Impact of heme on specific antibody production in mice: promotive, inhibitive or null outcome is determined by its concentration

Free heme is an endogenous danger signal that provokes innate immunity. Active innate immunity provides a precondition of an effective adaptive immune response. However, heme catabolites, CO, biliverdin and bilirubin trigger immunosuppression. Furthermore, free heme induces expression of heme oxygenase-1 to increase production of CO, biliverdin and bilirubin. As such, free heme can play a paradoxical role in adaptive immunity. What is the outcome of the animal immune response to an antigen in the presence of free heme? This question remains to be explored. Here, we report the immunization results of rats and mice after intraperitoneal injection of formulations containing BSA and heme. When the heme concentrations were below 1 μM, between 1 μM and 5 μM and above 5 μM, production of anti-BSA IgG and IgM was unaffected, enhanced and suppressed, respectively. The results suggest that heme can influence adaptive immunity by double concentration-thresholds. If the heme concentrations are less than the first threshold, there is no effect on adaptive immunity; if the concentrations are more than the first but less than the second threshold, there is promotion effect; and if the concentrations are more than the second threshold, there is an inhibitory effect. A hypothesis is also presented here to explain the mechanism.