Nina Rautonen

Serum interleukin-6 concentrations are elevated and associated with elevated tumor necrosis factor-α and immunoglobulin G and A concentrations in children with HIV infection

Hypergammaglobulinemia is one of the most consistent, and usually the first observable abnormality in infants vertically infected with HIV. We have analyzed serum interleukin (IL)-4, IL-6, tumor necrosis factor (TNF)-alpha, and immunoglobulin (Ig) concentrations in 23 HIV-infected and 21 uninfected children. IL-6 and TNF-alpha concentrations in HIV-infected children were significantly higher than those in uninfected children, and mutually correlated. No differences in serum IL-4 levels between infected and uninfected children were observed. There was a correlation between serum IL-6 and IgG and between IL-6 and IgA concentrations. Furthermore, during follow-up changes in IL-6 levels were usually accompanied by corresponding changes in IgG levels. Our data indicate an association between HIV, IL-6, TNF-alpha and hypergammaglobulinemia. Regardless of the source and initial stimulus, continued production of IL-6 and TNF-alpha may result in augmentation in an auto-feedback manner, accompanied by increases in Ig synthesis and, more importantly, HIV replication. Thus, elucidation of the mechanisms responsible for overproduction of these two cytokines in HIV-infected patients is not only interesting from a biologic point of view, but is likely to have important clinical implications as well.

Interleukin-10 Production by Cord Blood Mononuclear Cells

The production of IL-10 by newborns has not been studied in much detail. We analyzed the IL-10 production by, and surface marker distribution of, cord blood mononuclear cells (n = 47); adult peripheral blood mononuclear cells (n = 30) were used as controls. Both the baseline (0.79versus 1.54 ng/mL, p = 0.001) and lipopolysaccharide-stimulated (1.20 versus 2.88 ng/mL, p = 0.003) levels of IL-10 production were significantly lower in newborns than in adults. No significant differences were observed after stimulation with concanavalin A. Both cord blood and adult CD19+CD5+ cells were able to produce IL-10; however, the level of production was only an average of 16% of the total stimulated IL-10 production by unfractionated cells, indicating that CD5+ B cells are not the primary source of IL-10 in either adults or newborns. In newborns, the proportion of naive CD4+CD45RA+ cells was inversely correlated with IL-10 response to lipopolysaccharide (r = -0.49, p = 0.004) indicating a role for maturing T cells in neonatal IL-10 production; the number of macrophages was not significantly correlated with IL-10 response (r= 0.30, p = 0.10). In contrast, in adults IL-10 production correlated with the number of macrophages (r = 0.49, p = 0.01) but not CD4+CD45RA+ cells (r = -0.06,p = 0.77). We conclude that newborns produce less IL-10 than adults; the primary cells of origin and the regulatory mechanisms may be different from those observed in adults.

Imbalanced Cytokine Secretion in Newborns

In adults, a balance between Th1 and Th2 cytokine networks has been proposed to be associated with a healthy status. Newborn babies are reported to express Th2-type immune reactions. Further, the impaired protection of newborn babies against infections has been attributed to a deficient secretion of interferon gamma (IFN-γ) and interleukin-10 (IL-10). Using IFN-γ and IL-10 as surrogate markers of Th1 and Th2 orientation, we compared the patterns of IFN-γ and IL-10 secretion by peripheral blood mononuclear cells between 52 healthy newborns and 35 adults. The baseline secretion of IFN-γ in adults was similar to that of newborns. The lipopolysaccharide-stimulated IFN-γ secretion was higher in newborns than in adults, whereas the concanavalin-A-stimulated IFN-γ secretion was higher in adults. The unstimulated and stimulated IL-10 secretion was significantly lower in newborns than in adults. Using a threshold level of 1,000 pg/ml, we classified neonates and adults on the basis of their stimulated IL-10 and IFN-γ secretion. Four different groups were identified: IL-10-oriented secretion, IFN-γ- oriented secretion, balanced high secretion, and balanced low secretion. Only 25% of the neonates had a high IL-10 and a high IFN-γ secretion as compared with 77% of the adults. Eight percent of the newborns, but none of the adults, had a low secretion of both cytokines. Thirty-six percent of the neonates, but only 5% of the adults, had a high IL-10 and a low IFN-γ secretion. Thirty-one percent of the neonates and 18% of the adults had a high IFN-γ secretion, but a low IL-10 secretion. We conclude that neonates have an immature IL-10 and IFN-γ response as compared with adults. However, individual neonates may have a mature cytokine secretion, whereas others may have a Th1- or a Th2-directed immune response.

A Screening Test for the Detection of Anti-Hiv-1 IgA in Young Infants

A simple dot blot screening test for anti-HIV-1 IgA in infant sera was developed using recombinant HIV proteins. Ten control infants, 19 uninfected infants of seropositive mothers and 12 HIV culture positive infants were studied at 3 month and 18 month time points. Prior to IgG depletion of the serum samples, 11/12 (92%) of the infected infants, 2/19 (11%) of the uninfected and none of the control infants were anti-HIV IgA positive at 3 months of age. After depletion, no anti-HIV IgA antibodies could be detected in the samples from uninfected infants, whereas the antibodies persisted in all 11 samples from the infected infants, resulting in sensitivity and specificity of 91.7% (95% confidence limits 59.8-99.6%) and 100% (79.1-100%) respectively. The assay might prove useful in the early diagnosis of HIV infection and can be performed at a fraction of the cost of commercially available western blot strips.