Objective. To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.Methods. Genes influencing oil-induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis-resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single-nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age-, sex-, and area-matched healthy control subjects.Results. Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigenpresenting lectin-like receptor gene complex (APLEC), which encodes immunoregulatory C-type lectin-like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti-CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06-1.52; uncorrected P ‫؍‬ 0.0073) and 1.37 (95% CI 1.12-1.67; uncorrected P ‫؍‬ 0.0019). Results of permutation testing supported this association of the haplotype with RA.

We demonstrate increased protein and mRNA expression of DCIR in RA, especially in the rheumatic joint. Expression was widespread and included a subpopulation of T cells. This suggests that the inflammatory synovial environment induces DCIR expression, and this may be related to synovial T cell function. Ligation of DCIR, or lack thereof, could contribute to the chronic inflammation characterising autoimmune diseases such as RA.

Dendritic cell immunoreceptor (DCIR) deficiency is related to development of autoimmune disorders and DCIR gene polymorphisms are associated with rheumatoid arthritis (RA). We analyzed the mRNA expression from the four known transcripts of DCIR in IFN-g-treated human leukocytes together with fine mapping across the locus. RA patients and healthy controls were genotyped for several single nucleotide polymorphisms (SNPs) in DCIR and flanking regions. mRNA expression in peripheral blood mononuclear cells (PBMCs), stimulated with gamma-interferon (IFN-g) in vitro, was determined by transcript-specific PCR. Our data reveal that IFN-g significantly downregulates the average expression of transcripts DCIR_v1, DCIR_v2, DCIR_v3 and DCIR_v4 (Po0.0001 for v1, Po0.02 for v2, Po0.0001 for v3, Po0.001 for _v4, patients and controls, Wilcoxon signed-rank). The expression of DCIR showed significant association with variations in the gene. Cells with the RAassociated allele rs2024301 exhibit a significant increase in the expression of DCIR_v4. We also present a new fifth isoform lacking exons 2, 3 and 4. This data illustrate that common genetic variations may influence DCIR mRNA expression. We also show that the expression is regulated by the inflammatory mediator IFN-g, affecting all four transcripts and that this was independent of genotype.