Genetic control of T-cell autoimmunity and arthritis
- R Holmdahl1
© The Author(s) 2004
Published: 13 September 2004
Inbred animals are useful for studies of the identification of genes associated with rheumatoid arthritis (RA) since they are a more efficient tool for identification genes controlling complex diseases. There are several arthritis models, each of which may reflect various variants of the heterogeneity of RA in humans. Examples are collagen-induced arthritis and pristane-induced arthritis, which both fulfil 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 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 genes in this concert have been identified; the MHC class II Ab gene in the mouse  and the Ncf1 gene in the rat . 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 collagen-induced arthritis, 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.
- Brunsberg U, Gustafsson K, Jansson L, Michaëlsson E, Ährlund-Richter L, Pettersson S, Mattsson R, Holmdahl R: Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol. 1994, 24: 1698-1702.View ArticlePubMedGoogle Scholar
- Olofsson P, Holmberg J, Tordsson J, Lu S, Åkerström B, Holmdahl R: Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet. 2003, 33: 25-32. 10.1038/ng1058.View ArticlePubMedGoogle Scholar