Genetic and immunological studies of experimental arthritis, with emphasis on a novel C-type lectin receptor gene complex
Rheumatoid Arthritis (RA) is a chronic, systemic autoimmune syndrome primarily affecting peripheral joints. The etiology of RA is largely unknown but complex interactions between genetic and environmental factors contribute to the disease. Arthritis models more or less resembling RA are used to search for clues.
Our laboratory recently identified the antigen presenting lectin-like receptor complex (APLEC) as a genetic determinant for susceptibility of DA rats to arthritis induced by incomplete Freund´s adjuvant oil (IFA). The extent to which APLEC would influence other RA models and other immunity-related traits was unclear, and functional knowledge was lacking.
In this thesis, I developed an APLEC congenic strain (designated R17) with DA background but carrying APLEC from an arthritis-resistant rat strain (PVG). Any observed phenotypic difference between DA and R17 rats will thus depend on genetic variation in APLEC.
By comparing DA and R17 rat in six different RA models, it is demonstrated that APLEC regulates several RA models and phenotypes, sometimes depending on sex. A possible mechanism might be regulation of autoimmunity because in collagen-induced arthritis DA and R17 rats differed in their serum levels of autoantibodies and transcripts for pro-inflammatory cytokines, including IL-17. The much higher IL-17 mRNA levels in DA rats were subsequently demonstrated also in oil-induced arthritis (OIA, induced by IFA), and it was observed that the transcripts appear up to 10 days before disease onset in DA rats. Since IFA is a nonimmunogenic stimulator of the immune system, we next examined innate immunity related phenotypes.
Following infection with S. aureus and Herpes Simplex Virus, survival rates indeed differed between DA and R17 rats. Furthermore, bone marrow macrophages from the two strains also responded differently when stimulated in vitro with a panel of microbial agents, e.g. in terms of IL-6 and IL-10 secretion. Altogether, these data suggest that genetic variation in APLEC may play a role in many inflammatory diseases.
In pristane-induced arthitis, we searched for evidence of genetic interactions between APLEC and other genes, while at the same time performing fine-mapping of the arthritis-regulating QTLs Pia4, Oia3, and Oia2 (which harbors/equals APLEC). By high-resolution mapping in G7 advanced intercross line (AIL), novel arthritisregulating QTLs with limited sets of candidate disease genes were identified, as well as putative genetic interactions, possibly including APLEC.
Altogether, our results provide incentive for further studies e.g. on the role of APLEC in various inflammatory diseases in the rat, and in other species. In humans, it should be interesting, e.g. to use the results in this thesis to perform guided genetic studies on the human APLEC encoded C-type lectin-like receptors, which are expressed on leukocyte subsets, including macrophages and dendritic cells (i.e. DLEC/ BDCA-2, DCIR, DECTIN-2, MINCLE and MCL).
List of scientific papers
I. Bäckdahl L, Guo JP, Jagodic M, Becanovic K, Ding B, Olsson T, Lorentzen JC (2008). Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case control association data. Ann Rheum Dis. Dec 23: Epub ahead of print.
https://doi.org/10.1136/ard.2008.090803
II. Guo JP, Bäckdahl L, Marta M, Mathsson L, Rönnelid J, Lorentzen JC (2008). Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex. Arthritis Rheum. 58(5): 1343-53.
https://doi.org/10.1002/art.23434
III. Flornes LM, Guo JP, Dissen E, Daws MR, Lorentzen JC, Fossum S (2009). APLEC receptors influence IL-17 response in oil-induced arthritis. [Manuscript]
IV. Guo JP, Verdrengh M, Tarkowski A, Lange S, Jennische E, Lorentzen JC, Harris RA (2009). The rat antigen presenting lectin-like receptor complex influences innate immunity and development of infectious diseases. [Accepted]
https://doi.org/10.1038/gene.2009.4
History
Defence date
2009-03-26Department
- Department of Medicine, Solna
Publication year
2009Thesis type
- Doctoral thesis
ISBN
978-91-7409-335-3Number of supporting papers
4Language
- eng