Finding genes controlling arthritis in mice-Fcγ receptors and complement C5

Autoimmune diseases are dependent on multifactorial factors including genes, environment and interactions between them. This thesis is focused on a chronic inflammatory disorder, Rheumatoid arthritis (RA). So far only very few genes and environmental factors have been identified reflecting the complexity of the autoimmune processes. Identification of new genes and the underlying mechanisms leading to disease progression is absolutely crucial for finding more specific therapies. Understanding the pathogenic events causing chronic joint destruction can be best done using animal models.

The work in this thesis focused on well-defined mouse models of autoimmune diseases: collagen induced arthritis (CIA), collagen antibody induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE). We have used two different strategies to map the genes that influence arthritis development: congenic strains and heterogeneous stock inbred-outbred cross. Of particular interest in this thesis are gene regions previously identified in two-generation crosses between B10.Q and NOD strains; Cia9 and Cia2 loci that carry promising candidate genes such as FcγR cluster region and complement C5 respectively.

To be able to elucidate the role of underlying genes in arthritis in both the loci, we generated sub-interval congenic lines (paper III and IV). We found that FcγRIIb and FcγRIII are most likely candidates for the original Cia9 locus (paper III). Moreover, we were able to show that systemic rather than local production of complement C5 is crucial in arthritis development (paper IV). In order to identify additional loci controlling arthritis in mice we have used another genetic approach – using heterogeneous stock mice, a cross between eight different founders. At first, HS mice were screened for susceptibility to different animal models (paper II) and then CIA permissive H2q haplotype has been introduced and a large cohort of heterogeneous stock inbred-outbred cross was investigated for arthritis susceptibility (paper I). We found 18 new arthritis loci and fine mapped several already known loci including Cia9 and Cia2. The last part of this thesis describes the prospect of using a thermo-responsive polymer as an adjuvant (paper V). These results suggest mapping of causative genes in a complex disease is multifaceted and a challenging task.

List of scientific papers

I. High resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice. Ahlqvist E, Ekman D, Lindvall T, Popovic M, Förster M, Hultqvist M, Klaczkowska D, Teneva I, Johannesson M, Flint J, Valder W, Nandakumar KS, Holmdahl R. Hum Mol Genet. 2011 Aug 1; 20(15):3031-41.
https://doi.org/10.1093/hmg/ddr206

II. Heterogeneous stock mice are susceptible to encephalomyelitis and antibody initiated arthritis but not to collagen- and G6PI-induced arthritis. Dorota Klaczkowska, Bruno Raposo, Kutty Selva Nandakumar. Scand J Immunol. 2011, 73:46-52.
https://doi.org/10.1111/j.1365-3083.2010.02479.x

III. Polymorphisms in the FcγR gene cluster promote experimental arthritis: Differential IgG subclass pathogenicity. Dorota Klaczkowska, Rikard Holmdahl and Kutty Selva Nandakumar. [Manuscript]

IV. Different genetic strategies confirm the importance of complement factor 5 in experimental arthritis. Dorota Klaczkowska, Anna Blom, Diana Ekman, Kutty Selva Nandakumar and Rikard Holmdahl. [Manuscript]

V. Collagen type II and a thermo-responsive polymer of N-isopropylacrylamide adjuvant operates independent of toll-like receptors: a strong influence by MHC class II and Ncf1 genes on autoimmunity and arthritis. Akhilesh Kumar Shakya, Ashok Kumar, Dorota Klaczkowska, Malin Hultqvist, Kristin Hagenow, Rikard Holmdahl and Kutty Selva Nandakumar. Am J Pathol. 2011 Nov; 179(5):2490-500.
https://doi.org/10.1016/j.ajpath.2011.07.034