Project Details
Projekt
Immunological and cellular basis of orbital inflammation and tissue remodeling in a mouse model of Graves’ orbitopathy
Subject Area
Ophthalmology
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398840251
Graves’ orbitopathy (GO), also known as thyroid eye disease results as a consequence of autoimmunity to the TSH-receptor (TSHR) in Graves’ disease. An inflammation of orbital muscles together with adipogenesis and deposition of hyaluronan leads to remodeling of the orbital soft tissue, resulting in muscle dysfunction and/or forward protrusion of the eye (proptosis) with significant negative impact on quality-of-life. This orbital disease displays high variability among individual patients in its clinical presentation such as inflammation, myopathy and adipogenesis, whose origins remain undefined. Mounting evidence indicates that TSHR specific auto-antibodies and T cells by interacting with orbital fibroblasts appear to be principally responsible for GO onset. We recently described reproducibility of a preclinical mouse model of GO that is based upon immunization of female BALB/c mice with a plasmid encoding human TSHR A-subunit. Importantly, the mouse model shows a similar degree of variability in orbital pathology like in the human disease. Our studies have identified pro-inflammatory cytokines (IFN-g, TNF-a, IL-10 and IL-6) in the diseased GO mice which derived from TSHR specific T cells. One advantage of the model is that it allows us to identify the initial events in the origin and progress of the disease, which is not possible in GO patients. Our recent experiments indicate that early events in orbital pathology include accumulation of T cells in orbital muscles while the orbital fat tissue remains free of inflammation. We hypothesize that these T cells together with the cytokine milieu cause differential changes in cell activities of muscle orbital fibroblasts. These, in turn, determine whether the disease progresses to either expansion of muscle or adipose tissues each accompanied by hyaluronan deposition in the orbita. We propose to study the early events in the onset of orbital pathology using cytokine deficient mice in order to determine whether the different clinical presentations of GO are dependent on particular cytokine patterns in the orbita. Early stage-dependent signatures of the disease in the fibroblasts will be monitored by genome-wide microarray profiling. We will further test the contribution of B cells and their autoantibodies to the modulation of the disease progression using B cell deficient animals. In addition, we aim to follow the spatial and timely sequence of the early inflammatory events by performing serial non-invasive in vivo magnetic resonance imaging (MRI). The long-term objectives of this work are the understanding of the initial steps in autoimmunity to TSHR in Graves’ disease and the resulting orbital pathogenesis. This may lead to identification of novel biomarkers for early clinical diagnosis as well as critical cellular and humoral factors in pathogenesis. This will help to improve the treatment of the disease by identifying new targets for therapeutic intervention in GO.
DFG Programme
Research Grants
