Interaction of inflammatory cytokines and erythropoeitin in iron metabolism and erythropoiesis in anaemia of chronic disease

In chronic inflammatory conditions increased endogenous release of specific cytokines (TNFα, IL-1, IL-6, IFNγ and others) is presumed. It has been shown that those of monocyte lineage play a key role in cytokine expression and synthesis. This may be associated with changes in iron metabolism and impaired erythropoiesis and may lead to development of anaemia in patients with rheumatoid arthritis. Firstly, increased synthesis of acute phase proteins, like ferritin, during chronic inflammation is proposed as the way by which the toxic effect of iron and thereby the synthesis of free oxy-radicals causing the damage on the affected joints, may be reduced. This is associated with a shift of iron towards the mononuclear phagocyte system which may participate in the development of anaemia of chronic disease. Secondly, an inhibitory action of inflammatory cytokines (TNFα, IL-1), on proliferation and differentiation of erythroid progenitors as well as on synthesis of erythropoietin has been shown, thereby also contributing to anaemia. Finally, chronic inflammation causes multiple, complex disturbances in the delicate physiologic equilibrium of interaction between cytokines and cells (erythroid progenitors, cells of mononuclear phagocyte system and erythropoietin producing cells) leading to development of anaemia of chronic disease (Fig. 1)

Seven new mutations in the nicotinamide adenine dinucleotide reduced-cytochrome b(5) reductase gene leading to methemoglobinemia type I

Cytochrome b5 reductase (b5R) deficiency manifests itself in 2 distinct ways. In methemoglobinemia type I, the patients only suffer from cyanosis, whereas in type II, the patients suffer in addition from severe mental retardation and neurologic impairment. Biochemical data indicate that this may be due to a difference in mutations, causing enzyme instability in type I and complete enzyme deficiency or enzyme inactivation in type II. We have investigated 7 families with methemoglobulinemia type I and found 7 novel mutations in the b5R gene. Six of these mutations predicted amino acid substitutions at sites not involved in reduced nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FAD) binding, as deduced from a 3-dimensional model of human b5R. This model was constructed from comparison with the known 3-dimensional structure of pig b5R. The seventh mutation was a splice site mutation leading to skipping of exon 5 in messenger RNA, present in heterozygous form in a patient together with a missense mutation on the other allele. Eight other amino acid substitutions, previously described to cause methemoglobinemia type I, were also situated in nonessential regions of the enzyme. In contrast, 2 other substitutions, known to cause the type II form of the disease, were found to directly affect the consensus FAD-binding site or indirectly influence NADH binding. Thus, these data support the idea that enzyme inactivation is a cause of the type II disease, whereas enzyme instability may lead to the type I form