Beta 2-glycoprotein I protects mice against gram-negative septicaemia in a sexually dimorphic manner

The immune responses of males and females to bacterial infections display differences. The mechanisms that underlie this sexual dimorphism are multifactorial. Lipopolysaccharide (LPS) contributes to the pathogenesis of endotoxaemia. We have previously demonstrated that the plasma protein beta-2 glycoprotein-1 (beta 2GPI) reduces LPS-induced inflammation in male mice. In the present study using a more robust infection model of septicaemia the role of beta 2GPI is examined in both male and female wild type (WT) and beta 2GPI deficient (beta 2GPI(-/-)) mice challenged with Escherichia coli (E. coli) intravenously. beta 2GPI deficiency led to an increase of E. coli colony forming units (CFU) in the circulation of both male and female mice. In male beta 2GPI-/- mice this was associated with a worse clinical severity score. This difference was not observed between female beta 2GPI(-/-) and female WT mice. Male WT mice had decreased levels of total and increased levels of free thiol beta 2GPI following administration of LPS or E. coli. This pattern of sexual dimorphic response was also observed in our cohort of humans with sepsis. These findings support a role for beta 2GPI in modulating the sex-specific susceptibility to gram-negative septicaemia.