Gene expression profiling in autoimmune diseases : a story of ups and downs

Sammanfattning: Autoimmune diseases are believed to arise from a combination of genetic and environmental factors that affect normal function of immune cells. In this thesis, we studied the functional role of genetic variants, in peripheral blood cells, that relate to rheumatoid arthritis (RA) and myositis by gene expression profiling. Genome wide association studies have identified numerous susceptibility loci for autoimmune diseases, however, the precise mechanisms of how these loci lead to increased risk of autoimmunity remain mostly unknown. We therefore aimed to increase our understanding of the involvement of the susceptibility loci PTPN2, PTPN22 and HLA-DRB1 in the pathogenesis of RA. For the PTPN2 locus, we show that the long non-coding RNA (lncRNA) LINC01882 encoded on this locus can be linked to RA. We found that the genetic variants in the PTPN2 locus are associated with the expression of several lncRNAs, but not with the expression of PTPN2. By silencing LINC01882 in Jurkat T cells, we identified that LINC01882 might play a role in T-cell activation by regulating IL-2 levels, an important cytokine in RA. In addition, we show a new role for the PTPN22 risk allele in the context of RA through the generation of CD4+ T cells with cytotoxic characteristics. We found that genes related to T-cell survival and cytotoxic T-cell differentiation were differentially expressed between PTPN22 risk and non-risk allele carriers. This led us to identify an increased frequency of EOMES+CD4+ T cells in healthy individuals carrying the PTPN22 risk allele. Furthermore, we identified a difference in the expression of HLA-DRB1 and certain HLA-DQ genes between healthy individuals carrying RA HLA-DRB1 risk ('04:01) and non-risk ('15:01) alleles. These differences in gene expression were observed in different cell types, including CD4+ and CD8+ T cells. This data suggests that HLA-DRB and HLA-DQ levels, and potentially their corresponding proteins, might support loss of immune tolerance in RA patients carrying HLA-DRB1'04:01 alleles. In addition, we aimed to differentiate involvement of CD4+ and CD8+ T cells in the myositis subgroups, polymyositis (PM) and dermatomyositis (DM), by studying gene expression. We found two genes that were differentially expressed in CD4+ T cells of patients with PM compared to DM, whereas we identified 176 genes that were differentially expressed in CD8+ T cells of patients with PM compared to DM. Several of these genes were related to lymphocyte migration and regulation of T-cell differentiation. These results add to the evidence that different immune mechanisms are involved in patients with PM compared to patients with DM. In summary, this thesis presents several new mechanisms for the RA susceptibility loci PTPN2, PTPN22 and HLA-DRB1. As these susceptibility loci are shared between several autoimmune diseases, these results can be implicated in the pathogenesis of other autoimmune diseases as well. We further suggest that different immune mechanisms are involved in subgroups of RA and myositis patients. These results could ultimately lead to the identification of more specific therapeutic targets for different autoimmune diseases.