Interleukin-22 binding protein in multiple sclerosis and experimental inflammation models

Abstract

Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults. Although the cause of the disease is unknown, several genetic and environmental risk factors have been identified. By studying these risk factors in experimental systems we can learn more about the biological events that precede overt disease and then use this knowledge in the development of better and safer MS treatments.

The aim of the work presented in this thesis is to shed light on one of the established genetic risk factors, the single nucleotide polymorphism (SNP) rs17066096. Since this SNP is positioned close to the gene IL22RA2, we hypothesize that IL22RA2 mediates the effect on MS susceptibility. The gene product of IL22RA2 is interleukin-22 binding protein (IL-22BP), a soluble IL-22 antagonist. Consequently, in study I-IV below, we focus on the role of the IL-22-system in MS and experimental inflammation models.

In study I we reveal the role of IL-22BP in MS animal model experimental autoimmune encephalomyelitis (EAE). Il22ra2-deleted mice have less severe paralysis, immune cell infiltration, and demyelination compared to wild type mice. In study II we further investigate the biology of IL-22BP in inflammation. We use the mouse strain from study I, but now in two skin inflammation models: contact hypersensitivity and an imiquimod-induced psoriasis model. In contrast to EAE, the Il22ra2-deleted mice have more severe disease in both skin inflammation models. In study III we show that the risk genotype of rs17066096 is associated with higher expression of IL22RA2 in monocyte-derived dendritic cells from healthy blood donors and that MS patients with more lesions on magnetic resonance imaging have higher cerebrospinal fluid levels of IL-22BP. Using an inducible Il22ra2-knockdown rat strain we show that a relatively modest decrease in Il22ra2 expression is enough to make the rats resistant to EAE. Similarly, heterozygous deletion of Il22ra2 in mice is sufficient to achieve a protective effect. Furthermore, we establish that the protective effect in Il22ra2-deleted mice is dependent on the presence of IL-22. In study IV we investigate the effect of IL-22 signaling on the initiation of an adaptive immune response. Using the rat strain from study III, we show that knockdown of Il22ra2 expression just prior to immunization causes a reduction in lymphocyte expansion, preferentially affecting B cells, as well as a reduction in antigen specific effector functions in B cells and Th1 cells.

In conclusion, we present data in support of a disease-promoting role for IL-22BP in neuroinflammation in three species. We show that the effect is dependent on IL-22, which consequently has a therapeutic potential.