Giant cell arteritis (GCA) is a vision-threatening vasculitis that causes ocular ischemia due to occlusion of critical arteries supplying the optic nerve, the retina, the iris, or other orbital structures. The typical presentation of vision loss in GCA is arteritic anterior ischemic optic neuropathy (AION) or central retinal artery occlusion, with a high risk for progression to the second eye. Blindness is preventable if the disease is diagnosed and treated promptly. GCA patients have hyperreactive CD4 T cells that invade into the wall layers of arteries where together with macrophages they induce lumen-occlusive intimal hyperplasia. The defect driving CD4 T cell hyperreactivity is not understood. The current application will examine the hypothesis that CD4 T cells from GCA patients fail to activate the immuno-protective Programmed cell death protein 1 (PD-1) checkpoint. Upon binding its ligand Programmed death-ligand 1 (PD-L1), the PD-1 receptor transmits a STOP signal to inhibit T cell effector functions. The proposal builds on preliminary studies demonstrating low expression of the PD-L1 immuno-inhibitory ligand on dendritic cells (DC) and endothelial cells (EC) from GCA patients. Also, blockade of the PD-1 immune checkpoint in chimeric mice carrying human arteries and GCA CD4 T cells results in marked exacerbation of vasculitis, induces endothelial-mesenchymal transition and aggravates intimal layer outgrowth. Experiments designed in this proposal rely on a series of enabling resources, specifically on a large cohort of GCA patients, a biobank of GCA-affected temporal arteries and a chimera system in which vasculitis is induced in human arteries engrafted into immune-deficient mice.
Specific Aim 1 examines on a mechanistic level how PD-L1low dendritic cells affect the duration, the amplitude and the quality of vasculitogenic immune responses. Experiments have been designed to understand how insufficient expression of PD-L1 modulates T cell activation, expansion, tissue invasion, survival and cytokine production.
Specific Aim 2 investigates how PD-L1 expression on adventitial microvascular endothelial cells (MVEC) shields the vessel wall from immune attack and protects vascular barrier function. In vitro and in vivo, we will define how MVEC-derived negative signals modulate the behavior and effector functions of PD-1+ CD4 T cells and how endothelial PD-L1 deficiency promotes vasculitogenic T cells.
Specific Aim 3 will identify mechanisms leading to insufficient PD-L1 expression on GCA DC, with the goal to repair the defective immune checkpoint. By screening the responsiveness of GCA and control DC to stimuli and signaling pathway inhibitors, we have discovered the IFN-?-BMP4-pSMAD1/5-IRF1 module as a critical regulator of PD-L1 expression. Patient-derived DC display IFN-??insensitivity and fail to upregulate canonical bone morphogenetic protein (BMP4) signaling. We will probe the functionality of the BMP4- pSMAD1/5-IRF1 signaling axis and complement these experiments with epigenetic studies using ATAC sequencing to define regions of differential chromatin accessibility and regulatory transcription factor networks.
Giant cell arteritis (GCA) is an inflammatory blood vessel disease causing blindness and stroke. Because current therapies are limited, this project seeks to understand how the immune system of GCA patients malfunctions and how this malfunction leads to hypoperfusion of the eye. Specifically, we will explore why an ?immune break? is failing in affected patients and how this ?immune break? can be repaired to protect the patients?? eye sight.
| Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715 |
