Jukka 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.

Low number of antibody producing cells in patients with sickle cell anemia.

B cell function is impaired in patients with sickle cell anemia. Although the number of surface IgM positive cells was similar in sickle cell patients and controls, in vitro spontaneous IgM, and PWM stimulated IgA, IgM, and IgG synthesis was significantly lower in the patients than in controls. The number of PWM induced and antigen specific immunoglobulin producing cells after immunization with Pneumovax, containing 21 serotypes of Streptococcus pneumoniae, was about 100-fold lower in the patients as compared with controls. Finally, the ability of the patients peripheral blood mononuclear cells to proliferate in response to mitogens (PWM, SAC, PHA) was diminished. Because of the observed impairments in both nonspecific and antigen specific immunoglobulin synthesis and cell proliferation assays in the patients, we determined serum concentrations of IL-4 and IL-6, two cytokines associated with antibody production. IL-4 concentrations appeared low in sickle cell patients, and correlated with that of serum IgM. We hypothesize that B cell maturation in sickle cell patients is arrested at an IL-4 dependent stage.

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.

Serum levels of soluble CD8, neopterin, β2-microglobulin and p24 antigen as indicators of disease progression in children with AIDS on zidovudine therapy

ObjectiveTo test the hypothesis that serum levels of soluble markers in children change after initiation of zidovudine therapy and that the extent and pattern of these longitudinal changes correlates with clinical outcome. Patients and methodsWe measured serum levels of soluble CD8, neopterin, β2-microglobulin (βM), and p24 antigen, and CD4 cell counts, before the initiation of zidovudine therapy and at 12, 24 and 48 weeks of treatment in 24 HIV-1-infected children (Centers for Disease Control classification P2) and 15 controls. ResultsSoluble CD8 levels were elevated before therapy in 70% of the infected children; subsequent decreases were associated with lower risk of disease progression. The mean serum neopterin level before treatment was elevated in infected children; decreases in neopterin levels marginally reflected improved or stable clinical status. Serum β2M levels and CD4+ cell counts were not associated with clinical outcome. Only 10 out of the 24 patients had detectable levels of serum p24 antigen before treatment; again, the amount of decline after initiation of therapy did not predict clinical outcome. ConclusionDecreasing levels of soluble CD8 and neopterin in HIV-1-infected children receiving zidovudine therapy might reflect a good response to treatment and a slowing of disease progression.