The importance of major histocompatibility complex class II genes for the development of autoimmune inflammation

In this thesis the role of major histocompatibility complex (Mhc) class II molecules in development of autoimmune disease such as rheumatoid arthritis (RA), was studied. By combining an experimental model for RA, collagen type II induced arthritis (CIA), with molecular biology methods the importance of polymorphism in Mhc class II genes for disease development was investigated. The Mhc region confers genetic susceptibility in many tissue-specific autoimmune diseases such as multiple sclerosis and RA. Mice with the H-2q haplotype develop arthritis when immunised with rat type II collagen (rCII) whereas mice with the H-2p haplotype do not. Susceptibility to CIA has been mapped to the class II region, namely the A locus. When a Abp gene, mutated to resemble the Abq gene was introduced into a H-2p mouse, it became susceptible to CIA. This indicates that the Mhc class II region is an important susceptibility locus for CIA. It was also found that the immunodominant CII 256-270 peptide binds with lower affinity to the Ap molecule than to the Aq. This is probably due to differences in their A beta chains at position 85, which is part of the hydrophobic pocket of the antigen binding cleft. This pocket provides an anchor for the important P1 side chain found in most Mhc class II ligands. By breeding the transgenic Abq gene into different genetic backgrounds we could see a difference in CIA incidence. Our recent data indicate that both genes within and outside the Mhc region are involved in mediating susceptibility to CIA. In addition, sequence analysis was performed in both pig and rat to investigate the degree of polymorphism. Limited polymorphism was found in the rat RT1-D molecule with very few substitutions in the alpha genes and only 6 different beta alleles were detected. In the pig, three DRB genes were identified but only one seemed to be expressed. All three DRB genes existed in several allelic forms. There is evidence for genetic exchange between alleles of the different DRB genes by gene conversion like mechanisms. Finally, regulation of Mhc class II expression in placental cells during pregnancy was studied in mouse. The mice were treated either with IFNg or 5-azacytidine in order to induce Mhc II expression. No Mhc class II could be found in any region of the foetal placenta