Helmut Wachter

Association between immune activation, changes of iron metabolism and anaemia in patients with HIV infection

Abstract:u2002 The pathogenesis of anaemia associated with human immunodeficiency virus infection is still far from being understood. It cannot be explained by direct effects of the virus on the haematopoietic system. Recent data suggest a role for immune activation. In a cross‐sectional study we compared blood cell counts, haemoglobin and erythropoietin levels of 63 HIV‐seropositive individuals with immune activation markers (interferon‐γ, serum and urine neopterin, and β2‐microglobulin) and with parameters or iron metabolism (serum iron, transferrin, free iron binding capacity, ferritin). We found significant correlations between the concentrations of haemoglobin and the immune activation markers and erythropoietin concentrations. Additional significant correlations existed between the parameters of iron metabolism and haemoglobin levels, and ferritin correlated inversely with transferrin. In sum, low haemoglobin levels in patients were associated with enhanced cellular immune activation, as seen by increased interferon‐γ, neopterin and β2‐microglobulin, and with changes of iron metabolism: low haemoglobin was associated with low transferrin and free iron binding capacity and high ferritin levels. Endogenous release of cytokines such as interferon‐γ‐inhibiting crythropoiesis may be one underlying cause of anaemia in these patients.

Inhibition of xanthine oxidase by pterins

The effect of a panel of pterins on xanthine oxidase was investigated by measuring formation of urate from xanthine as well as formazan production from nitroblue tetrazolium. The pterin derivatives, depending on their chemical structure, decreased urate as well as formazan generation: 200 microM neopterin and biopterin suppressed urate formation (90% from baseline) and formazan production (80% from baseline) as well. Their reduced forms, 7,8-dihydroneopterin and 5,6,7,8-tetrahydrobiopterin, showed a lesser but still strongly diminishing influence (40% from baseline). Another oxidized pterin namely leukopterin showed only a weak inhibitory effect. Xanthopterin, a known substrate of xanthine oxidase, had a strong effect on urate formation (80% inhibition), but a lesser effect on formazan production (30% reduction). When iron-(III)-EDTA complex was added to the reaction mixture all the effects were more pronounced. Superoxide dismutase, which removes superoxide anion by dismutation into oxygen, decreased formazan production in addition to pterin derivatives and had a small but enhancing effect on urate formation. Also the reductant N-acetylcysteine had an additive effect to pterins to diminish formazan production in a dose-dependent way. The results of our study suggest that depending on their chemical structure pterins reduce superoxide anion generation by xanthine oxidase.

Neopterin release in human mixed lymphocyte culture: Requirement of HLA-DR disparity

Recent evidence suggests that immune responses in vivo as well as in vitro are accompanied by release of neopterin [C. H. Huber, et al. (1983) J. Immunol. 130, 1047]. This investigation aimed to elucidate the genetic control of in vitro neopterin release in family mixed lymphocyte culture (MLC) studies. Neopterin levels and responder cell proliferation were assessed in a total of 92 MLCs established from different intrafamilial combinations. Results indicated a strong association between the magnitude of responder cell proliferation and the neopterin levels induced by stimulation with allogeneic cells. This conclusion was based on three findings: first, almost no neopterin release and proliferation was seen in MLCs established between HLA genotypically identical siblings; secondly, very low proliferation and neopterin levels were observed in MLCs between HLA-DR phenotypically identical family members; and thirdly, high neopterin release and strong cellular proliferation were a feature of MLCs established between individuals differing for at least one HLA-DR antigen. We thus conclude that T cell activation subsequent to recognition of HLA-DR disparity represents an essential prerequisite for induction of neopterin release in human MLC.