From genes to function in autoimmunity : a salty story

Autoimmunity is a condition in which the ability to tolerate self breaks down, resulting in immune responses against the body’s own healthy cells and tissues. Autoimmune diseases are complex and multifactorial, and both genetic and environmental factors are known to play a crucial role. Using animal models, it is possible to study different aspects of arthritis disease development in an environmentally and genetically controlled setting. In this thesis, I have investigated the effect of genetic risk loci and the single environmental factor sodium chloride (NaCl) on immune cell function and the development of autoimmune diseases using mouse models.

In Paper I, using four congenic sub-loci within the arthritis susceptible Cia9 locus on chromosome 1, we found that the NOD.Q polymorphic Fc gamma receptor gene (FcγR) cluster located within sub-loci Cia9i and Cia9k, regulated arthritis. Polymorphic FcγR2b and FcγR4 were contained in both Cia9i and Cia9k, whereas Cia9i mice also carried polymorphic FcγR3. FcγR2b gene and protein expression were downregulated in Cia9i and Cia9k mice, whereas FcγR3 was upregulated in Cia9i mice and found downregulated in Cia9k mice compared to littermate control mice. This difference in FcγR3 expression affected killing by NK cells and phagocytosis by macrophages in vitro and PC61 antibody induced regulatory T cell depletion in vivo. Interestingly, arthritis development was regulated by interaction between FcγR2b and FcγR3 without affecting anti-collagen type II antibody secretion. These results show that polymorphisms in both FcγR2b and FcγR3 regulate the severity of inflammatory responses. In paper II, we investigated the importance of the system A family of amino acid transporters (SNAT), based on an identified congenic locus, as mediators of immune cell function and arthritis development. We demonstrated that SNAT proteins affect the initial stages of lymphocyte activation by regulating glutamine uptake in the presence of Na+, and that the effector phase of arthritis could be suppressed by blocking SNAT proteins. Paper III describes the effect of salt (e.g. NaCl) on the development of autoimmunity. Here we show that a moderate salt intake affects both T cell and macrophage phenotypes in vitro and ex vivo. However, these moderate levels of salt intake did not alter the development of T cell-dependent autoimmunity, whereas the dextran sulphate sodium (DSS)-induced colitis was exacerbated in mice pre-exposed to salt.

Taken together, I have shown that the interplay between two genes enhances arthritis disease development, whereas a single environmental factor has no impact on arthritis despite triggering the immune system. These results contribute to the understanding of the mechanism behind complex multifactorial diseases as a small building block towards therapeutic intervention.

List of scientific papers

I. Vaartjes D, Klaczkowska D, Nandakumar KS, Holmdahl R. Immune complex receptors FcγR2b and FcγR3 alleles act in concert to regulate inflammation. [Manuscript]

II. Raposo B, Vaartjes D, Ahlqvist E, Nandakumar KS, Holmdahl R. System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis. Immunology. 2015 Sep 8.
https://doi.org/10.1111/imm.12531

III. Vaartjes D, Nandakumar KS, Holmdahl R, Raposo B. Increased salt exposure affects both lymphoid and myeloid effector functions, influencing innate-associated disease but not T cell-associated autoimmunity. Immunology. Mar 7 2018.
https://doi.org/10.1111/imm.12923