Genetic dissection of immunity and inflammation using ENU mutagenesis

Our ability to fight infection is a result of a complex system of defences. In many cases we fail to fight an infection adequately and in specific cases this can be due to defects in genes we require for this process. We propose to identify genes that have hitherto eluded identification but are important in fighting infections or causing allergic responses such as asthma. We propose to use a system that will enable us to find variant mice that are unable to respond normally to infection. We do not intend to infect the mice with live bacteria or viruses but will instead use chemicals that stimulate important aspects of white blood cell functions in immunity, allergy and inflammation. The benefit to human health is that by identifying the genes that control some of our immediate responses to invading organisms, we will be able to develop therapies that will assist patients who lack those responses or reacts inappropriately to exogenous stimuli.

The immune response to antigenic and infectious challenge consists of innate and adaptive responses, which mediate host protection, but also hypersensitivity and tissue injury. Genetic defects in man and mouse have proved highly informative in identifying the molecular and cellular basis for immunodeficiency. In this project random genetic mutations will be introduced by ENU mutagenesis in mice. Phenotypic screens will be used to identify functional abnormalities in macrophage activation by an alternative, IL-4-dependent pathway, with particular reference to induced cell-cell fusion, and in natural antibody production by B lymphocytes. Identification of novel genes implicated in these functions will increase our knowledge of the pathogenesis of infectious, allergic and inflammatory diseases.