Genetic and immunological studies of DCIR in inflammatory arthritis

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: Rheumatoid arthritis (RA) is a clinically heterogeneous condition with a wide spectrum of clinical manifestations, great variability in severity and disease progression rate. Thus, it is important to define new genetic and immunological markers, which could be useful for sub-grouping of RA, and for new targeted therapies. The dendritic cell immunoreceptor (DCIR) is a candidate molecule that is expressed on many different immune cells. DCIR deficiency in the mouse leads to development of autoimmune disorders, and genetic variations in the human DCIR gene are associated with RA. Thus DCIR is an immunity-related protein that could be a target for future therapeutic settings. We have demonstrated that DCIR is widely expressed on many different immune cells in the rheumatic joint. Interestingly, we detected DCIR expression on a small subpopulation of T cells, and these DCIR+ T cells displayed different phenotypes depending on compartment of residence. In circulation, DCIR+ T cells were found to be either naïve or activated cells with cell-surface markers enabling entry into the lymph node. DCIR+ memory T cells in the joint were either CD62L+ or CD62L-. Interestingly, the most pronounced population, the CCR7-CD62L- DCIR+ T cells, was virtually missing in blood. The DCIR+ T cells in both blood and synovial fluid, co-expressed FOXP3, but with minimal overlap with the classical Treg marker CD25. Our data suggest that the DCIR+FOXP3+CD25low T cells could represent a unique subset of Tregs in the rheumatic joint. The human DCIR gene is located in chromosome 12p13, a region that has been associated with inflammatory disorders. In total 35 SNPs were used to target five type II C-type lectin genes located in an evolutionary conserved gene complex, named antigen-presenting lectin-like receptor complex (APLEC). One haplotype, defined by five SNPs located in two recombination blocks covering DCIR and flanking regions, show significant association with a subgroup of the disease characterized by the absence of anti-citrullinated protein antibodies (ACPA). Moreover, we demonstrate that variations in the gene displayed significant association with DCIR mRNA expression levels. Cells with the RA-associated allele of rs2024301 showed a significant increase in the expression of one of the DCIR transcripts. Shifting the balance of expression of different DCIR isoforms, could be one way of regulating DCIR function in the cells. In conclusion, our genetic and immunological studies indicate the significance of DCIR in immune signalling pathways and relation to the development of inflammation.

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