Abstract
Endotoxin (LPS) hypersensitivity may be induced in mice by live or killed Gram-negative and Gram-positive bacteria. It is characterized by an overproduction of pro-inflammatory cytokines in response to LPS and by an enhanced susceptibility of the mice to the lethal activity of LPS and TNFα. The induction of LPS hypersensitivity by bacteria is mediated by IFN-γ. Consequently, its development can be inhibited by anti-IFN-γ antibodies and is absent in mice with an impaired IFNγ receptor. In sensitized mice, the enhanced activity of LPS is strictly LBP-dependent. Bacteria-treated, LBP-deficient mice exhibit only a marginally enhanced LPS responsiveness. In such mice, the administration of exogenous LBP at the time of LPS challenge restores the LPS hyper-response. Mice hypersensitive to purified LPS are also hypersensitive to whole Gram-negative bacteria. Such mice, however, are only moderately sensitized to Gram-positive bacteria or to the bacterial superantigen SEB. This sensitization, in contrast to the LPS and Gram-negative bacteria hypersensitivity, is IFN-γ independent. The role of LPS hypersensitivity for the outcome of Gram-negative infection is a dual one. At the early stages of infection, hypersensitivity enables the host to sense minute quantities of bacterial antigens and react against the infection. A failure of this early protective mechanism to eliminate the invading bacteria may have disastrous consequences, since the threshold of development of endotoxin shock is considerably lower in the hypersensitive host.