The genetics of experimental arthritis in rodents

Unravelling the genetic susceptibility to complex autoimmune diseases and understanding these pathologies on a mechanistic level are major obstacles to improve our possibilities for therapeutic intervention and an increase in the quality of life of affected patients. Studies in experimental rodent models, that can be run under stable environmental conditions, which itself can be subjected to experimental manipulation, and in cohorts of potentially unlimited size, hold significant promise for the understanding of genes and pathways involved in complex autoimmune diseases. In this thesis, which is based on five scientific manuscripts, we initially investigated the influence of the genetic background on the ability to detect three major genetic loci (Pia4/Cia12, Pia5/Cia3, Pia7/Cia13) for pristane induced arthritis (PIA) in the rat.

We also investigated the effect of Pia1, which includes the RT1 region (major histocompatibility complex (MHC) in the rat). We could show that the major arthritis regulator NCF1 as well as the MHC are silent in certain genetic backgrounds, whereas their genetic effect on PIA susceptibility can be detected in other, distinct genetic setups, arguing for the importance of genetic interactions between MHC and non-MHC genes for PIA development. In the second and third paper, we used a unique approach with a heterogeneous stock (HS) derived inbred-outbred mouse cohort that had been backcrossed to the arthritis susceptible C57BL10/Q (BQ) mouse strain, in order to map clinical phenotypes and the autoantibody response during collagen induced arthritis (CIA) development. We defined numerous novel loci and fine mapped already described quantitative trait loci (QTL) associated with clinical disease and/or autoantibody production providing the to date most comprehensive mapping study in CIA. The papers 4 and 5 concern the positional identification of candidate genes for the CIA loci Cia21 and Cia22 in the mouse. We propose the costimulatory molecule CD2 as a female specific genetic risk factor for autommunity in the joint and the central nervous system (CNS).

We also pinpoint the chitinase like gene Chi3l3, also denoted as Ym1, as an important immunomodulator in experimental murine arthritis models based on both active immunization with collagen (CII) and passive transfer of arthritogenic antibodies. Hopefully, the findings presented in this thesis will have clinical implications based on the novel genetic targets, we identified. In addition, our data demonstrate the difficulties and pitfalls that are associated with gene identification using a hypothesis free positional cloning approach in experimental rodent populations.

List of scientific papers

I. Detection of arthritis-susceptibility loci, including Ncf1, and variable effects of the major histocompatibility complex region depending on genetic background in rats. Carola Rintisch, Michael Förster, Rikard Holmdahl. Arthritis Rheum. 2009 Feb;60(2):419-27.
https://doi.org/10.1002/art.24292

II. High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice. Emma Ahlqvist, Diana Ekman, Therese Lindvall, Marjan Popovic, Michael Förster, Malin Hultqvist, Dorota Klaczkowska, Ivanka Teneva, Martina Johannesson, Jonathan Flint, William Valdar, Kutty Selva Nandakumar, Rikard Holmdahl. Hum Mol Genet. 2011 Aug 1;20(15):3031-41.
https://doi.org/10.1093/hmg/ddr206

III. Genetic control of antibody production during collagen induced arthritis development in heterogeneous stock mice. Michael Förster, Bruno Raposo, Diana Ekman, Dorota Klaczkowska, Marjan Popovic, Kutty Selva Nandakumar, Therese Lindvall, Malin Hultqvist, Ivanka Teneva, Martina Johannesson, Emma Ahlqvist, Rikard Holmdahl. Arthritis Rheum. [Accepted]
https://doi.org/0.1002/art.34658

IV. Positional identification of CD2 as a risk factor involved in sexual dimorphism of murine autoimmune susceptibility. Michael Förster, Katarina Vlachou, Sara Lind, Erik Lönnblom, Martina Johannesson, Rikard Holmdahl. [Manuscript]

V. Positional identification of the chitinase like gene locus as a risk factor for experimental arthritis in mice. Michael Förster, Bruno Raposo, Manuel Kulagin, Ivanka Teneva, Martina Johannesson, Nicola L. Harris, Rikard Holmdahl. [Manuscript]