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Project

IL-10 in the pathogenesis of systemic juvenile idiopathic arthritis and regulation of its production by IFN-y in TLR-triggered inflammation

Systemic juvenile idiopathic arthritis (sJIA) is a rare but severe childhood immune disorder and is a subtype of JIA, a heterogeneous group of arthritic diseases. In contrast to other JIA subtypes, sJIA is characterised by systemic features, such as fever, rash and enlargement of lymph nodes, spleen or liver, which are often more prominent than joint inflammation. The aetiology of sJIA remains largely unknown. One hypothesis is that sJIA results from the inappropriate control of the immune response to an initially harmless trigger in predisposed children. In line with this, polymorphisms in the anti-inflammatory cytokine IL-10, resulting in a lower IL-10 production, are associated with sJIA disease development.

In the first part of this thesis, we investigated whether a defective IL-10 production underlies the pathogenesis of sJIA. To this end, we took advantage of a recently developed mouse model for sJIA and used plasma and blood cells from sJIA patient. In the mouse model, injection of IFN-γ deficient (KO) mice with Complete Freund’s Adjuvant (CFA) results in the development of sJIA-like symptoms, while CFA-injected wild type (WT) mice only develop a subtle inflammatory reaction and serve as a control. In the diseased CFA-injected IFN-γ KO mice, we observed a cell-specific defect in IL-10 production in B cells, regulatory T cells and NK cells, with B cells being the major source of IL-10. Furthermore, neutralisation of IL-10 signalling in CFA-injected WT mice resulted in an immune-inflammatory disorder that is clinically and haematologically reminiscent of sJIA, indicating that a defective IL-10 production contributes to the development of sJIA symptoms. In line with the observations in the mouse model, we observed low levels of IL-10 in the plasma of sJIA patients and demonstrated a decreased IL-10 production by B cells, both ex vivo and after in vitro stimulation. Together, our data show that a decreased IL-10 production may underlie sJIA development.

The defective IL-10 production in sJIA mice which genetically lack IFN-γ came as a surprise considering the traditional paradigm of IL-10 and IFN‑γ as each other’s antagonists. Since the sJIA mouse model is induced with CFA, an adjuvant that contains several Toll-like receptor (TLR) ligands, the influence of IFN-γ on TLR-induced IL-10 production was explored in the second part of this thesis. The study was performed by using different cell types obtained from naïve mice and from human healthy donors. In agreement with the traditional viewpoint of IL-10 and IFN-γ as antagonists, we confirmed that IFN-γ inhibits TLR-induced IL‑10 production by monocytes and macrophages. In contrast, we observed an opposite scenario when B cells were stimulated with CpG, a TLR9 ligand. Thus, IFN-γ stimulated TLR9-induced IL-10 production in B cells, and this observation is in line with the defective IL-10 production in the CFA-injected IFN-γ KO mice. Further research into the mechanisms involved revealed that the increase of TLR9-induced IL-10 by IFN-γ was restricted to B cells. We excluded involvement of B cell proliferation, increased TLR9 expression, type I IFN production, IL-6 production, IL-10 mRNA stabilisation and B cell activating factor but demonstrated that the mitogen-activated protein kinases (MAPK) p38 and JNK are essential players in the stimulatory effect of IFN-γ on CpG-induced IL-10. Furthermore, we showed that the MAPK phosphatase MKP1, which is an inhibitor of p38 and JNK, is downregulated by IFN-γ, potentially contributing to the increased IL-10 production. Together, these data may represent a novel anti-inflammatory property of the traditionally considered pro-inflammatory IFN-γ, by stimulating TLR-induced IL-10 production in B cells.

Date:1 Oct 2014 →  5 Oct 2018
Keywords:Interleukin-10, interferon-gamma, auto-inflammation
Disciplines:Immunology
Project type:PhD project