Genetic regulation of autoantibodies in arthritis : lessons from mouse models

Autoimmune diseases such as rheumatoid arthritis (RA) or multiple sclerosis (MS) are commonly regarded as complex or multifactorial diseases. This complexity regards to effector mechanisms involved in pathologic manifestations, and also to the diversity of genetic and environmental factors that predispose individuals to such diseases. Identification of genetic traits becomes relevant to better understand the progression of these diseases, enabling the development of new therapies. Autoantibody formation against cartilage structures (e.g. collagen type II, CII), anticitrullinated proteins (ACPA) and anti-Fc domains of other antibodies (rheumatoid factors, RF) are pathogenic and typically observed in RA patients. It is thus important to investigate their role in the disease development.

In study I we evaluated the usefulness of a particular outbred stock of mice, the Northport heterogeneous stock (HS), in the study of genetic associations of different animal models. We observed that HS mice were suitable for studying disease models of MS, while being limited to study certain RA models, due to the absence of particular major histocompatibility complex (MHC) alleles. By introducing an arthritis permissive MHC H-2q allele, in study II we made use of the best characterized animal model of RA in mice (collagen-induced arthritis, CIA), and evaluated the genetic associations of autoantibody production during the course of the disease. The genetic associations with RF and ACPA production were evident and clearly distinct from anti- CII antibody responses. Amongst several identified quantitative trait loci (QTLs), we distinguished the Fc gamma receptor (FcγR) and immunoglobulin heavy chain (IgH) loci as the most central QTL regulating autoantibody formation. The Cia9 congenic fragment confirmed our FcγR association, while the involvement of the IgH locus on specific antigen recognition was thoroughly investigated in study III. Here we identified different germ-line polymorphisms controlling the antibody production and recognition of a specific CII epitope, named J1. Finally, in study IV, Cia37 congenic mice were used to investigate the role of vitamin D receptor (VDR) polymorphisms in arthritis susceptibility. The influence of vitamin D on cytokine secretion and the VDR gene expression profile observed, strongly implicate the VDR and vitamin D as regulators of autoimmunity in mice.

In summary, several genetic associations as well as mechanistic hypothesis involving autoantibody formation are described in this thesis. We hope these findings can be of use for better understanding the pathology of RA, as well as for the development of new therapeutics to treat RA patients.

List of scientific papers

I. Heterogeneous stock mice are susceptible to encephalomyelitis and antibody-initiated arthritis but not to collagen- and G6PI-induced arthritis. D. Klaczkowska, B. Raposo, K.S. Nandakumar. Scandinavian journal of Immunology. 2011, 73:46-52.
https://doi.org/10.1111/j.1365-3083.2010.02479.x

II. Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice. M. Förster, B. Raposo, D. Ekman, D. Klaczkowska, M. Popovic, K.S. Nandakumar, T. Lindvall, M. Hultqvist, I. Teneva, M. Johannesson, E. Ahlqvist, R. Holmdahl. Arthritis and Rheumatism. 2012, 64:3594-603.
https://doi.org/10.1002/art.34658

III. Immunoglobulin heavy chain V gene polymorphism controls epitopespecific antibody response. B. Raposo, D. Dobritzsch, D. Ekman, M. Förster, C. Ge, H. Uysal, I. Lindh, K.S. Nandakumar, E. Ahlqvist, R. Holmdahl. [Manuscript]

IV. Functional implications of the vitamin D receptor in collagen-induced arthritis. B. Raposo, J. Tuncel, S. Haag, S. Winter, E. Ahlqvist, R. Holmdahl. [Manuscript]