Virulent Toxoplasma gondii strain RH promotes T-cell-independent overproduction of proinflammatory cytokines IL12 and gamma-interferon.

The aim of this study was the analysis of the cytokine response in BALB/c mice infected with the highly virulent RH or the weakly virulent Beverley strains of Toxoplasma gondii. Analysis of cytokine messages showed increased expression of IL12, IFN-gamma and TNF-alpha, but not IL4 mRNAs in spleen cells after infection with the T. gondii strains RH and Beverley. High levels of circulating IL12 and IFN-gamma were detected in the serum of mice infected with strain RH, although TNF-alpha levels remained low. In contrast, the same cytokines were detected at only low levels in the serum of mice infected with the Beverley strain. Administration of antibody against IL12 or IFN-gamma significantly delayed time to death of mice infected with strain RH compared to controls. T-Cell-deficient as well as normal mice were equally infected by strain RH, suggesting that T lymphocytes do not contribute to the response. Depletion of natural killer cells from the splenocyte population abolished the in vitro production of IFN-gamma. Together, our data suggest that the virulent strain RH induces in BALB/c mice a type 1 cytokine pattern with T-cell-independent overproduction of IL12 and IFN-gamma that may be involved in the pathogenesis of this micro-organism.

Distinct requirements for IL-6 in polyclonal and specific Ig production induced by microorganisms.

The role of IL-6 in Ig production induced in the mouse by lactate dehydrogenase-elevating virus (LDV), Toxoplasma gondii or lipopolysaccharide (LPS) was assessed. Following infection with LDV, a strong activator of B cells, an early and transient IL-6 production was observed, that originated predominantly from macrophages. Whereas LDV-induced B lymphocyte proliferation appeared independent of IL-6, mice deficient for this cytokine showed a marked reduction in their total T-dependent IgG2a production when compared to their normal counterparts. By contrast, specific responses directed against either LDV or non-viral antigens administered at the time of infection were not decreased in the absence of IL-6. Similarly, polyclonal, but not anti-parasite IgG2a production triggered by T. gondii infection was strongly dependent on the presence of IL-6. Finally, T-independent total IgG3 secretion triggered by LPS was also markedly reduced in IL-6-deficient mice. These results suggest that IL-6 plays a major role in T-dependent and T-independent polyclonal Ig production following B lymphocyte activation by viruses, and parasites, but not in specific antibody responses induced by the same microorganisms.

IFN-gamma-independent IgG2a production in mice infected with viruses and parasites.

After infection with some viruses and intracellular parasites, antibody production is restricted to IgG2a. We first observed that, whereas live viruses such as lactate dehydrogenase-elevating virus (LDV) or mouse adenovirus induced mostly an IgG2a response, a large proportion of antibodies produced against killed viruses were IgG1. This IgG1 antiviral response was suppressed when live virions were added to inactivated viral particles. These results indicate that the IgG2a preponderance is related to the infectious process itself rather than to the type of antigen involved. Since IFN-gamma is known to stimulate IgG2a production by activated B lymphocytes and to be secreted after infection, we examined the role of this cytokine in the antibody isotypic distribution caused by LDV. Most IgG2a responses were relatively unaffected in mice deficient for the IFN-gamma receptor or treated with anti-IFN-gamma antibody. A similar IFN-gamma-independent IgG2a secretion was observed after infection with the parasites Toxoplasma gondii and Trypanosoma cruzi. However, the IFN-gamma-independent IgG2a production triggered by infection still required the presence of functional T(h) lymphocytes. Therefore, signal(s) other than IFN-gamma secretion may explain the T(h)-dependent isotypic bias in antibody secretion triggered by viruses and parasites.