in Balb/c mice (p < 0.05), with those of B6 and CBA of intermediary values. Again, NZW were highly parasitaemic (20.7%) and the other strains (Balb/c, B6 and CBA) ranged between 2.2-2.8% (p = 0.015). Anti-EPO Ab correlated positively with extent of Hb loss (r = 0.5861; p = 0.003). Correlation of anti-EPO antibody with EPO was significant only in Balb/c mice (r = −0.83; p = 0.01). Significant levels of IL6 and IFNγ (p < 0.0001), both known to be associated with erythropoiesis suppression were observed in the Balb/c. Transferrin was significantly lower in Balb/c (p < 0.0001) when compared with the other mice strains (B6, CBA and NZW).ConclusionThis is the first ever report in estimating endogenous anti-EPO antibodies in malaria anaemia. The data presented here suggest that anti-EPO Ab is produced at infection and is associated with Hb loss. Host factors appear to influence anti-EPO antibody levels in the different strains of mice.

Elevated IL-17 levels in semi-immune anaemic mice infected with Plasmodium berghei ANKA

“…Mechanisms proposed to be involved in the anaemia in malaria have ranged from rupture of infected red blood cell (iRBC) due to parasite proliferation [ 19 ], immune mediated dependent destruction of RBC (antibody, complement, cytokines, cellular) [ 20 – 24 ] to suppression of the bone marrow [ 25 ]. A study has shown variation of IL-17 levels in different semi-immune mice strains implicating a role of IL-17 in RBC loss due to Plasmodium infection [ 24 ]. Recent reports have also shown IL-17 relationship with SMA [ 26 , 27 ].…”

“…Apart from these studies linking IL-17 with haemoglobin (Hb) loss, other studies have shown IL-17 to be involved in multiple organ dysfunction [ 28 ], and also found to be associated with higher risk in developing cerebral malaria (CM) [ 29 ]. Since previous studies have reported the recovery of a group of semi-immune mice at low parasitaemia [ 23 , 24 ], and also for the fact that IL-17 was implicated in one study [ 24 ], it is hypothesized that IL-17 is involved in the recovery/protection of the semi-immune mice at low Hb levels. The aim of this study, therefore, was to assess levels of IL-17 in anaemic condition as well as evaluate its association with host genetic factors.…”

The immunological balance between host and parasite in malaria

“…However, no association was found between hepcidin and Hb levels and low hepcidin levels are found in SMA patients (Howard et al 2007;de Mast et al 2010;Burte et al 2013;Glinz et al 2015). Anti-Epo auto-Abs are negatively correlated with Hb levels in semi-immune mice, which could point to an additional mechanism why erythroid progenitors are not responding accurately (Helegbe et al 2013). Also phagocytosis of erythroid precursors and dyserythropoiesis, i.e.…”

Baseline Soluble Anti-erythropoietin Antibody Level Is an Independent Associated Factor for Follow-Up Erythropoietin Demand in Maintenance Dialysis Patients With End-Stage Renal Disease: A Prospective Cohort Study

“…Others' studies have also found that anti-EPO antibody prevalence in ESRD patients who receive ESA may be associated with EPO resistance and demand, resulting in anemia (9,20). Studies in patients with some autoimmune diseases and patients with HIV revealed high levels of anti-EPO antibodies (8,21). Thus, EPO antibodies may participate in a variety of diseases.…”

“…In recent decades, the anti-EPO antibody and anti-EPO receptor (anti-EPOR) antibody have been reported to be associated with EPO resistance (8)(9)(10). In addition, they may play an important role in anemia among maintenance dialysis patients combined with insufficient EPO production (6,11).…”