Rheumatoid arthritis (RA) is a chronic, systemic, and clinically heterogeneous disease characterized by symmetric inflammation in the peripheral joints, leading to cartilage destruction and bone erosion. Epidemiologic data indicate that the disease evolves from complex interactions of multiple environmental and genetic factors. Experimental arthritis models provide opportunities to both control and manipulate genetic and environmental factors, in order to identify these factors.
Here we have used the oil induced arthritis (OIA) model to map a genetic factor that determines the outcome arthritis development in a susceptible rat strain. We have fine-mapped the gene locus to reside in the Antigen presenting cell lectin-like receptor gene complex, APLEC. APLEC encode receptors with immunoregulatory function. We have further narrowed down the gene candidates to Mincle, Dcir1 and Dcar1 based on sequence and expression analysis. A SNP analysis of human RA patients revealed an association of anti-CCP negative RA to Dcir, the human ortholog to Dcir1. Thus, data from both the experimental model and human studies points to a role of APLEC genes in precipitation of inflammatory joint disease.
List of papers Papers II-V are removed from the thesis due to copyright restrictions.
I. Flornes, LM., Nylenna, Ø., Saether, PC., Daws, MR., Dissen, E. and Fossum, S. The complete inventory of genes in the rat natural killer cell gene complex. Manuscript (submitted). Published in: Immunogenetics. 2010 Aug;62(8):521-30. DOI: 10.1007/s00251-010-0455-y
II. Ribbhammar, U., Flornes, LM., Bäckdahl, L., Luthman, H., Fossum, S. and Lorentzen, JC. High resolution mapping of an arthritis susceptibility locus on rat chromosome 4, and characterization of regulated phenotypes. Hum. Mol. Genet. 2003 12:2087-96 DOI: 10.1093/hmg/ddg224
III. Flornes, LM., Bryceson, YT., Spurkland, A., Lorentzen, JC., Dissen, E. and Fossum, S. Identification of lectin-like receptors expressed by antigen-presenting cells and neutrophils and their mapping to a novel gene complex. Immunogenetics. 2004 Oct;56(7):506-17 DOI: 10.1007/s00251-004-0714-x
IV. Lorentzen JC, Flornes L, Eklöw C, Bäckdahl L, Ribbhammar U, Guo JP, Smolnikova M, Dissen E, Seddighzadeh M, Brookes AJ, Alfredsson L, Klareskog L, Padyukov L, Fossum S. Association of arthritis with a gene complex encoding C-type lectin-like receptors. Arthritis Rheum. 2007 Jul 30;56(8):2620-2632 DOI: 10.1002/art.22813
V. Flornes, LM., Guo, JP., Dissen, E., Daws, MR., Lorentzen, JC. and Fossum, S. APLEC receptors influence IL-17 response in oil induced arthritis. Manuscript.