New targets identified by positional cloning in animal models

Genetic projects based on linkage analysis of complex disorders are time and lab consuming, especially as isolation of associated loci in congenic strains demands years of breeding. Hence, there have been doubts concerning the potential of reverse genetics and positional cloning of polygenic disease genes, both in humans and in animal models [26, 40]. Quite numerous numbers of QTL have been assigned in mouse and rat models of arthritis [56-58]. Some of these are now get ting closer to identification of the arthritis regulating genes [59, 60]. The first of these genes to be positionally identified was the successful isolation of a functional polymorphism of Ncfl, explaining the effect on arthritis severity by the quantitative trait locus Pia4, through positional cloning in rats, and later also verified to be of importance in collagen induced arthritis in Ncfl deficient mice [61, 62]. Positional identification of Ncf1 was probably the first in a long range of genes that will be identified in animal models of arthritis, that all will be important pieces in a puzzle of the complex inheritance of arthritis. Eventual assembly of this puzzle will give deeper understanding of the pathogenesis of many autoimmune diseases. Identification of arthritis regulating genes, like Ncf1, in rodents can directly be transferred to analysis in human populations. In most cases genes in rodents will play a similar role in human arthritis. More important, however, is to use this information to address the molecular pathways surrounding the identified gene in RA. In the case of Ncf1 it was found that the capacity to produce radical oxygen species was of utmost importance for the regulation of autoreactive T-cells in rats. Interestingly, the susceptibility to adjuvant-induced arthritis was correlated to a reduced capacity of the NADPH oxidase to produce radical oxygen species. With this approach new mechanisms for regulation of arthritis are revealed. By investigating the relevance of the new pathways in the RA and other autoimmune conditions, as well as in other animal models, novel targets for drug development will be displayed.

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