The use of animal models to find and understand arthritis genes

Abstract

Inbred animals are useful for studies of the identification of genes associated with rheumatoid arthritis (RA) since they are more efficient tools for identification of genes controlling complex diseases. There are several arthritis models, which each may reflect various variants of the heterogeneity of RA in humans. Examples are collagen-induced arthritis (CIA) and pristane-induced arthritis, which both fulfill the clinical diagnostic criteria for RA. Type II collagen (CII) is immunogenic and contains peptides that can be bound to major histocompatibility complex (MHC) class II and can be presented to T cells, whereas pristane is not immunogenic by itself. Both diseases are genetically complex and the susceptibility is, as RA, dependent on many polymorphic genes operating in concert. So far two of these genes have been identified; the MHC class II Ab gene in the mouse [1] and the Ncf1 gene in the rat [2]. The Ncf1 protein is a part of the NADPH oxidase complex involved in generation of the inducible oxidative burst. The discovery of the Ncf1 polymorphism led to a new proposed pathway in which oxygen radicals modify antigen presentation and the resulting activation of autoreactive T cells. This hypothesis has now been further documented by the identification of an Ncf1 mutation in the mouse that reproduces the effects earlier observed in the rat. Mice with the deficient Ncf1 allele, and expressing the MHC class II allele Aq, binding CII peptides, could be shown to be dramatically more susceptible to CIA, and also developed a chronic form of arthritis. Interestingly, the immune response to CII was enhanced by the Ncf1 deficiency linking the Ncf1 pathway to the adaptive immune response.